Clinical trial NCT04729101
Conditions: Healthy Participants
Keywords: Vonoprazan Lansoprazole
Sponsor: Phathom Pharmaceuticals, Inc.
Start date: 2021-01-28; Completion date: 2021-06-26
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of vonoprazan (20 mg) and lansoprazole (30 mg) following single (Day 1) and multiple doses (Day 7).

Detailed description:
This clinical trial information was submitted voluntarily under the applicable law and, therefore, certain submission deadlines may not apply. (That is, clinical trial information for this applicable clinical trial was submitted under section 402(j)(4)(A) of the Public Health Service Act and 42 CFR 11.60 and is not subject to the deadlines established by sections 402(j)(2) and (3) of the Public Health Service Act or 42 CFR 11.24 and 11.44.).

Arms: arm 1: Participants will be randomized to receive vonoprazan (treatment A) and lansoprazole (treatment B) in a two period sequence, following either treatment sequence AB or BA. There will be a washout period of at least 7 days between Period 1 and Period 2.

Vonoprazan will be administered via 20 mg oral tablet once daily on Day 1 through to Day 7 in a period, where each period is up to 8 days. arm 2: Participants will be randomized to receive vonoprazan (treatment A) and lansoprazole (treatment B) in a two period sequence, following either treatment sequence AB or BA. There will be a washout period of at least 7 days between Period 1 and Period 2.

Lansoprazole will be administered via 30 mg oral capsule once daily on Day 1 through to Day 7 in a period, where each period is up to 8 days.
Interventions: intervention 1: Vonoprazan intervention 2: Lansoprazole
Intervention descriptions: intervention 1: Oral tablet intervention 2: Oral capsule

Protocol documents:
Prot_000.pdf: 
Protocol Number:  VONO-103 
 
Official Title:  A Phase 1, Open-Label, Randomized, Crossover Study to Evaluate the 
Pharmacokinetics, Pharmacodynamics, and Safety of Vonoprazan (20 mg) and 
Lansoprazole (30 mg) in Healthy Subjects 
 
NCT Number: NCT04729101 
 
Document Date: 15-Apr-2021 







































































































SAP_001.pdf: 
Protocol Number:  VONO-103 
 
Official Title:  A Phase 1, Open-Label, Randomized, Crossover Study to Evaluate the 
Pharmacokinetics, Pharmacodynamics, and Safety of Vonoprazan (20 mg) and 
Lansoprazole (30 mg) in Healthy Subjects 
 
NCT Number: NCT04729101 
 
Document Date:  06-Jul-2021 


STATISTICAL ANALYSIS PLAN 
 
A Phase 1, Open-Label, Randomized, Crossover Study to Evaluate the 
Pharmacokinetics, Pharmacodynamics, and Safety of Vonoprazan (20 mg) and 
Lansoprazole (30 mg) in Healthy Subjects 
 
Sponsor Project No.: VONO-103 
Final Protocol Amendment 1 Date: 08 March 2021 
Final Protocol Date: 30 December 2020 
 
Compound Name: Vonoprazan 
US IND Number: 079212 
 
 
Celerion Project No.: CA32534 
Final Version 1.0 
Date: 06 July 2021 
 
 
 
Phathom Pharmaceuticals, Inc.  
2150 East Lake Cook Road, Suite 800 
Buffalo Grove, Illinois 60089, USA 
 
 
Prepared by: 
 
Celerion 
621 Rose Street, Lincoln, Nebraska 68502, USA  
 
 
 


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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Compound Name: Vonoprazan 
Protocol No: CA32534 
Study Title: A Phase 1, Open-Label, Randomized, Crossover Study to Evaluate the 
Pharmacokinetics, Pharmacodynamics, and Safety of Vonoprazan (20 mg) and 
Lansoprazole (30 mg) in Healthy Subjects 
Issue Date: 06 July 2021 
 
Signature
 
 
Principal Scientist, Biostatistics  
Data Management and Biometrics 
 
 
Signature:
 
 
Principal Scientist, Clinical Pharmacology and Pharmacometrics, 
Data Management and Biometrics 
 
 
 
 
 
 


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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Compound Name: Vonoprazan 
Protocol No: CA32534 
Study Title: A Phase 1, Open-Label, Randomized, Crossover Study to Evaluate the 
Pharmacokinetics, Pharmacodynamics, and Safety of Vonoprazan (20 mg) and 
Lansoprazole (30 mg) in Healthy Subjects 
Issue Date: 06 July 2021 
 
Signature: 
 
 
Senior Director, Biostatistics and Programming 
Phathom Pharmaceuticals, Inc 
 
Signature:
 
 
Clinical Pharmacology Consultant 
Phathom Pharmaceuticals, Inc 
 


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TABLE OF CONTENTS 
1. 
INTRODUCTION ..............................................................................................................6 
2. 
OBJECTIVES AND ENDPOINTS ....................................................................................6 
2.1 
Objectives ..................................................................................................................6 
2.2 
Endpoints ..................................................................................................................6 
3. 
STUDY DESIGN ...............................................................................................................6 
SAMPLE SIZE ..........................................................................................................................7 
4. 
ANALYSIS POPULATIONS ............................................................................................8 
4.1 
Analysis Populations .................................................................................................8 
4.2 
Preliminary Data and Interim Analysis .....................................................................8 
5. 
TREATMENT DESCