Clinical trial NCT02401035
Conditions: Gastroesophageal Reflux Disease
Keywords: candidate for acid suppression therapy presumptive diagnosis of GERD clinical diagnosis of suspected GERD symptomatic GERD endoscopically proven GERD
Sponsor: Pfizer
Start date: 2017-05-09; Completion date: 2021-06-18
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to characterize the pharmacokinetics (PK) and safety of intravenous (IV) pantoprazole in patients 1 to 16 years old who are candidates for acid suppression therapy.

Detailed description:
In hospitalized pediatric subjects, age 1 to 16 years who in the judgment of the investigator are candidates for acid suppression therapy, the following are the objectives of this trial:

Primary Objectives To characterize the PK of single and multiple IV doses of pantoprazole in pediatric subjects aged 1 to less than 2 years old.

To characterize the PK of single and multiple IV doses of pantoprazole in pediatric subjects aged 2 to 16 years old.

Secondary Objectives To determine the safety, tolerability, and PK of single and multiple IV doses of pantoprazole in each of the independent age cohorts.

To assess the CYP2C19 genotype in pediatric subjects receiving IV pantoprazole, to determine the presence of the gene for the major enzyme responsible for metabolism of pantoprazole.

Arms: arm 1: Patients will receive 10 mg, 20 mg, or 40 mg IV pantoprazole determined by weight.
Interventions: intervention 1: IV pantoprazole
Intervention descriptions: intervention 1: Patients will receive 10 mg, 20 mg, or 40 mg IV pantoprazole determined by weight

Protocol documents:
Prot_000.pdf: 
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CLINICAL PROTOCOL
AN OPEN-LABEL, MULTICENTER STUDY TO EVALUATE THE
PHARMACOKINETICS OF SINGLE AND MULTIPLE INTRAVENOUS DOSES OF
PANTOPRAZOLE IN TWO AGE COHORTS OF HOSPITALIZED PEDIATRIC 
SUBJECTS 1 TO 16 YEARS OF AGE WHO ARE CANDIDATES FOR ACID 
SUPPRESSION THERAPY
Compound:
PF-05208751
Compound Name :
Pantoprazole sodium
US IND (United States Investigational 
New Drug) Number:
52,132
European Clinical Trial Database
(EudraCT) Number: 
Protocol Number:
2014-002182-29
B1791089
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.


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Document History
Document
Version Date
Summary of Changes and 
Rationale
Amendment 3
07 November 2018
PK sampling: 9 samples 
total (4 samples on Day 1 
and 5 samples on Day 2) for 
all age cohorts in order to 
make the study more 
feasible.
Consequently, pantoprazole 
concentration data will be 
analyzed by nonlinear 
mixed-effects models.
Treatment duration is 
flexible, depending on 
subject need (4-7 days), to 
make the study more 
feasible.
Physical examination and 
safety laboratory 
assessments have been 
moved from the day of the 
last dose to the day after the 
last dose to ensure all 
evaluations are done after 
treatment is completed.  
Assessments of vital signs, 
adverse events, and 
concomitant medications 
have been extended to 
include the day after the last 
dose.
Formatting and editing 
throughout.
Amendment 2
29 June 2017
Reduce PPI and H2RA 
washout periods, as prior 
use ≥48 and 24 hours prior 
to Day 1, respectively, is 
not expected to impact PK 
or safe use of pantoprazole 


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Document
Version Date
Summary of Changes and 
Rationale
sodium. 
Remove exclusion criteria 
for upper GI abnormalities 
and treatment for GI ulcers, 
as they are not expected to 
impact objectives of the 
study.
Update content from 
Protocol Administrative 
Change Letters, including 
the diagnosis of GERD in 
young children 
(Section 7.1), collection of 
PK samples (Section 7.2), 
and collection of 
temperature (Section 7.8).
Every effort should be made 
to collect blood pressure at 
approximately the same 
time each day. 
If a pulse rate abnormality 
is detected, ECG or rhythm 
strip should be obtained to 
document this.
Reduce background 
information that is already 
addressed in IB.
Screening numbers assigned 
by investigator via IRT 
– clarified wording.
Clarify dose selection 
rationale.
Update text and formatting 
per protocol template.
Make editorial changes and 
correct typographical errors 


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Document
Version Date
Summary of Changes and 
Rationale
throughout.
Amendment 1
28 October 2014
Changed compound number 
from PF-00579917 to 
PF-05208751.
Changed protocol number 
from B2851006 to 
B1791089.
Specified that this is a 
Post-Authorization Safety 
Study
Removed 1-11 month 
cohort, as efficacy has not 
previously been 
demonstrated in this age 
group with the oral 
formulation.
Removed subject selection 
criteria from protocol 
summary, as this is 
addressed in the body of the 
protocol.
Updated exclusion criteria 
to reflect that screening 
endoscopy is not required 
(eg, patients with known 
eosinophilic esophagitis or 
H. pylori infection are 
excluded, instead of 
requiring investigators to 
demonstrate these 
conditions).
Removed Day 1 pregnancy 
test and specified that 
Screening pregnancy test 
must be evaluated in serum 
within 24 hours before 
administration of 
investigational product.


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Document
Version Date
Summary of Changes and 
Rationale
Removed electrocardiogram 
and exclusion criterion 
related to QT prolongation, 
as there is no evidence of 
proarrhythmic potential 
with short-term exposure to 
pantoprazole.
Removed exclusion 
criterion relating to 
elevation of AST, as this 
could unnecessarily exclude 
patients with transient 
elevations that do not 
indicate liver injury.  The 
exclusion of patients with 
ALT elevations >2 x ULN 
has been maintained.
Added daily vital signs 
during treatment period.
Added instructions for 
assessing blood pressure 
and pulse.
Changed investigational 
product dosing in response 
to FDA request.
Moved drug administration 
instructions to a separate 
document.
Allowing standard-of-care 
laboratory results to serve as 
study entry labs, provided 
they are collected in 
appropriate time frame.
Specifying that PK samples 
are to be collected from IV 
line.
Updated text under sections 


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Document
Version Date
Summary of Changes and 
Rationale
Administration, Adverse 
Event Reporting and 
Communication of Results 
by Pfizer per protocol 
template. 
Original Protocol
27 March 2014
Not applicable (N/A)
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...................................................................................................................10
APPENDICES .........................................................................................................................10
PROTOCOL SUMMARY.......................................................................................................11
SCHEDULE OF ACTIVITIES................................................................................................16
1. INTRODUCTION ...............................................................................................................17
1.1. Indication.................................................................................................................17
1.2. Background and Rationale ......................................................................................17
1.2.1. Clinical Pharmacology................................................................................18
1.2.1.1. Pharmacokinetics ......................................................................18
1.2.2. Pediatric Pharmacokinetics.........................................................................19
1.2.2.1. Similar PK  Between Single- and Multiple-Dose .....................20
1.2.3. Pharmacogenomics.....................................................................................20
1.2.4. Safety..........................................................................................................21
1.2.4.1. Adults ........................................................................................21
1.2.4.2. Pediatric Patients.......................................................................21
1.2.5. Benefit Risk Assessment ............................................................................21
1.3. Study Rationale .......................................................................................................22
1.3.1. Dose Selection Rationale............................................................................22
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................23
2.1. Objectives................................................................................................................23
2.1.1. Primary Objectives .....................................................................................23
2.1.2. Secondary Objective...................................................................................23
2.2. Endpoints.................................................................................................................23
2.2.1. Primary Endpoints ......................................................................................23
2.2.2. Secondary Endpoints ..................................................................................23
3. STUDY DESIGN.................................................................................................................24
4. SUBJECT SELECTION......................................................................................................24
4.1. Inclusion Criteria.....................................................................................................24
4.2. Exclusion Criteria....................................................................................................26
4.3. Life Style Guidelines...............................................................................................27
4.4. Sponsor Qualified Medical Personnel.....................................................................28


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5. STUDY TREATMENTS.....................................................................................................28
5.1. Allocation to Treatment ..........................................................................................29
5.2. Subject Compliance.................................................................................................29
5.3. Investigational Product Supplies.............................................................................29
5.3.1. Dosage Form and Packaging ......................................................................29
5.3.2. Preparation and Dispensing........................................................................29
5.4. Administration.........................................................................................................30
5.5. Investigational Product Storage ..............................................................................30
5.6. Investigational Product Accountability...................................................................31
5.6.1. Destruction of Investigational Product Supplies ........................................31
5.7. Concomitant Treatment(s).......................................................................................31
6. STUDY PROCEDURES .....................................................................................................32
6.1. Screening.................................................................................................................32
6.2. Treatment Period.....................................................................................................33
6.2.1. Study Day 1 ................................................................................................33
6.2.2. Study Day 2 ................................................................................................34
6.2.3. Daily During Treatment..............................................................................34
6.3. Day After Last Dose................................................................................................35
6.4. Follow-Up Telephone Call......................................................................................35
6.5. Subject Withdrawal.................................................................................................36
7. ASSESSMENTS..................................................................................................................36
7.1. Diagnosis of GERD.................................................................................................37
7.2. Pharmacokinetics ....................................................................................................37
7.2.1. Shipment of Pharmacokinetic Samples ......................................................38
7.2.2. Bioanalytical Methodology ........................................................................38
7.3. Pharmacogenomics..................................................................................................38
7.3.1. Shipment of Pharmacogenomic Samples ...................................................38
7.4. Physical Examination..............................................................................................38
7.5. Safety Laboratory....................................................................................................39
7.6. Pregnancy Testing...................................................................................................40
7.7. Blood Pressure and Pulse Rate................................................................................40
7.8. Temperature ............................................................................................................40


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7.9. Blood Volume .........................................................................................................41
8. ADVERSE EVENT REPORTING......................................................................................41
8.1. Adverse Events........................................................................................................41
8.2. Reporting Period .....................................................................................................41
8.3. Definition of an Adverse Event...............................................................................42
8.4. Medication Errors....................................................................................................43
8.5. Abnormal Test Findings..........................................................................................43
8.6. Serious Adverse Events...........................................................................................43
8.6.1. Protocol-Specified Serious Adverse Events...............................................44
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................44
8.7. Hospitalization ........................................................................................................45
8.8. Severity Assessment................................................................................................46
8.9. Causality Assessment..............................................................................................47
8.10. Exposure During Pregnancy..................................................................................47
8.11. Occupational Exposure .........................................................................................48
8.12. Withdrawal Due to Adverse Events (See Also the Section on Subject 
Withdrawal)...............................................................................................................48
8.13. Eliciting Adverse Event Information ....................................................................49
8.14. Reporting Requirements........................................................................................49
8.14.1. Serious Adverse Event Reporting Requirements .....................................49
8.14.2. Non-Serious Adverse Event Reporting Requirements .............................49
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................50
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................50
9.1. Sample Size Determination.....................................................................................50
9.2. Efficacy Analysis ....................................................................................................50
9.3. Population Pharmacokinetic Analysis.....................................................................50
9.4. Analysis of Other Endpoints ...................................................................................51
9.5. Safety Analysis........................................................................................................51
9.6. Interim Analysis ......................................................................................................51
9.7. Data Monitoring Committee ...................................................................................51
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................51
11. DATA HANDLING AND RECORD KEEPING .............................................................52


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11.1. Case Report Forms/Electronic Data Record .........................................................52
11.2. Record Retention...................................................................................................53
12. ETHICS..............................................................................................................................53
12.1. Institutional Review Board/Independent Ethics Committee.................................53
12.2. Ethical Conduct of the Study ................................................................................53
12.3. Subject Information and Consent..........................................................................54
12.4. Subject Recruitment ..............................................................................................55
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................55
13. DEFINITION OF END OF TRIAL...................................................................................55
13.1. End of Trial in a Member State.............................................................................55
13.2. End of Trial in all other Participating Countries...................................................55
14. SPONSOR DISCONTINUATION CRITERIA ................................................................55
15. PUBLICATION OF STUDY RESULTS..........................................................................56
15.1. Communication of Results by Pfizer ....................................................................56
15.2. Publications by Investigators ................................................................................56
16. REFERENCES ..................................................................................................................58
LIST OF TABLES
Table 1.
Safety Labs ...........................................................................................................39
APPENDICES
Appendix 1. Abbreviations......................................................................................................60


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PROTOCOL SUMMARY
BACKGROUND AND RATIONALE
Pantoprazole sodium is a proton pump inhibitor indicated in adults and pediatric patients 
12 years of age and above (5 years of age and above in the US) as oral treatment for the 
healing and symptomatic relief of erosive esophagitis.  Pantoprazole sodium is also indicated 
as oral treatment for maintenance of healing of erosive esophagitis and reduction in relapse 
rates of daytime and nighttime heartburn symptoms in adult patients with gastroesophageal 
reflux disease (GERD).  Pantoprazole sodium is further indicated as long-term oral treatment 
of pathological hypersecretory conditions in adult patients, including Zollinger-Ellison 
syndrome.  Pantoprazole sodium intravenous (IV) formulation is indicated for short-term 
treatment (7 to 10 days) of adult patients with GERD and a history of erosive esophagitis.  
The IV formulation is not indicated for use in children.
The US Food and Drug Administration (FDA) Modernization Act, issued in 1997, stresses 
the need for improved information about drugs used in the pediatric population.
The rationale for conducting this Post Authorization Safety Study (PASS) is to characterize 
the pharmacokinetic (PK) of pantoprazole, following single and repeated once daily IV doses 
of pantoprazole sodium in hospitalized pediatric subjects in age groups of 1 to 16 years who 
in the judgment of the investigator are candidates for gastric acid suppression therapy.  These 
data will address FDA Post Marketing Requirements issued under the Pediatric Research 
Equity Act (PREA).
Rationale for dose selection is based on:

The safety and tolerability of 0.8 mg/kg and 1.6 mg/kg doses of pantoprazole sodium 
administered IV in children aged 1 to 2 years (3001K1-117) and 2 to 16 years
respectively (3001K1-110). 

The efficacy, safety, and tolerability of 0.3 mg/kg to 1.2 mg/kg oral doses of 
pantoprazole sodium in children aged 1 to 5 years of age (3001B3-328).

The efficacy of 20 mg and 40 mg oral doses of pantoprazole sodium in children aged 
5 to 11 years of age (3001A1-322).

The efficacy, safety, and tolerability of 20 mg and 40 mg oral doses of pantoprazole 
sodium in children aged 12 to 16 years of age (3001A1-326 and 3001A3-337).

The exposures were approximately similar following IV and oral administrations, as 
the absolute bioavailability of pantoprazole is about 77%.


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
According to population PK analysis across the age groups, the body weight was the 
most influencing covariate to clearance of pantoprazole in pediatric patients.  FDA 
recommended that pediatric doses be based on body weight as well as age to match 
the adult exposure more closely.  The proposed 10 mg dose for pediatric subjects 
aged 1 to <2 years (body weight 8 to <15 kg), 20 mg dose for 2 to 11 years (body 
weight >15 to <40 kg), and 40 mg dose for 12 to 16 years old (body weight 40 kg) 
are based on body weight and age of the patients in this study. 

Based on modeling and simulation analysis, the predicted systemic exposures
– maximum plasma concentration (Cmax) and area under the concentration-time curve 
(AUC) – in patients aged 1 to <2 years, 2 to 11 years, and 12 to 16 years at the
respective doses of 10, 20 and 40 mg were similar to the exposures seen in adults.
OBJECTIVES AND ENDPOINTS
In hospitalized pediatric subjects, age 1 to 16 years who in the judgment of the investigator 
are candidates for gastric acid suppression therapy, the following are the objectives of this 
trial:
Primary Objectives

To characterize the PK of pantoprazole, following single and multiple IV doses of 
pantoprazole sodium in pediatric subjects aged 1 to less than 2 years old. 

To characterize the PK  of pantoprazole, following single and multiple IV doses of 
pantoprazole sodium in pediatric subjects aged 2 to 16 years old. 
Secondary Objectives

To determine the safety, tolerability, and PK of single and multiple IV doses of 
pantoprazole sodium in each of the two independent age cohorts. 

To assess the CYP2C19 genotype in pediatric subjects receiving IV pantoprazole
sodium, to determine the presence of the gene for the major enzyme responsible for 
metabolism of pantoprazole.
Endpoints
Primary Endpoints

PK Parameters: clearance (CL) and volume of distribution (Vd).


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Secondary Endpoints

PK Parameters to be estimated from the population PK model:
Maximum plasma concentration (Cmax), area under the plasma concentration-time 
profile from time zero to the 24 hour time post dose (AUC24), area under the plasma 
concentration-time profile from time zero extrapolated to infinite time (AUCinf) and 
terminal phase half-life (T1/2) of pantoprazole following single and multiple IV doses.

Safety and tolerability of single- and multiple doses of IV pantoprazole sodium for 
each of the two age cohorts will be assessed by physical examinations, adverse event 
(AE) monitoring, clinical laboratory measurements, blood pressure, and pulse rate.

CYP2C19 genotype to determine the presence of the gene for the major enzyme 
responsible for metabolism of pantoprazole. 
STUDY DESIGN
This is a non-randomized, open-label, multicenter study to characterize the pharmacokinetics 
of single and multiple IV doses of pantoprazole sodium in hospitalized pediatric subjects in 
two independent age cohorts of 1 to 16 years who in the judgment of the investigator are 
candidates for gastric acid suppression therapy.  There will be approximately 12 subjects per 
age cohort (1 to less than 2 years; 2 to 16 years old) and a total of approximately 24 subjects 
for this two-cohort study.
Eligible subjects will be assigned to the following main age cohorts: 

Cohort 1: 1 to less than 2 years;

Cohort 2: 2 to 16 years old.  In Cohort 2, there will be approximately equal 
distribution across the age sub-cohorts of 2 to 5 years, 6 to 11 years and 12 to 
16 years. 
All subjects in each cohort will receive a fixed dose of IV pantoprazole sodium according to 
weight.  The maximum dose per 24 hour period for a subject who weighs at least 40 kg will 
not exceed 40 mg, irrespective of weight or age.  Pantoprazole sodium will be administered 
IV over 15 minutes through a Y-site or dedicated line (if Y-site is used, IV line must be 
flushed before and after dose administration) once daily for 4 to 7 days, approximately every 
24 hours, preferably in the morning.  Guidance will be provided to the investigator site 
regarding preparation and administration instructions.  PK samples will be collected to 
measure plasma concentrations of pantoprazole on study Day 1 and Day 2.  Vital signs, 
adverse events, and concomitant medications will be evaluated daily during treatment and on 
the day after the last dose; physical examination and safety laboratory assessments will be 
performed on the day after the last dose.  A follow up post treatment telephone contact will 
occur approximately 31 days after the last dose. 


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DATA ANALYSIS/STATISTICAL METHODS
Sample Size Determination
A sample size of 12 subjects in each age cohort is likely to have an 80% chance to achieve 
20% Relative Standard Error (RSE) for both clearance (CL) and volume of distribution (Vd). 
This sample size was estimated using simulations of a previous population PK model of
pantoprazole in pediatric patients reported by Knebel et al. (2011).16 The simulations used 
the sparse PK sampling scheme specified in Section 7.2.
Population Pharmacokinetic Analysis
Pantoprazole concentration data will be analyzed using a population PK analysis approach
(nonlinear mixed-effects models).  Prior pediatric PK data may be used to guide and assist 
the model building and covariate selection. A two-compartment model with IV infusion will 
be used to describe pantoprazole concentrations, with clearance (CL) and volume of 
distribution (Vd) of the central compartment being the key population PK parameters in the 
model. The potential influence of covariates, including age and body weight, on these 
parameters will be explored during the model building phase of the analysis.  Other 
covariates, including gender and baseline values, may also be explored using graphical 
approaches. 
The final population PK model will also be used to estimate the following PK Parameters: 
maximum plasma concentration (Cmax),  area under the plasma concentration-time profile 
from time zero to the 24 hour time post dose (AUC24), area under the plasma 
concentration-time profile from time zero extrapolated to infinite time (AUCinf) and terminal 
phase half-life (T1/2) of pantoprazole following single and multiple IV doses.
A Population Modeling Analysis Plan (PMAP) describing the details of the model building, 
covariate assessment, model validation and PK parameter estimation will be provided 
separately.
Analysis of Other Endpoints
Pharmacogenomic Endpoint:
CYP2C19 genotype: buccal cell samples will be collected at pre-dose by using a brush 
(supplied by the laboratory) and by scraping the inside of the subject’s cheek.  These samples 
will be examined to determine the presence of genes for the major (CYP2C19) enzymes 
responsible for metabolism of pantoprazole.


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Safety Analysis
Adverse events, physical examinations, blood pressure, pulse rate, and safety laboratory data 
will be reviewed and summarized on an ongoing basis during the study to evaluate the safety 
of subjects.  Any clinical laboratory, blood pressure, and pulse rate abnormalities of potential 
clinical concern will be described.  Safety data will be presented in tabular and/or graphical 
format and summarized descriptively, where appropriate. 
Safety results will be reported separately for each age cohort.
Safety summaries will be produced in accordance with Clinical Data Interchange Standards 
Consortium (CDISC) and Pfizer Standards (CaPS) for safety reporting.
Baseline characteristics (eg, demographics, medical history) will be also summarized using 
CaPS for reporting.


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SCHEDULE OF ACTIVITIES
The Schedule of Activities below provides an overview of the protocol visits and procedures.  
Refer to 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 
wellbeing of the subject.
Protocol Activity
Screening
Treatment Period
Day After 
Last Dose
Follow- Up
31 (3) Days 
After Last 
Dose
Day 0 or Day 
1 Prior to 
Treatment
Day 1
Day 2
-Daily During 
Treatment
Subject/parent/legal guardian 
informed consent
X
Review Inclusion/Exclusion 
X
Medical historya
X
Physical examinationb
X
X
Vital Signsc
X
X
X
X
X
Safety Laboratory evaluationd
X
Xh
Pregnancy teste
X
X
Subject Enrollment
X
Investigational product 
administrationf
X
X
X
PK blood sample collectiong
X
X
Pharmacogenomics (Buccal 
cell collection for 
CYP2C19 genotyping)
X
Drug Accountability
X
X
X
Prior/Concomitant Medication
X
→
→
→
X
X
Telephone contact
X
Adverse Event Monitoring 
X
→
→
→
X
X
a. Medical history includes complete history of all prescription or nonprescription drugs, vitamins, and dietary supplements 
taken prior to screening procedures, history of drug, alcohol, and tobacco use.
b. Physical exam will include height (cm) (Screening only) and weight (kg).
c. Blood pressure, pulse rate, and temperature (C).  Every effort should be made to collect blood pressure at approximately 
the same time each day.  If a pulse rate abnormality is detected, ECG or rhythm strip should be obtained to document this.
d. Refer to ASSESSMENTS sectionfor a list of laboratory parameters.
e. For female subjects of childbearing potential, a serum pregnancy test, with sensitivity of at least 25 mIU/mL, will be 
performed at screening, within 24 hours before investigational product administration.  On the day after the last dose a 
serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL will be performed.  Pregnancy tests may also be 
repeated as per request of IRB/IECs or if required by local regulations.
f. Refer to the Preparation and Dispensing section of this protocol and IP Manual, which is provided separately. 
g. Refer to the Pharmacokinetics section of this protocol for PK collection times. 
h. To minimize the amount of blood collected, routine laboratory studies planned within 48 hours after the last dose of 
investigational product may be used as the final study evaluation safety laboratory values, provided the information 
specified in the protocol is obtained.


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1. INTRODUCTION
1.1. Indication
Pantoprazole sodium is a proton pump inhibitor indicated in adults and pediatric patients 
12 years of age and above (5 years of age and above in the US) as oral treatment for the 
healing and symptomatic relief of erosive esophagitis.  Pantoprazole sodium is also indicated 
as oral treatment for maintenance of healing of erosive esophagitis and reduction in relapse 
rates of daytime and nighttime heartburn symptoms in adult patients with GERD.  
Pantoprazole sodium is further indicated as long-term oral treatment of pathological 
hypersecretory conditions in adult patients, including Zollinger-Ellison syndrome.  
Pantoprazole sodium IV formulation is indicated for short-term treatment (7 to 10 days) of 
adult patients with GERD and a history of erosive esophagitis.  The IV formulation is not 
indicated for use in children. Pantoprazole sodium is approved for marketing in more than 
90 countries and registered clinical indications vary among countries.
1.2. Background and Rationale
The North American Society for Pediatric Gastroenterology Hepatology and Nutrition
(NASPGHAN) has acknowledged that gastroesophageal reflux, defined as the regurgitation 
of gastric contents into the esophagus, and gastroesophageal reflux disease (GERD), defined 
as symptoms or complications of this regurgitation, are common pediatric problems.1
Gastroesophageal reflux disease is a common clinical disorder in children that can cause 
esophagitis and lead to or predispose a child to other medical problems such as malnutrition 
or respiratory disease.  Symptoms of GERD in children differ depending on their age and on 
the extent of the exposure of the esophageal epithelium to refluxed gastric contents.  Clinical 
manifestations can include spitting-up/regurgitation, vomiting, poor weight gain, dysphagia, 
abdominal or substernal pain, esophagitis, and respiratory disorders.  The symptoms of 
GERD can cause significant distress to children.2,3 The prevalence of GERD in children is 
unknown, but is thought to be increasing.4,5 Incidence is age-dependent and varies from 
5% to 35%.  In children diagnosed with GERD between the ages of 3.5 and 16 years, it is 
estimated that less than 50% will have spontaneous resolution of symptoms and that many 
will require continued medical or surgical management.6,7 In contrast, many infants develop 
GERD in the first few months of life but few infants and younger children will require 
long-term medical intervention because GERD generally resolves spontaneously by 12 to 
14 months of age.  Diagnostic testing, such as barium contrast (upper gastrointestinal series) 
radiographic studies and radionuclide scintiscanning tests are commonly used to diagnose 
GERD in children.  Esophageal pH monitoring is used to measure the presence of abnormal 
acid reflux.  Esophagogastroduodenoscopy (EGD) with biopsy is used to determine the 
presence and severity of esophagitis, strictures, and Barrett's esophagus, as well as to exclude 
other disorders (eg, Crohn's disease and eosinophilic or infectious esophagitis). 
Treatment options for children and adolescents with GERD include dietary changes, lifestyle 
modifications, and antacids for symptom relief.  When these conservative measures are 
unsuccessful, other pharmacologic treatments are used to relieve symptoms and promote 
healing of esophagitis. 


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Proton pump inhibitors (PPIs) and histamine2-receptor antagonists (H2RAs) are used to 
relieve symptoms and promote healing of esophagitis, although prescribing information for 
the pediatric population is limited.8,9 Antireflux surgery may be of benefit in selected 
children with chronic-relapsing GERD.
Pantoprazole sodium was synthesized and developed by Altana Pharma (formerly Byk 
Gulden Pharmaceuticals), Konstanz, Germany.  Pantoprazole sodium 20 mg is approved for 
marketing in more than 95 countries, the 40 mg tablet in more than 100 countries, and the 
40 mg powder for injection solution is approved in more than 90 countries.  Pfizer holds the 
marketing authorization for pantoprazole sodium in the US under the brand name Protonix, 
whilst Takeda has marketing authorization rights in territories outside the US. 
Pantoprazole sodium is a PPI that suppresses the final step in gastric acid production by 
covalently binding to the (H+, K+)-ATPase enzyme system at the secretory surface of the 
gastric parietal cell.  This effect leads to inhibition of both basal and stimulated gastric acid 
secretion, irrespective of the stimulus.  The binding to the (H+, K+)-ATPase results in a 
duration of antisecretory effect that persists longer than 24 hours for all doses tested (20 mg 
to 120 mg).
Pantoprazole sodium is commercially available as delayed-release granules for oral 
suspension and as delayed-release 20 mg or 40 mg oral tablets.  It is also available as a 40 mg 
powder for injection solution for intravenous administration.
1.2.1. Clinical Pharmacology
1.2.1.1. Pharmacokinetics 
In adults, pantoprazole peak serum concentration (Cmax) and area under the serum 
concentration-time curve (AUC) increase in a manner proportional to intravenous doses from 
10 mg to 80 mg.  Pantoprazole does not accumulate and its pharmacokinetics are unaltered 
with multiple daily dosing.  Following IV administration of pantoprazole sodium, the serum 
concentration of pantoprazole declines biexponentially with a terminal elimination half-life 
of approximately one hour.  In CYP2C19 extensive metabolizers with normal liver function 
receiving a 40 mg IV dose of pantoprazole sodium by constant rate over 15 minutes, the peak 
concentration (Cmax) is 5.52 1.42 g/mL and the total area under the plasma concentration 
versus time curve (AUC) is 5.4 1.5 g•hr/mL.  The total clearance is 7.6-14.0 L/hr. 
The absolute bioavailability of oral pantoprazole is about 77%.  The exposures were 
approximately similar following IV and oral administrations.11,12
1.2.1.1.1. Distribution 
The apparent volume of distribution of pantoprazole is approximately 11.0-23.6 L, 
distributing mainly in extracellular fluid.  The serum protein binding of pantoprazole is about 
98%, primarily to albumin. 


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1.2.1.1.2. Metabolism 
Pantoprazole is extensively metabolized in the liver through the cytochrome P450 (CYP) 
system.  Pantoprazole metabolism is independent of the route of administration (intravenous 
or oral).  The main metabolic pathway is demethylation, by CYP2C19, with subsequent 
sulfation; other metabolic pathways include oxidation by CYP3A4.  There is no evidence 
that any of the pantoprazole metabolites have significant pharmacologic activity.  
CYP2C19 displays a known genetic polymorphism due to its deficiency in some 
sub-populations (eg, 3% of Caucasians and African-Americans and 17-23% of Asians).  
Although these sub-populations of slow pantoprazole metabolizers have elimination half-life 
values from 3.5 to 10.0 hours, they still have minimal accumulation (23%) with once daily 
dosing. 
1.2.1.1.3. Excretion
After administration of a single intravenous dose of 14C-labeled pantoprazole sodium to 
healthy, extensive CYP2C19 metabolizers, approximately 71% of the dose was excreted in 
the urine with 18% excreted in the feces through biliary excretion.  There was no renal 
excretion of unchanged pantoprazole.
1.2.2. Pediatric Pharmacokinetics
Following single intravenous doses of pantoprazole sodium administered over 15 minutes as 
a single dose of 0.8 mg/kg or 1.6 mg/kg to 19 hospitalized subjects aged 2 to 16 years (study 
3001K1-110), the pharmacokinetics of pantoprazole were similar in the age groups 2 to 
4 years, 5 to 10 years, and 11 to 16 years. The mean Cmax and AUC values increased with 
dose from 0.8 mg/kg to 1.6 mg/kg. No trends toward a change with age were observed in the 
dose-independent pharmacokinetic (PK) parameters (ie, clearance, CL and volume of 
distribution at steady state, Vss) normalized by body weight in pediatric subjects aged 2 to 
16 years. The values of CL and T1/2 (ie, mean half life: 1.2 hours) of IV pantoprazole sodium
in these pediatric subjects were similar to those previously observed with IV pantoprazole
sodium (40 mg) in healthy adult subjects. 
In a different study (3001K1-117), the PK, safety, and tolerability of pantoprazole following 
administration of a single IV dose of 0.8 mg/kg or 1.6 mg/kg to hospitalized pediatric 
subjects at least 1 year but less than 2 years of age were assessed. The study 
3001K1-117 was conducted in 2 patients at each dose level.  The Cmax and AUC of 
pantoprazole increased proportionally with dose from 0.8 mg/kg to 1.6 mg/kg doses. The t½ 
value of pantoprazole in children 1 to 2 years of age were similar to that observed in 2 to 
16-year olds (ie, mean of 1.2 hours).  Children younger than 2 years required the higher dose 
(1.6 mg/kg) to achieve exposure similar to that seen in older children (2-16 years) with the 
lower dose (0.8 mg/kg). 
The observed Cmax values of pantoprazole following a 0.8 mg/kg IV dose were 4,846 and 
5,613 ng/mL in 1-2 year-olds in study 3001K1-117, which is comparable to that observed 
(Cmax of 5,520 ng/mL) in adults after 40 mg IV dose.10,11 The observed exposure (AUC) 
values of pantoprazole following a 0.8 mg/kg IV dose were 2,224 and 1762 ng.hr/mL in the 
two pediatric patients (ie, less than two years old) in study 3001K1-117, and the mean 


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exposures in the adults were 5,400 ng.hr/mL and 4,000 ng.hr/mL with a range of 
1,400 – 13,300 ng.hr/mL following IV and oral administrations of 40 mg pantoprazole
sodium, respectively.11,12 Although the exposures in the less than 2 years old pediatrics fall 
in the lower end of the exposure range (1,400 – 13,300 ng.hr/mL) observed in the adults, the
individual AUC values in two pediatrics appear lower than those mean exposures in adults.
1.2.2.1. Similar PK Between Single- and Multiple-Dose
Following single-dose IV administration in pediatrics, the elimination half-life of 
pantoprazole is approximately one hour. Pantoprazole does not accumulate and its PK is 
unaltered with multiple daily dosing (Ref. PROTONIXfor intravenous use United States 
Package Insert (USPI) – Revised: 10/2016).  Following single-dose IV dosing in pediatrics 
aged 1 to 16 years old, plasma concentrations of pantoprazole were close to the lower limit of 
quantification (ie, 10 ng/mL) of the bioanalytical assay at 12 hours post dose, providing 
further evidence that there will be no accumulation with multiple-day dosing (ref. studies 
3001K1-117 and 3001K1-110, and New Drug Application (NDA) 22-020 FDA Review of 
Clinical Pharmacology). In conclusion, these data provide further evidence to indicate that 
the PK profile of pantoprazole following a single IV dose on Day 1 is expected to be similar 
to the multiple dose PK profile on Day 7 after once-daily dosing in pediatric subjects.
In addition, a PK modeling and simulation analysis was performed for pediatric subjects aged 
1 to <2 years (body weight 8 to <15 kg), 2 to 11 years (body weight >15 to <40 kg), and 
12 to 16 years old (body weight ≥40 kg) at the respective doses of 10, 20 and 40 mg 
pantoprazole proposed for this study protocol. The simulation results showed similar 
concentration–time profiles between Day 1 and Day 7 following once-daily IV 
administrations. The simulation results also confirmed that there was no accumulation of 
pantoprazole following the once-daily dosing of 10, 20 and 40 mg IV pantoprazole for 
7 days.
1.2.3. Pharmacogenomics 
CYP2C19 displays a known genetic polymorphism due to its deficiency in some 
subpopulations (eg, approximately 3% of Caucasians and African-Americans and 17% to 
23% of Asians are poor metabolizers).  Although these subpopulations of pantoprazole poor 
metabolizers have elimination half-life values of 3.5 to 10.0 hours in adults, they still have 
minimal accumulation (23%) with once-daily dosing.  For adult patients who are 
CYP2C19 poor metabolizers, no dosage adjustment is needed. 
Similar to adults, pediatric patients who have the poor metabolizer genotype of 
CYP2C19 (CYP2C19 *2/*2) exhibited greater than a 6-fold increase in AUC compared to 
pediatric extensive (CYP2C19 *1/*1) and intermediate (CYP2C19 *1/*x) metabolizers.  
Poor metabolizers exhibited approximately 10-fold lower apparent oral clearance compared 
to extensive metabolizers.


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1.2.4. Safety
1.2.4.1. Adults 
The safety and tolerability of pantoprazole sodium has been assessed in more than 
250 clinical studies and through post-marketing surveillance that has occurred since the 
product was first approved in 1996. 
Approximately 5% of adult patients can be expected to experience adverse drug reactions 
(ADRs).  The most commonly reported ADR with the IV formulation in adults was injection 
site thrombophlebitis. Diarrhea and headache occurred in approximately 1% of patients.
1.2.4.2. Pediatric Patients
Safety of oral pantoprazole sodium in the treatment of erosive esophagitis associated with 
GERD was evaluated in pediatric patients aged 1 year through 16 years in 3 clinical trials.  
Safety trials involved pediatric patients with erosive esophagitis; however, as erosive 
esophagitis is uncommon in the pediatric population, 249 pediatric patients with 
endoscopically-proven or symptomatic GERD were also evaluated.  The most commonly 
reported (>4%) adverse reactions included upper respiratory infection (URI), headache, 
fever, diarrhea, vomiting, rash, and abdominal pain.
The safety of IV pantoprazole sodium was investigated as a single dose of 0.8 mg/kg or 
1.6 mg/kg randomly administered to 19 hospitalized patients aged 2 to 16 years
(3001K1-110).  Intravenous pantoprazole sodium at both doses was well tolerated with 
treatment emergent adverse events (TEAEs) reported for 3 patients in the 11 to 16 years age 
group and no patients in the other age groups.  All TEAEs were mild in severity and 
considered to be unrelated to pantoprazole sodium.
1.2.5. Benefit Risk Assessment
The safety and effectiveness of oral pantoprazole sodium for the short-term treatment (up to 
eight weeks) of erosive esophagitis associated with GERD has been established in pediatric 
patients 1 year through 16 years of age.  In adults, both the IV (short term therapy only) and 
oral formulations of pantoprazole sodium have been found to be safe and effective in 
management and prevention of relapse in reflux esophagitis.  Pantoprazole sodium is well 
tolerated and has demonstrated an acceptable safety profile in adult patients when 
administered by either the oral or IV routes.  Oral pantoprazole sodium has also 
demonstrated an acceptable safety profile in pediatric patients from 1 month to 16 years of 
age and the IV formulation was well tolerated after a single dose.
The vast majority of adverse drug reactions with oral and IV pantoprazole sodium are mild 
and/or resolve upon treatment discontinuation.  Based on the efficacy and safety profile of 
oral pantoprazole sodium in children aged 1 to 16 years of age and single dose pediatric 
safety data, the benefit-risk profile of multiple dose IV pantoprazole sodium use in pediatric 
patients participating in this study is anticipated to be positive.
Complete information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the Investigator’s Brochure.10


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1.3. Study Rationale
The US Food and Drug Administration (FDA) Modernization Act, issued in 1997, stresses 
the need for improved information about drugs used in the pediatric population.
The rationale for conducting this post authorization safety study (PASS) is; to characterize 
the PK of pantoprazole, following single and repeated once daily IV doses of pantoprazole
sodium in hospitalized pediatric subjects in age group of 1 to 16 years who in the judgment 
of the investigator are candidates for gastric acid suppression therapy.  These data will 
address FDA Post Marketing Requirements (PMRs) issued under PREA.
This protocol is composed of two independent age cohorts (1 to less than 2 years and 2 to 
16 years), which will be operationalized under a single protocol for logistical efficiency.  
While each cohort will have the same primary objective, they will be powered independently 
of each other and will be analyzed separately; data/results will not be combined or pooled 
across the two age cohorts.
1.3.1. Dose Selection Rationale
Rationale for dose selection is based on:

The safety and tolerability of 0.8 mg/kg and 1.6 mg/kg IV doses of pantoprazole
sodium in children aged 1 to 2 years (3001K1-117) and 2 to 16 years respectively
(3001K1-110).

The efficacy, safety, and tolerability of 0.3 mg/kg to 1.2 mg/kg oral doses of 
pantoprazole sodium in children aged 1 to 5 years of age (3001B3-328).

The efficacy of 20 mg and 40 mg oral doses of pantoprazole sodium in children aged 
5 to 11 years of age (3001A1-322).

The efficacy, safety, and tolerability of 20 mg and 40 mg oral doses of pantoprazole
sodium in children aged 12 to 16 years of age (3001A1-326 and 3001A3-337).

The exposures were approximately similar following IV and oral administrations, as 
the absolute bioavailability of pantoprazole is about 77%. 

According to population PK analysis across the age groups, the body weight was the 
most influencing covariate to clearance of pantoprazole in pediatric patients.  FDA 
recommended that pediatric doses be based on body weight as well as age to match 
the adult exposure more closely.  The proposed 10 mg dose for pediatric subjects 
aged 1 to <2 years (body weight 8 to <15 kg), 20 mg dose for 2 to 11 years (body 
weight >15 to <40 kg),  and 40 mg dose for 12 to 16 years old (body weight ≥40 kg) 
are based on body weight and age of the patients in this study. 

Based on modeling and simulation analysis, the predicted systemic exposures (Cmax
and AUC) in patients aged 1 to < 2 years, 2 to 11 years, and 12 to 16 years at the
respective doses of 10, 20 and 40 mg were similar to the exposures seen in adults.


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2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
In hospitalized pediatric subjects aged 1 to 16 years who in the judgment of the investigator
are candidates for gastric acid suppression therapy, the following are the objectives of this 
trial:
2.1.1. Primary Objectives

To characterize the PK of pantoprazole, following single and multiple IV doses of 
pantoprazole sodium in pediatric subjects aged 1 to less than 2 years old.

To characterize the PK of pantoprazole, following single and multiple IV doses of 
pantoprazole sodium in pediatric subjects aged 2 to 16 years old.
2.1.2. Secondary Objectives

To determine the safety, tolerability, and PK of single and multiple IV doses of 
pantoprazole sodium in each of the two independent age cohorts. 

To assess the CYP2C19 genotype in pediatric subjects receiving IV pantoprazole
sodium, to determine the presence of the gene for the major enzyme responsible for 
metabolism of pantoprazole.
2.2. Endpoints
2.2.1. Primary Endpoints

PK Parameters: clearance (CL) and volume of distribution (Vd).
2.2.2. Secondary Endpoints

PK Parameters to be estimated from the population PK model:
Maximum plasma concentration (Cmax), area under the plasma concentration-time 
profile from time zero to the 24 hour time post dose (AUC24), area under the plasma 
concentration-time profile from time zero extrapolated to infinite time (AUCinf) and 
terminal phase half-life (T1/2) of pantoprazole following single and multiple IV doses.

Safety and tolerability of single- and multiple doses of IV pantoprazole sodium for 
each of the two age cohorts will be assessed by physical examinations, adverse event 
(AE) monitoring, clinical laboratory measurements, blood pressure, and pulse rate.

CYP2C19 genotype to determine the presence of the gene for the major enzyme 
responsible for metabolism of pantoprazole. 


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3. STUDY DESIGN
This is a non-randomized, open-label, multicenter study to characterize the pharmacokinetics 
of single and multiple IV doses of pantoprazole sodium in hospitalized pediatric subjects in 
two independent age cohorts of 1 to 16 years who in the judgment of the investigator are 
candidates for gastric acid suppression therapy.  There will be approximately 12 subjects per 
age cohort (1 to less than 2 years and 2 to 16 years old) and a total of approximately 
24 subjects for this two-cohort study.
Eligible subjects will be assigned to the following main age cohorts: 

Cohort 1: 1 to less than 2 years,

Cohort 2: 2 to 16 years old.  In Cohort 2, there will be approximately equal 
distribution across the age sub-cohorts of 2 to 5 years, 6 to 11 years and 12 to 
16 years. 
All subjects in each cohort will receive fixed dose IV pantoprazole sodium according to 
weight.  The maximum dose per 24 hour period for a subject who weighs at least 40 kg will 
not exceed 40 mg, irrespective of weight or age.  Pantoprazole sodium will be administered 
IV over 15 minutes through a Y-site or dedicated line (if Y-site is used, IV line must be 
flushed before and after dose administration) once daily for 4 to 7 days, approximately every 
24 hours, preferably in the morning.  Guidance will be provided to the investigator site 
regarding administration instructions. PK samples will be collected to measure plasma 
concentrations of pantoprazole on study Day 1 and Day 2.  Vital signs, adverse events, and 
concomitant medications will be evaluated daily during treatment and on the day after the 
last dose; physical examination and safety laboratory assessments will be performed on the 
day after the last dose.  A follow up, post treatment telephone contact will occur 
approximately 31 days after the last dose.
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 this 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 appropriately qualified 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 that 
the parent/legal guardian has been informed of all pertinent aspects of the study.


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2. Evidence of a personally signed and dated assent, indicating that the subject 
understands the nature of all pertinent aspects of the study, and is willing to 
participate in the study activities, if applicable, as consistent with the subject’s age 
and ability to provide assent.
3. The subject (to degree appropriate for age) and parent or legal guardian are able to 
understand and comply with protocol requirements, instructions and protocol-stated 
restrictions and are likely to complete the study as planned. 
4. Subjects aged 1 to 16 years who in the judgment of the investigator are candidates for
gastric acid suppression therapy (ie, those with a presumptive diagnosis of GERD, a 
clinical diagnosis of suspected GERD, symptomatic GERD, or endoscopically proven 
GERD) and whom the investigator judges would need to receive IV PPI therapy for at 
least 4 days.  See Section 7.1.
5. Physical examination and clinical laboratory evaluations within normal limits unless 
the investigator documents that the deviations are not clinically significant or are 
directly related to the reason for gastric acid suppression therapy or to the subject’s 
underlying disease process.
6. Body weight >5th percentile for subject’s age. 
7. Y-site or dedicated IV line for administration of pantoprazole sodium. 
8. Expected survival for at least 30 days. 
9. The subject (to degree appropriate for age) and parent or legal guardian are willing 
and able to comply with scheduled visits, treatment plan, laboratory tests, and other 
study procedures.
10. Fertile male subjects and female subjects of childbearing potential and at risk for 
pregnancy must agree to use a highly effective method of contraception throughout 
the study and for at least 28 days after the last dose of assigned treatment.
a.
If subject is a female of childbearing potential, she must agree to use adequate 
contraception and must have a negative serum pregnancy test within 24 hours 
prior to administration of investigational product.
Female subjects of non-childbearing potential must meet at least one of the following 
criteria:
a.
Premenarchal: The investigator (or other appropriate staff) must discuss the 
subject’s premenarchal status with the subject or parent/caregiver at office visits 
and during telephone contacts, as subjects who achieve menarche during the study 
would no longer be considered “female subjects of nonchildbearing potential” and 
must comply with the protocol requirements applicable to women of childbearing 
potential;


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b. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
c.
Have medically confirmed ovarian failure; or 
d. Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; status may be confirmed by having a serum follicle 
stimulating hormone (FSH) level confirming the post-menopausal state.
All other female subjects (including females with tubal ligations) will be 
considered to be of childbearing potential.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study: 
1. Subjects who are investigational site staff members directly involved in the conduct 
of the trial and their family members, site staff members otherwise supervised by the 
Investigator, or subjects who are Pfizer employees directly involved in the conduct of 
the trial.
2. Participation in other studies involving investigational drug(s) within 30 days or 
5 half-lives prior to study entry and/or during study participation.
3. Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality 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.
4. Pregnant females; breastfeeding females; fertile male subjects and female subjects of 
childbearing potential who are unwilling or unable to use a highly effective method of 
contraception as outlined in this protocol for the duration of the study and for at least 
28 days after last dose of investigational product.
5. Serum creatine kinase levels >3x upper limit of normal. 
6. Known history of human immunodeficiency virus (HIV) or clinical manifestations of 
acquired immune deficiency syndrome (AIDS). 
7. Known hypersensitivity to proton pump inhibitors (PPIs), including pantoprazole
sodium or to any substituted benzimidazole or to any of the excipients.
8. History of treatment with any PPI (eg, omeprazole, esomeprazole, lansoprazole, 
rabeprazole, or pantoprazole sodium) within 2 days (ie, 48 hours) before 
investigational product dosing on Day 1.


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9. Use of Histamine 2 Receptor Blockers (H2RAs) (eg, cimetidine, famotidine, 
ranitidine or nizatidine), sucralfate, misoprostol, or prokinetic agents (eg, cisapride, 
urecholine, erythromycin or metoclopramide), and bismuth preparations within 1 day 
(ie, 24 hours) before investigational product dosing on Day 1, whether prescription or 
over the counter. 
10. Any disorder requiring chronic (every day) use of warfarin, carbamazepine, or 
phenytoin, methotrexate, atazanavir or nelfinavir, clopidogrel, and potent inhibitors 
and inducers of CYP2C19.
11. Chronic (daily) use of glucocorticoids (eg, prednisone, prednisolone, 
dexamethasone). Steroid inhalers and topical steroids may be used.
12. Active malignancy of any type, or history of a malignancy (Subject with a history of 
malignancies that have been surgically removed or eradicated by irradiation or 
chemotherapy and who have no evidence of recurrence for at least 5 years before 
Screening are acceptable). 
13. Alanine aminotransferase (ALT) or Blood urea nitrogen (BUN) >2.0 Upper limit of 
normal (ULN) or estimated creatinine >1.5 X ULN for age or any other laboratory 
abnormality considered by the Investigator to be clinically significant within 14 days 
before Screening. 
14. In the Investigator’s opinion, a chronic condition (eg, diabetes, epilepsy), which is 
either not stable or well controlled and may interfere with the conduct of the study. 
15. History of sensitivity to heparin or heparin-induced thrombocytopenia. 
4.3. Life Style Guidelines 
All fertile male subjects and female subjects who are of childbearing potential who are, in the 
opinion of the investigator, sexually active and at risk for pregnancy with their partner(s)
must agree to use a highly effective method of contraception consistently and correctly for 
the duration of the active treatment period and for at least 28 days after the last dose of 
investigational product.  The investigator or his or her designee, in consultation with the 
subject, will confirm that the subject has selected an appropriate method of contraception for 
the individual subject and his or her partner from the permitted list of contraception methods
(see below) and will confirm that the subject has been instructed in its consistent and correct 
use.  At time points indicated in the Schedule of Activities, the investigator or designee will 
inform the subject of the need to use highly effective contraception consistently and correctly 
and document the conversation and the subject’s affirmation in the subject’s chart (subjects 
need to affirm their consistent and correct use of at least 1 of the selected methods of 
contraception).  In addition, the investigator or designee will instruct the subject to call 
immediately if the selected contraception method is discontinued or if pregnancy is known or 
suspected in the subject or the partner. 


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Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted transdermal) provided the subject or 
male subject’s female partner plans to remain on the same treatment throughout the 
entire study and has been using that hormonal contraceptive for an adequate period of 
time to ensure effectiveness.
2. Correctly placed copper containing intrauterine device (IUD). 
3. Male condom or female condom used WITH a separate spermicide product (ie, foam, 
gel, film, cream, or suppository).  For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate.
4. Male sterilization with absence of sperm in the post-vasectomy ejaculate.
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
4.4. Sponsor 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.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigator product identifiers, subject study numbers, contact 
information for the investigator site, and contact details for a contact center in the event that 
the investigator 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 investigator staff if they 
are seeking advice on medical questions or problems; however, it should be used only in the 
event that the established communication pathways between the investigator site and the 
study team are not available. It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the 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 directly, and if a subject calls that number, he 
or she will be directed back to the investigator site.
5. STUDY TREATMENTS
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/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 


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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).
For this study, the investigational product is IV pantoprazole sodium.
5.1. Allocation to Treatment
The investigator’s knowledge of the treatment should not influence the decision to enroll a
particular subject or affect the order in which subjects are enrolled.
Upon completion of screening assessments, if the subject is found to be eligible for the study, 
they will be entered into the interactive response technology (IRT) system.  The IRT will 
assign a subject identification (ID).
5.2. Subject Compliance
All doses of investigational product will be administered by the appropriately designated and 
qualified study staff at the investigator site.  Study treatment will be administered under the 
supervision of investigator site personnel and verified.
5.3. Investigational Product Supplies
Pantoprazole sodium for injection is supplied as a freeze-dried powder containing 40 mg of 
pantoprazole sodium per vial. 
5.3.1. Dosage Form and Packaging
Pantoprazole sodium for injection 40 mg will be supplied by Pfizer, Inc. as single use vial for 
IV administration in a single subject and will be labeled according to local regulations.
5.3.2. Preparation and Dispensing
See the Investigational Product (IP) Manual for instructions on how to prepare the 
investigational product for administration.
Investigational product should be prepared and dispensed by an appropriately qualified and 
experienced member of the investigator site staff (eg, physician, nurse, physician’s assistant, 
practitioner, or pharmacist) as allowed by local, state, and institutional guidance.
Lyophilized powder for solution for injection will be provided by Pfizer and will be 
reconstituted according to the directions in IP Manual.  The IP Manual will be provided to 
sites in advance and will contain instructions for reconstitution, and administration, shelf life, 
storage conditions, and other necessary information for the proper handling and management 
of the investigational product.  Sites are required to comply with the IP Manual.


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5.4. Administration
The pantoprazole sodium dose is fixed according to subject weight.  See the Investigational 
Product Dosing Table below. The maximum dose per 24 hour period for a subject who 
weighs at least 40 kg will not exceed 40 mg, irrespective of weight or age. Pantoprazole
sodium will be administered intravenously through a Y-site or dedicated line (if Y-site is 
used, IV line must be flushed before and after dose administration) once daily for 4 to 7 days,
approximately every 24 hours, preferably in the morning. The IP Manual will be provided to 
the investigator site and include pantoprazole sodium administration instructions.
Investigational Product Dosing
IV Dose of Pantoprazole Sodium
Subject Weight
Total Daily Dose
Less than 15 kg
10 mg 
At least 15 kg to less than 40 kg
20 mg 
At least 40 kg
40 mg 
Pantoprazole sodium IV for Injection should be inspected visually for particulate matter and 
discoloration prior to and during administration whenever solution and container permit.  
When administered via a Y-site, immediately stop use if precipitation or discoloration occurs.
5.5. Investigational Product Storage 
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products 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.  See the IP Manual for storage conditions of the product once reconstituted.
Any storage conditions stated in the Single Reference Safety Document (SRSD) (eg, 
Investigator Brochure (IB)) will be superseded by the storage conditions stated on the 
product label.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 


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Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer.  Once 
an excursion is identified, the investigational product must be quarantined and not used until 
Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation.
Specific details regarding information the site should report for each excursion will be 
provided to the site.
5.6. Investigational Product Accountability
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.
5.6.1. Destruction of Investigational Product Supplies
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.7. Concomitant Treatment(s)
Subjects will continue their usual medical therapies according to standard clinical practice.  
Continuous treatment with theophylline derivatives or digoxin should be closely monitored 
throughout the study to assure that proper serum levels of these drugs are maintained.
Medications used to treat non-gastrointestinal (GI) conditions are allowed (with the 
exception of prohibited treatment).  The use of any concomitant treatment (eg, the treatment 
of an adverse event) must be recorded on the case report form (CRF).
Concurrent treatment with any of the following medications (whether prescription or over the 
counter) during the treatment period of this study is prohibited:
1. Other PPIs (eg, omeprazole, esomeprazole, lansoprazole, or rabeprazole).
2. Prokinetic agents (eg, cisapride, urecholine, erythromycin, domperidone, 
bethanechol, or metoclopramide).
3. H2RAs (eg, cimetidine, famotidine, ranitidine, or nizatidine).
4. Antacids or other drugs that affect luminal pH or pH dependent drugs.


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5. Bismuth-containing agents (eg, Pepto-Bismol).
6. Anticholinergics (eg, scopolamine, belladonna, or Donnatal).
7. Chronic (daily) use of glucocorticoids (eg, prednisone, prednisolone, 
dexamethasone).  Steroid inhalers and topical steroids may be used.
8. Chronic (daily) use of carbamazepine, phenytoin, methotrexate, atazanavir or 
nelfinavir, clopidogrel, and potent inhibitors and inducers of CYP2C19.
9. Prostaglandins (eg, misoprostol).
10. Sucralfate (Carafate).
11. Warfarin (Coumadin), heparin, or other anticoagulants.
12. Any other medication used to treat a GI condition.
13. Use of special diets or herbal or alternative medications that might affect the 
metabolism of the investigational product.
6. STUDY PROCEDURES 
The subjects will be hospitalized due to their primary medical condition or the need for a 
surgical procedure. 
6.1. Screening
Subjects will be screened on Day 0 or on Day 1 prior to investigational product 
administration to confirm that they meet the subject selection criteria for the study.  The 
investigator (or an appropriate delegate at the investigator site) will obtain informed consent 
and assent (depending on subject age and ability to provide assent) from each 
subject/parent/legal guardian in accordance with section Subject Information and Consent.  
The following procedures will be obtained:

Obtain written parent/legal guardian informed consent, assent as appropriate.

Review Inclusion/Exclusion criteria.

Complete medical history, including documentation of diagnosis of GERD
(Section 7.1), all prescription or nonprescription drugs, vitamins, and dietary
supplements taken prior to screening procedures.

Obtain history of drug, alcohol and tobacco use.

Conduct physical examination, including height and weight.


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
Obtain vital signs (blood pressure, pulse rate, and temperature).  If a pulse rate 
abnormality is detected, electrocardiogram (ECG) or rhythm strip should be obtained 
to document this.

Collect blood and urine specimens for the following:

Safety laboratory tests (to minimize the amount of blood collected, laboratory 
studies performed within 1 week before investigational administration may serve 
as screening safety laboratory values provided the information specified in the 
protocol is obtained).  See Section 7.5.

Pregnancy test for female subjects of childbearing potential.

Assess symptoms/adverse events.

Review prior or concomitant medications.
Laboratory results for standard care may serve as study entry labs (eg, safety laboratory tests 
and vital signs), provided they are collected within the protocol-specified timeframe.
6.2. Treatment Period
For the treatment period described below, where multiple procedures are scheduled at the
same time point(s) relative to dosing, the following chronology of events should be adhered 
to, where possible.

Blood pressure/pulse rate: obtain prior to blood specimen collections on Day 1 and 
Day 2.  Every effort should be made to collect blood pressure at approximately the 
same time each day.  If a pulse rate abnormality is detected, ECG or rhythm strip 
should be obtained to document this.

Pharmacokinetic blood specimens: obtain at scheduled PK collection times on Day 1 
and Day 2.
Other Procedures

All other procedures should be obtained as close as possible to the scheduled time, 
but may be obtained before or after blood specimen collection.
6.2.1. Study Day 1
Subjects will be enrolled into the study provided that they meet all the inclusion/exclusion
criteria.
On study Day 1, the following procedures will be performed according to the Schedule of 
Activity (SOA), preferably in the morning, to allow adequate time for collection of PK 
samples:


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
Vital signs (blood pressure, pulse rate, and temperature).  Every effort should be 
made to collect blood pressure at approximately the same time each day.  If a pulse 
rate abnormality is detected, ECG or rhythm strip should be obtained to document 
this.

Buccal cells will be collected pre-dose for pharmacogenomic analysis.

The actual time at which the IV pantoprazole sodium infusion begins will be 
documented as hour 0 of the study.  At 0 hour, the subject will begin receiving 
pantoprazole sodium.  The IV infusion will continue for 15 minutes.

PK blood sample collection, times specified in Section 7.2.

Assess adverse events.

Review concomitant medications.

Drug accountability.
6.2.2. Study Day 2
The following activities will be completed on Study Day 2:

Pantoprazole sodium IV infusion.

Vital signs (blood pressure, pulse rate, and temperature).  Every effort should be 
made to collect blood pressure at approximately the same time each day.  If a pulse 
rate abnormality is detected, ECG or rhythm strip should be obtained to document 
this.

PK sample collection.  Times are specified in Section 7.2.

Assess adverse events.

Review concomitant medications. 

Drug accountability.
6.2.3. Daily During Treatment
Doses should be given approximately 24 hours apart. The following activities will be 
completed daily during treatment:

Pantoprazole sodium IV infusion.


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
Vital signs (blood pressure, pulse rate, and temperature).  Every effort should be 
made to collect blood pressure at approximately the same time each day.  If a pulse 
rate abnormality is detected, ECG or rhythm strip should be obtained to document 
this.

Assess adverse events.

Review concomitant medications.

Drug accountability.
6.3. -Day After Last Dose
The following activities will be completed on the day after the last dose:

Physical examination including weight.

Vital sign (blood pressure, pulse rate, and temperature).  Every effort should be made 
to collect blood pressure at approximately the same time each day.  If a pulse rate 
abnormality is detected, ECG or rhythm strip should be obtained to document this.

Collect blood and urine specimens for the following:

Safety laboratory evaluation (Section 7.5).  To minimize the amount of blood 
collected, routine laboratory studies planned within 48 hours after the last dose of 
investigational product may be used as the final study evaluation safety laboratory 
values provided the information specified in the protocol is obtained.

Pregnancy test for female subjects of childbearing potential.

Assess adverse events.

Review concomitant medications.
6.4. Follow-Up Telephone Call
A follow-up telephone call will occur approximately 31 days (3 days) after the last dose of 
investigational product was taken.  All outstanding unresolved adverse events and serious 
adverse events will be followed-up at this time.  The follow-up telephone call should be 
noted and documented in the subject’s primary source records.  If the subject had no new or 
ongoing adverse events or serious adverse events during this time, this should also be noted 
and added to the subject’s primary source records.  Any serious adverse events should be 
reported to Pfizer within 24 hours. Concomitant medications will also be reviewed.


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6.5. Subject Withdrawal
Subjects may withdraw from the study at any time at their own request and/or parent/legal 
guardian, 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 and/or parent/legal 
guardian to comply with the protocol required schedule of study visits or procedures at a 
given investigator site. 
If a subject does not complete a scheduled visit, every effort should be made to contact the 
subject. All attempts to contact the subject 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 for the final visit, if 
applicable, and follow up with the subject regarding any unresolved adverse events (AEs).
If the subject withdraws, the following procedures will be completed:

Physical examination including weight.

Vital signs (blood pressure, pulse rate, and temperature).  Every effort should be 
made to collect blood pressure at approximately the same time each day.  If a pulse 
rate abnormality is detected, ECG or rhythm strip should be obtained to document 
this.

Safety laboratory evaluation.

Assess adverse events.

Review prior or concomitant medications.
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 continue to use any data collected before such withdrawal of 
consent.
7. ASSESSMENTS
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
wellbeing of the subject.  When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventative 
actions which s/he has taken to ensure that required processes are adhered to as soon as
possible.  The study team must be informed of these incidents in a timely fashion.


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7.1. Diagnosis of GERD
“In infants and toddlers, there is no symptom or symptom complex that is diagnostic of 
GERD or predicts response”.1 Therefore it would be expected that younger children who are 
enrolled in this study would have had an objective diagnosis of GERD, as described in the 
American Academy of Pediatrics’ Gastroesophageal Reflux Management Guidance for the 
Pediatrician.
“Diagnostic tests must be used in a thoughtful and serial manner to document the presence of 
reflux of gastric contents in the esophagus, to detect complications, to establish a causal 
relationship between reflux and symptoms, to evaluate the efficacy of therapies, and to 
exclude other conditions.  The diagnostic methods most commonly used to evaluate pediatric 
patients with GERD symptoms are upper gastrointestinal (GI) tract contrast radiography, 
esophageal pH and/or impedance monitoring, and upper endoscopy with esophageal 
biopsy”.13 These or other medically appropriate, objective methods should be employed in 
young children for whom symptoms would not be diagnostic.
7.2. Pharmacokinetics
Blood samples (0.5 mL) for pharmacokinetic analysis of pantoprazole will be collected at 
times specified below. Pharmacokinetic blood samples (0.5 mL at each time point listed 
below) can be collected either by direct venipuncture or from an intravenous catheter.  The 
samples must not be collected from a catheter that is connected to the study drug infusion 
line.  The samples must be collected at a different access site that is not downstream from the 
site of drug administration.  Additional details are found in the laboratory manual.

Day 1: Venous blood samples (0.5 mL) will be collected to measure plasma 
concentrations of pantoprazole at 0.25 (the 0.25 hour sample is to be taken at the end 
of the 15-minute infusion), 1 to 2, 3 to 4, and 5 to 6 hours after the start of the 
infusion.

Day 2: Venous blood samples (0.5 mL) will be immediately collected predose and at
0.25 (the 0.25 hour sample is to be taken at the end of the 15-minute infusion), 1 to 2,
3 to 4, and 5 to 6 hours after the start of the infusion. 
Total blood sampling volume for PK analysis is approximately 4.5 mL for an 
individual subject. 
If the actual PK sample collection times differ from the nominal times relative to dosing, the 
number of samples collected must remain the same.  All efforts will be made to obtain the 
pharmacokinetic samples within the specified windows relative to dosing.  However, samples 
obtained within ± 15 minutes of the nominal time from dosing (ie, for the 1 to 2, 3 to 4, and
5 to 6 hour post-dose samples) will not be captured as a protocol deviation, as long as the 
exact time of the sample collection is noted on the source document and data collection tool 
(eg, CRF/DCT). The 0.25 hour (the 0.25 hour sample is to be taken at the end of the 
15-minute infusion) sample must be taken at the exact nominal time relative to dosing.


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Samples will be collected, processed, stored, and shipped according to the instructions 
provided by the sponsor to the investigator site under separate cover prior to study start.
As part of evaluation of the investigational product, samples may be used for evaluation of 
the bioanalytical method.  These data will be used for internal exploratory purposes and will 
not be included in the clinical report.  Samples collected for this purpose will be retained in 
accordance to local regulations and if not used within this timeframe, will be destroyed.
7.2.1. Shipment of Pharmacokinetic Samples
The shipment address and bioanalytical assay lab contact information will be provided to the 
investigator site prior to initiation of the study.
7.2.2. Bioanalytical Methodology
The plasma samples will be analyzed for pantoprazole using a validated analytical method in 
compliance with Pfizer standard operating procedures.
7.3. Pharmacogenomics
CYP2C19 genotype: buccal cell samples will be collected at pre-dose by using a brush 
(supplied by the laboratory) and by scraping the inside of the subject’s cheek.  These samples 
will be examined to determine the presence of genes for the major (CYP2C19) enzyme 
responsible for metabolism of pantoprazole.
The detailed instructions for sample collection, processing, storage, and shipment will be 
provided by the sponsor.
The buccal samples will be analyzed in compliance with Pfizer standard operating 
procedures.
7.3.1. Shipment of Pharmacogenomic Samples
The shipment address and assay lab contact information will be provided to the investigator 
site prior to initiation of the study.
7.4. Physical Examination
Physical examinations 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, heart and lung examinations, lymph nodes, 
gastrointestinal, musculoskeletal, and neurological systems.  The limited or abbreviated 
physical examination will be focused on general appearance, the respiratory and 
cardiovascular systems, as well as towards subject reported symptoms.
For measuring weight, a scale with appropriate range and resolution is used and must be 
placed on a stable, flat surface.  Subjects must remove shoes, bulky layers of clothing, and 
jackets so that only light clothing remains.  They must also remove the contents of their 
pockets and remain still during measurement of weight. 


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The following parameters will be assessed and the results recorded as part of the complete 
physical examination:

Height and Weight (kg) -height only at screening.

Note: It is recommended that length be used for subjects younger than 2 years of 
age.
7.5. Safety Laboratory
The following safety laboratory tests below will be performed at times defined in the 
Treatment Period section of this protocol.  Additional laboratory results may be reported on 
these samples as a result of the method of analysis or the type of analyzer used by the clinical 
laboratory; or as derived from calculated values.  These additional tests would not require 
additional collection of blood.  Unscheduled clinical labs may be obtained at any time during 
the study to assess any perceived safety concerns (Table 1).  To minimize the amount of 
blood collected, routine laboratory studies planned within 48 hours after the last dose of 
investigational product may be used as the final study evaluation safety laboratory values,
provided the information specified in the protocol is obtained.
Table 1.
Safety Labs
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
Red blood cell
count with
indices (MCV,
MCH, and
MCHC)
White blood cell
count with
differential
Platelet count
Sodium
Potassium
Chloride
Bicarbonate or CO2
Glucose
Bun or Urea
Creatinine
Uric acid
Magnesium
Total bilirubin
Total protein
Serum albumin
Aspartate aminotransferase 
(AST)
Alanine aminotransferase 
(ALT)
Creatine kinase (CK)
Alkaline phosphatase (ALP)
pH
Specific gravity
Protein/albumin
Glucose/sugar
Ketones/acetone
Blood/ hemoglobin
Nitrites
Leukocyte esterase
Bilirubin
Serum gastrin level
(fasting if possible)
Serum or urine pregnancy test a
a.
For female subjects of childbearing potential, a serum pregnancy test, with sensitivity of at least 
25 mIU/mL, will be performed at screening, within 24 hours before investigational product administration.  
On the day after the last dose, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL will 
be performed.  Pregnancy tests may also be repeated as per request of IRB/IECs or if required by local 
regulations.


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7.6. Pregnancy Testing
For female subjects of childbearing potential, a serum pregnancy test, with sensitivity of at 
least 25 mIU/mL, will be performed at screening, within 24 hours before investigational 
product administration.  A negative pregnancy result is required before the subject may 
receive the investigational product.  On the day after the last dose, a serum or urine 
pregnancy test, with sensitivity of at least 25 mIU/mL will be performed.  Pregnancy tests 
will also be done whenever one menstrual cycle is missed during the active treatment period 
(or when potential pregnancy is otherwise suspected).  Pregnancy tests may also be repeated 
as per request of Institutional Review Boards/Independent Ethics Committees (IRB/IECs) or 
if required by local regulations.
In the case of a positive confirmed pregnancy, the subject will be withdrawn from 
investigational product but may remain in the study. 
7.7. Blood Pressure and Pulse Rate
Blood pressure and pulse rate will be measured at times relative to blood specimen collection 
specified in Section 6 of this protocol.  Every effort should be made to collect blood pressure 
at approximately the same time each day.  Additional collection times, or changes to 
collection times of blood pressure and pulse rate will be permitted, as necessary, to ensure 
appropriate collection of safety data.  If a pulse rate abnormality is detected, ECG or rhythm 
strip should be obtained to document this.
Supine blood pressure will be measured with the subject’s arm supported at the level of the 
heart, and recorded to the nearest mm Hg after approximately 5 minutes of rest.  The same 
arm (preferably the dominant arm) will be used throughout the study.  Blood pressure should 
not be taken from the arm with an intravenous infusion. Subjects should be instructed not to 
speak during measurements. 
The same properly sized and calibrated blood pressure cuff will be used to measure blood 
pressure each time.  The use of an automated device for measuring BP and pulse rate is 
acceptable, although, when done manually, pulse rate will be measured in the brachial/radial 
artery for 30 seconds .  When the timing of these measurements coincides with a blood 
collection, blood pressure and pulse rate should be obtained prior to the nominal time of the 
blood collection.
7.8. Temperature
No eating, drinking or smoking is allowed for 15 minutes prior to the measurement.
“Each part of the body has a unique temperature based on perfusion, hemodynamic 
circumstances, and thermal conditions”14 and because institutional standards for 
measurement of temperature may vary, this protocol will not restrict the accepted routes of 
temperature measurement.  The route selected for each patient should be used consistently.


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Investigators are therefore recommended “to evaluate temperature sites available and select 
the temperature measurement site depending on the patient’s age and level of physiologic 
stability”.14 Furthermore, “an optimal thermometer should provide ease of application within 
a brief period, accurate temperature measurement, safety, tolerability by the patient, and no 
potential risks”.15
7.9. Blood Volume
The total PK blood sampling volume for individual subjects in this study is approximately 
4.5 mL.  If the actual PK sample collection times differ from the nominal times relative to 
dosing, the number of samples collected must remain the same.  Additional blood samples 
may be taken for safety assessments at times specified by Pfizer, provided the total volume 
taken during the study does not exceed 550 mL during any period of 30 consecutive days.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
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 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a 
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  
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.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event 
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. 
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  Serious adverse events occurring to a subject 
after the active reporting period has ended should be reported to the Sponsor if the 
investigator becomes aware of them; at a minimum, all serious adverse events that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product are to be reported to the Sponsor.


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AEs (serious and non-serious) should be recorded on the case report form (CRF) from the 
time the subject has taken at least one dose of investigational product through the subject’s 
last visit.
8.3. Definition of an Adverse Event
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;

Occupational exposure.


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8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong subject, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF which is a specific version of the AE page and on the SAE form when appropriate.  
In the event of medication dosing error, the sponsor should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

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.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE CRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

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 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.
8.6. 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;


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
Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
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.
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.
8.6.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see Section on Serious Adverse Event Reporting Requirements).
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminostransferase 
(ALT) levels concurrent with abnormal elevations in total bilirubin level that meet the 
criteria outlined below in the absence of other causes of liver injury are considered potential 
cases of drug-induced liver injury (potential Hy’s law cases) and should always be 
considered important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions.  Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of 
normal (× ULN) concurrent with a total bilirubin value 2 × ULN with no evidence 
of hemolysis and an alkaline phosphatase value 2 × ULN or not available;

For subjects with preexisting ALT OR AST OR total bilirubin values above the 
upper limit of normal, the following threshold values should be used in the definition 
mentioned above:

For subjects with pre-existing 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).


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Concurrent with

For subjects with pre-existing values of total bilirubin above the normal range: 
Total bilirubin increased from baseline by an amount of at least 1 × ULN or if the 
value reaches 3 × ULN (whichever is smaller).
The subject should return to the investigational 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, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/international normalized ratio (INR), and alkaline 
phosphatase. A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug, and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for LFT (liver function test) abnormalities identified at 
the time should be considered potential Hy’s law cases irrespective of availability of all the 
results of the investigations performed to determine etiology of the abnormal LFTs.  Such 
potential Hy’s law cases should be reported as SAEs.
8.7. 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, or 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 should be 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).


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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;

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 AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
If required on the AE case report forms (CRFs), 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


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8.9. 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 in the CRF, as appropriate, 
and report such an assessment in accordance with the serious adverse 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 (see the Section on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product", 
this should be clearly documented on study records. 
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of 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;
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).
2. A male has been exposed (eg, because of 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 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer Drug Safety Unit on an 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 woman (eg, a 
subject reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage) 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).


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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 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 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 
serious adverse events 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 investigator.  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.
8.11. 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 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.
8.12. Withdrawal Due to Adverse Events (See Also the Section on Subject Withdrawal)
Withdrawal due to AE should be distinguished from withdrawal due to other causes,
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page. 


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When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject/parent/legal guardian.  In addition, each study subject/parent/legal guardian
will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event. 
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This timeframe also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of EDP, exposure via breastfeeding and 
occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his/her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the timeframes for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or 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 or its 
designated representative. 
8.14.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.


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8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for population pharmacokinetic analysis of the data collected in this 
study is described in Section 9.3 and in Section 11, and will be included in the Clinical Study 
Report and maintained by the sponsor. This document may modify the plans outlined in the 
protocol; however, any major modifications of the primary endpoint definition and/or its 
analysis will also be reflected in a protocol amendment.
9.1. Sample Size Determination
A sample size of 12 subjects in each age cohort is likely to have an 80% chance to achieve 
20% Relative Standard Error (RSE) for both clearance (CL) and volume of distribution (Vd). 
This sample size was estimated using simulations of a previous population PK model of
pantoprazole in pediatric patients reported by Knebel et al. (2011).16 The simulations used 
the sparse PK sampling scheme specified in Section 7.2.
9.2. Efficacy Analysis
There is no efficacy analysis for this study.
9.3. Population Pharmacokinetic Analysis
Pantoprazole concentration data will be analyzed using a population PK analysis approach 
(nonlinear mixed-effects models).  Prior pediatric PK data may be used to guide and assist 
the model building and covariate selection. A two-compartment model with IV infusion will 
be used to describe pantoprazole concentrations, with clearance (CL) and volume of 
distribution (Vd) of the central compartment being the key population PK parameters in the 
model.  The potential influence of covariates, including age and body weight, on these 
parameters will be explored during the model building phase of the analysis.  Other 
covariates, including gender and baseline values, may also be explored using graphical 
approaches. 
The final population PK model will also be used to estimate the following PK Parameters: 
maximum plasma concentration (Cmax), area under the plasma concentration-time profile 
from time zero to the 24 hour time post dose (AUC24), area under the plasma 
concentration-time profile from time zero extrapolated to infinite time (AUCinf) and terminal 
phase half-life (T1/2) of pantoprazole following single and multiple IV doses.
A Population Modeling Analysis Plan (PMAP) describing the details of the model building,
covariate assessment, model validation and PK parameter estimation will be provided 
separately.


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9.4. Analysis of Other Endpoints
Pharmacogenomic Endpoint:

CYP2C19 genotype: buccal cell samples will be collected at pre-dose by using a 
brush (supplied by the laboratory) and by scraping the inside of the subject’s cheek.  
These samples will be examined to determine the presence of genes for the major 
(CYP2C19) enzymes responsible for metabolism of pantoprazole.
9.5. Safety Analysis
Adverse events, physical examinations, blood pressure, pulse rate, and safety laboratory data 
will be reviewed and summarized on an ongoing basis during the study to evaluate the safety 
of subjects.  Any clinical laboratory, blood pressure, and pulse rate abnormalities of potential 
clinical concern will be described.  Safety data will be presented in tabular and/or graphical 
format and summarized descriptively, where appropriate.
Safety results will be reported separately for each age cohort.
Safety summaries will be produced in accordance with Clinical Data Interchange Standards 
Consortium (CDISC) and Pfizer Standards (CaPS) for safety reporting.
Baseline characteristics (eg, demographics, medical history) will be also summarized using 
CaPS for reporting.
9.6. Interim Analysis 
There will be no interim analysis for this study.
9.7. Data Monitoring Committee 
This study will not use a data monitoring committee.
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 Practices (GCPs) 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 investigator site may be subject to 
review by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC), 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.


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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 investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection. The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject's medical records.  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.
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 is true.  Any corrections to entries made in the CRFs, 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's 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 investigator 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.


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11.2. Record Retention
To enable evaluations and/or inspections/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/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 the 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.
12. ETHICS
12.1. Institutional Review Board/Independent 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/IEC 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 the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of
Medical Sciences 2002), ICH Guideline for GCP (ICH 1996), and the Declaration of 
Helsinki. 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.


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12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names
on any sponsor forms, 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, birth date and other identifiable data will be replaced by numerical codes
based on a numbering system provided by Pfizer in order to de-identify study subjects.  The 
investigator 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/assent document must be in compliance with ICH GCP, local 
regulatory requirements, and legal requirements, including applicable privacy laws.
The informed consent/assent document used during the informed consent process must be 
reviewed and approved by Pfizer, approved by the IRB/IEC before use, and available for 
inspection.
The investigator must ensure that each study subject, or his or her parent(s) or legal guardian
are fully informed about the nature and objectives of the study and possible risks associated 
with participation.
Whenever consent is obtained from a subject’s parent(s) or legal guardian, 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 the subject's parent(s) or legal guardian and the subject’s assent, when 
applicable, before any study-specific activity is performed, unless a waiver of informed 
consent has been granted by an IRB/EC.  The investigator will retain the original of each 
subject's signed consent/assent document.


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12.4. Subject Recruitment
Advertisements approved by IRBs/ECs and investigator databases may be used as 
recruitment procedures.
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.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
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 which 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 that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State 
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of subjects have been recruited and completed the study as 
stated in the regulatory application (ie, Clinical Trial Application (CTA)) and ethics 
application in the Member State.  Poor recruitment (recruiting less than the anticipated 
number in the CTA) by a Member State is not a reason for premature termination but is 
considered a normal conclusion to the study in that Member State.
13.2. End of Trial in all other Participating Countries
End of Trial in all other participating countries is defined as Database Lock.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
pantoprazole sodium at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within 5 days.  As directed by Pfizer, all study materials must be collected and 
all CRFs completed to the greatest extent possible.


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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 pre-specified 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.
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, Investigator will provide Pfizer an opportunity to review any proposed 


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publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
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, 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 sites, Investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the Study, 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 Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.
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.
Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux 
clinical practice guidelines: joint recommendations of the North American Society for 
Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European 
Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J 
Pediatr Gastroenterol Nutr 2009;49(4):498-547.
2.
Cuthrell C, Rubino C, Ransom JL, Gal P. GERD in neonates and pediatrics: use of 
omeprazole. Pharm Pract. 1999;12:492-503.
3.
Orenstein S. Gastroesophageal reflux disease. Semin Gastrointest Dis. 1994;5:2-14.
4.
Coletti RB and Di Lorenzo C. Overview of pediatric gasrroesophageal reflux disease 
and proton pump inhibitor therapy. J Pediatr Gastroenterol Nutr. 2003;37:S7-S11.
5.
Badriul H and Vandenplas Y. Gastro-oesophageal reflux in infancy. J Gastroenterol 
Hepato.l 1999;14:13-19.
6.
Gold BD. Review Article: epidemiology and management of gastro-oesophageal reflux 
in children. Aliment Pharmcol Ther. 2004;19(Supp1):22-27.
7.
Gremse DA. Gastroesophageal reflux disease in children: an overview of 
pathophysiology, diagnosis and treatment. J Pediatr Gastroenterol Nut. 
2002;35(Suppl 4):S297-299.
8.
Rudolph CD. Are proton pump inhibitors indicated for the treatment of 
gastroesophageal reflux in infants and children. J Pediatr Gastroenterol Nutr. 
2003;37(Supp1) S60-S64.
9.
Cezard JP. Managing gastro-oesophgeal reflux disease in children. Digestion. 
2004;69(supp1):3-8.
10.
Investigator’s Brochure: Pantoprazole [PF-05208751] Oral & IV.  May 2014.
11.
PROTONIX I.V.  (pantoprazole sodium) for injection, for intravenous use USPI –
Revised: 10/2016. 
12.
PROTONIX (pantoprazole sodium) delayed-release tablets PROTONIX (pantoprazole 
sodium) for delayed-release oral suspension USPI – Revised: 10/2016.
13.
Lightdale JR, Gremse DA. Gastroesophageal reflux: management guidance for the 
pediatrician. Pediatrics 2013;131(5):e1684-e1695.
14.
Martin SA, Kline AM. Can there be a standard for temperature measurement in the 
pediatric intensive care unit? AACN Clinical Issues. 2004;15(2):254-266.


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15.
Sahin SH, Duran R, Sut N, et al. Comparison of temporal artery, nasopharyngeal, and 
axillary temperature measurement during anesthesia in children. Journal of Clinical 
Anesthesia. 2012;24:647-651.
16.
Knebel W, Tammara B, Udata C, et al. Population pharmacokinetic modeling of 
pantoprazole in pediatric patients from birth to 16 years. J Clin Pharmacol. 
2011;51:333-345.


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Appendix 1. Abbreviations
This is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
ADR
adverse drug reaction
AE
adverse event
AIDS
acquired immune deficiency syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC24
AUC from 0 to 24 hours
AUCinf
AUC extrapolated to infinite time
BUN
blood urea nitrogen
CaPS
CDISC and Pfizer Standards
CDISC
Clinical Data Interchange Standards Consortium
CK
creatine kinase
CL
clearance
Cmax
maximum plasma concentration
CRF
case report form
CSA
clinical study agreement
CTA
clinical trial application
CYP
cytochrome P450
DCT
data collection tool
DNA
deoxyribonucleic acid
DU
dispensable unit
EC
ethics committee
ECG
electrocardiogram
EDP
exposure during pregnancy
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act (United States)
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GERD
gastroesophageal reflux disease
GI
gastrointestinal
H2RA
histamine2-receptor antagonist
HIV
human immunodeficiency virus
IB
investigator’s brochure
ICH
International Conference on Harmonisation
ID
identification
IND
investigational new drug application


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Abbreviation
Term
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IRT
interactive response technology
IUD
intrauterine device
IV
intravenous
LFT
liver function test
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
N/A
not applicable
NASPGHAN
North American Society for Pediatric Gatroenterology, 
Hepatology, and Nutrition
NDA
New Drug Application
PASS
post-authorization safety study
PK
pharmacokinetics
PMAP
Population Modeling Analysis Plan
PMR
post-marketing requirement
PPI
proton pump inhibitor
PREA
Pediatric Research Equity Act
PT
prothrombin time
RSE
relative standard error
SAE
serious adverse event
SAP
statistical analysis plan
SOA
schedule of activities
SRSD
single reference safety document
T½ 
half-life
TEAE
treatment emergent adverse event
ULN
upper limit of normal
URI
upper respiratory infection
US
United States
USPI
United States package insert
Vd
volume of distribution
Vss
steady state volume of distribution

SAP_001.pdf: 
Protocol B1791089 (Pantoprazole sodium) Statistical Analysis Plan
Page 1 of 14
PFIZER CONFIDENTIAL
Protocol B1791089
AN OPEN-LABEL, MULTICENTER STUDY TO EVALUATE THE 
PHARMACOKINETICS OF SINGLE AND MULTIPLE INTRAVENOUS 
DOSES OF PANTOPRAZOLE IN TWO AGE COHORTS OF 
HOSPITALIZED PEDIATRIC SUBJECTS 1 TO 16 YEARS OF AGE WHO 
ARE CANDIDATES FOR ACID SUPPRESSION THERAPY
Statistical Analysis Plan 
(SAP)
Version:
2.0
SAP Author:
Date:
03-OCT-2022
PPD


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PFIZER CONFIDENTIAL
Revision History
Version
Date
Author(s)
Summary of Changes/Comments
2.0
03OCT2022

Removed a table of list of reviewers from current page.

Following updates are based on Protocol Amendment 3 
(07NOV2018):

Added text for flexible dosing duration (Section 2.1).

Added text changing the PK sampling to Days 1 and 2
(Section 2.1).

Updated both primary objectives and the first secondary 
objective (Sections 2.2.1 and 2.2.2) to align with the 
amended protocol.

Removed Table 1 (Section 6.3.1) and replaced it with text 
from the amended protocol.

Inserted pop PK modeling verbiage (Section 8.3).

Updated the TOC.
1.0
17FEB2016
Original SAP
NOTE: Italicized text within this document has been taken verbatim from the Protocol.
PPD
PPD


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TABLE OF CONTENTS 
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................4
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Design .............................................................................................................5
2.2. Study Objectives .......................................................................................................6
2.2.1. Primary .........................................................................................................6
2.2.2. Secondary .....................................................................................................6
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................6
4. HYPOTHESES AND DECISION RULES...........................................................................6
4.1. Statistical Hypotheses ...............................................................................................6
4.2. Statistical Decision Rules..........................................................................................6
5. ANALYSIS SETS .................................................................................................................6
5.1. Pharmacokinetic (PK) Analysis Set ..........................................................................6
5.1.1. Concentration Analysis Set...........................................................................6
5.1.2. Parameter Analysis Set.................................................................................6
5.2. Pharmacodynamic Analysis Set................................................................................6
5.3. Safety Analysis Set....................................................................................................7
5.4. Other Analysis Sets ...................................................................................................7
5.5. Treatment Misallocations..........................................................................................7
5.6. Protocol Deviations...................................................................................................7
5.6.1. Deviations Assessed Prior to Randomization...............................................7
5.6.2. Deviations Assessed Post-Randomization....................................................7
6. ENDPOINTS AND COVARIATES .....................................................................................7
6.1. Efficacy Endpoint(s) .................................................................................................7
6.2. Safety Endpoints .......................................................................................................7
6.3. Other Endpoints.........................................................................................................8
6.3.1. PK Endpoints................................................................................................8
6.3.2. PD Endpoints................................................................................................8


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6.3.3. Pharmacogenomics.......................................................................................8
6.4. Covariates..................................................................................................................8
7. HANDLING OF MISSING VALUES ..................................................................................8
7.1. Concentrations Below the Limit of Quantification...................................................9
7.2. Deviations, Missing Concentrations and Anomalous Values ...................................9
7.3. Pharmacokinetic Parameters .....................................................................................9
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ............................9
8.1. Statistical Methods ....................................................................................................9
8.2. Population Pharmacokinetic Analyses....................................................................10
8.3. Safety Analysis........................................................................................................11
8.3.1. Treatment and Disposition of Subjects.......................................................11
8.3.2. Demographic and Clinical Examination Data............................................11
8.3.3. Discontinuation(s).......................................................................................11
8.3.4. Adverse Events ...........................................................................................11
8.3.5. Laboratory Data..........................................................................................11
8.3.6. Vital Signs Data..........................................................................................12
8.3.7. Other Safety Data .......................................................................................12
8.3.8. Concomitant Treatments.............................................................................12
8.3.9. Screening and Other Special Purpose Data ................................................12
9. REFERENCES ....................................................................................................................13
10. APPENDICES ...................................................................................................................14
LIST OF TABLES
No table of figures entries found.None.
LIST OF FIGURES
None.
APPENDICES
Appendix 1. SAS CODE FOR ANALYSES...........................................................................14


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PFIZER CONFIDENTIAL
1. AMENDMENTS FROM PREVIOUS VERSION(S) 
None.
2. INTRODUCTION
Pantoprazole sodium is a proton pump inhibitor indicated for oral use in adults and 
pediatric patients 12 years of age and above (5 years of age and above in the US) for 
treatment in the healing and symptomatic relief of erosive esophagitis (EE) associated with 
gastroesophageal reflux disease (GERD).  The intravenous (IV) formulation is approved for 
use in adults for the same indication but is not approved for use in children.
The rationale for conducting this Post Authorization Safety Study (PASS) is to characterize 
the PK profile of single and repeated IV doses of pantoprazole in hospitalized pediatric 
subjects in age groups of 1 to less than 2 years, and 2 to 16 years who in the judgment of the 
investigator are candidates for acid suppression therapy.  These data will fulfill the FDA 
Post Marketing Requirement (PMRs 145-1 and 255-6).
2.1. Study Design
This is a non-randomized, open-label, multicenter study to characterize the pharmacokinetics
of single and multiple IV doses of pantoprazole in hospitalized pediatric subjects in two 
independent age cohorts of 1 to 16 years (1 to less than 2 years; 2 to 16 years old) who in the 
judgment of the investigator are candidates for acid suppression therapy. There will be
approximately 12 subjects per age cohort and a total of approximately 24 subjects for this
two-cohort study.
Eligible subjects will be assigned to the following main age cohorts:

Cohort 1: 1 to less than 2 years;

Cohort 2: 2 to 16 years old. 
In Cohort 2, there will be approximately equal distribution across the age sub-cohorts of 2 to 
5 years, 6 to 11 years and 12 to 16 years.
All subjects will receive a fixed dose of IV pantoprazole according to weight. The maximum
dose per 24 hour period will not exceed 40 mg. Pantoprazole will be administered IV over
15 minutes through a Y-site or dedicated line in the morning of Day 1 and once daily for 
7 days (fixed dosing, every 24 hours for 7 days, prior to Protocol Amendment 3, whilst 
flexible dosing will be used afterwards (4-7 days as needed)). Guidance will be provided to 
the clinical site regarding preparation and administration instructions. PK samples will be 
collected, using the IV line, to measure plasma concentrations of pantoprazole on study 
Day 1 and Day 7 (prior to Protocol Amendment 3, whilst Days 1 and 2 afterwards). A follow 
up post treatment telephone contact will occur approximately 31 days after the last dose. 


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2.2. Study Objectives
2.2.1. Primary

To characterize the PK of single and multiple IV doses of pantoprazole in pediatric 
subjects aged 1 to less than 2 years old.

To characterize the PK of single and multiple IV doses of pantoprazole in pediatric 
subjects aged 2 to 16 years old.
2.2.2. Secondary

To determine the safety, tolerability, and PK of single and multiple IV dose 
pantoprazole in each of the two independent age cohorts.

To assess the CYP2C19 genotype in pediatric subjects receiving IV pantoprazole, to 
determine the presence of the gene for the major enzyme responsible for metabolism 
of pantoprazole.
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
No interim analysis is planned.  Final analysis will follow the official database release.  As 
this will be an open-label study, there is no formal unblinding of the randomization code.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
No hypotheses are required.
4.2. Statistical Decision Rules
No decision rules are required.
5. ANALYSIS SETS
5.1. Pharmacokinetic (PK) Analysis Set
5.1.1. Concentration Analysis Set
The PK concentration population is defined as all subjects treated with pantoprazole who 
have at least 1 concentration.
5.1.2. Parameter Analysis Set
The PK parameter analysis population is defined as all subjects treated with pantoprazole 
who have at least 1 of the PK parameters of primary interest.
5.2. Pharmacodynamic Analysis Set
None.


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5.3. Safety Analysis Set
All subjects who receive at least 1 dose of study medication will be included in the safety 
analyses and listings.
5.4. Other Analysis Sets
None.
5.5. Treatment Misallocations 
All analyses will be performed on an “as-treated” basis and will not include data from 
subjects who are randomized but not treated.
If a subject takes a treatment that is not consistent with the treatment they are randomized to, 
for example takes a treatment out of sequence or takes the same treatment twice, then they 
will be reported under the treatment that they actually receive for all safety, PK and 
pharmacodynamic analyses, where applicable.
5.6. Protocol Deviations
Subjects who experience events that may affect their PK profile (eg lack of compliance with 
dosing) may be excluded from the PK analysis.  At the discretion of the pharmacokineticist a 
concentration value may also be excluded if the deviation in sampling time is of sufficient 
concern or if the concentration is anomalous for any other reason.
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure.
5.6.1. Deviations Assessed Prior to Randomization
At Screening, the investigator will assess subjects against the inclusion and exclusion criteria 
as set out in Sections 4.1 and 4.2 of the protocol.
5.6.2. Deviations Assessed Post-Randomization
A full list of protocol deviations for the study report will be compiled prior to database 
closure.  Any significant deviation from the protocol will be reviewed prior to database 
closure and a decision taken regarding evaluation for each analysis population.
6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoint(s)
None.
6.2. Safety Endpoints
Any events occurring following start of treatment or increasing in severity will be counted as 
treatment emergent.


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Events that occur in a non-treatment period (for example, Washout or Follow-up) will be 
counted as treatment emergent and attributed to the previous treatment taken.
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters):

adverse events,

laboratory data,

vital signs data.
6.3. Other Endpoints
6.3.1. PK Endpoints
Blood samples for PK analysis of pantoprazole will be taken according to the Schedule of 
Activities given in the protocol.
PK parameters to be estimated from the population PK model:
Clearance (CL), volume of distribution (Vd), maximum plasma concentration (Cmax), area 
under the plasma concentration-time profile from time zero to the 24 hour time post dose 
(AUC24), area under the plasma concentration-time profile from time zero extrapolated to 
infinite time (AUCinf) and terminal phase half-life (T1/2) of pantoprazole following single and 
multiple IV doses.
6.3.2. PD Endpoints
None.
6.3.3. Pharmacogenomics
Buccal cell collection for CYP2C19 genotyping will be taken to determine the presence of 
the gene for the major enzyme responsible for metabolism of pantoprazole.
6.4. Covariates
None.
7. HANDLING OF MISSING VALUES
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.


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7.1. Concentrations Below the Limit of Quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification).
7.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie not done) or NS (ie no sample).
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 
50% of the data are missing.
7.3. Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a subject’s concentration data, the parameter will 
be coded as NC (ie not calculated). (Note that NC values will not be generated beyond the 
day that a subject discontinues).
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular cohort with ≥3 evaluable measurements.  For statistical 
analyses (ie, analysis of variance), PK parameters coded as NC will also be set to missing; 
and analyses will not be performed for a particular parameter if more than 50% of the data 
are NC.
If an individual subject has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as shortened intravenous infusion), this will be footnoted in 
summary tables and will not be included in the calculation of summary statistics or statistical
analyses.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods
As this is a descriptive study only, no formal hypothesis testing will be performed.  No 
pooled analyses across the two independent age cohorts are planned.


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8.2. Population Pharmacokinetic Analyses
Pantoprazole concentration data will be analyzed using a population PK analysis approach 
(nonlinear mixed-effects models).  Prior pediatric PK data may be used to guide and assist 
the model building and covariate selection.  A two-compartment model with IV infusion will 
be used to describe pantoprazole concentrations, with clearance (CL) and volume of 
distribution (Vd) of the central compartment being the key population PK parameters in the 
model.  The potential influence of covariates, including age and body weight, on these 
parameters will be explored during the model building phase of the analysis. Other 
covariates, including gender and baseline values, may also be explored using graphical 
approaches. 
The final population PK model will also be used to estimate the following PK Parameters: 
maximum plasma concentration (Cmax), area under the plasma concentration time profile 
from time zero to the 24 hour time post dose (AUC24), area under the plasma concentration 
time profile from time zero extrapolated to infinite time (AUCinf) and terminal phase half life 
(T1/2) of pantoprazole following single and multiple IV doses.
Box and whisker plots for individual subject parameters (AUC24, AUClast and Cmax) be 
presented by cohort and dosing and overlaid with geometric means.
A Population Modeling Analysis Plan (PMAP-EQDD-B179a-sNDA-1153) describing the 
details of the model building, covariate assessment, model validation and PK parameter 
estimation will be provided separately.
Presentations for pantoprazole concentrations will include:

A listing of all concentrations sorted by cohort (present in heading), subject id, day
and nominal time postdose.  The concentration listing will also include the actual 
times.  Deviations from the nominal time will be given in a separate listing.

A summary of concentrations by cohort, day and nominal time postdose, where the 
set of statistics will include n, mean, median, standard deviation, coefficient of 
variation (cv), minimum, maximum and the number of concentrations above the 
lower limit of quantification.

Median concentrations time plots (on both linear and semi-log scales) against 
nominal time postdose by dosing (single dose (Day 1) and multiple dose (Days 2 & 7 
combined) on the same plot per scale, based on the summary of concentrations by 
cohort, dosing (single dose and multiple dose) and time postdose).

Mean concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by dosing (single dose (Day 1) and multiple dose (Days 2 & 7 
combined) on the same plot per scale, based on the summary of concentrations by 
cohort, dosing (single dose and multiple dose) and time postdose).


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
Individual concentration time plots by cohort and dosing (single dose and multiple 
dose) (on both linear and semi-log scales) against actual time postdose (there will be 
separate spaghetti plots for each cohort and dosing per scale).

Individual concentration time plots by subject (on both linear and semi-log scales) 
against actual time postdose [there will be separate plots for each subject (containing 
both dosing (single dose and multiple dose)) per scale].
For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used, for individual subject plots by time, the actual PK sampling time will be 
used.
8.3. Safety Analysis
A set of summary tables split by age cohort will be produced to evaluate any potential risk 
associated with the safety and toleration of administering pantoprazole.
8.3.1. Treatment and Disposition of Subjects
Subject evaluation groups will show end of study subject disposition and will show which 
subjects were analyzed for pharmacokinetics, as well as for safety (adverse events and 
laboratory data).  Frequency counts will be supplied for subject discontinuation(s) by cohort.
Data will be reported in accordance with the sponsor reporting standards.
8.3.2. Demographic and Clinical Examination Data
A break down of demographic data will be provided for age, race, weight, body mass index, 
and height.  Each will be summarized by sex at birth and ‘All Subjects’ in accordance with 
the sponsor reporting standards.
8.3.3. Discontinuation(s)
Subject discontinuations, temporary discontinuations or dose reductions due to adverse 
events will be detailed and summarized by cohort.
Data will be reported in accordance with the sponsor reporting standards.
8.3.4. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards by 
cohort.
8.3.5. Laboratory Data
Laboratory data will be listed in accordance with the sponsor reporting standards.


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8.3.6. Vital Signs Data
The baseline measurement is the last predose measurement.
For each planned timepoint, baseline values and change from baseline values within each 
cohort will be summarized with descriptive statistics (using sponsor default standards).
These data will be listed in accordance with the sponsor reporting standards.
8.3.7. Other Safety Data
Primary diagnosis, including method of diagnostic confirmation, will be summary tabulated 
by cohort.  These data will be listed in accordance with the sponsor reporting standards.
8.3.8. Concomitant Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.
8.3.9. Screening and Other Special Purpose Data

CYP2C19 genotyping data will be listed in accordance with the sponsor reporting 
standards.

Serum B-hCG for all females of childbearing potential will be obtained at Screening.  
These data will not be brought in-house, and therefore will not be listed.


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9. REFERENCES
None.


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10. APPENDICES
Appendix 1. SAS CODE FOR ANALYSES
Not applicable.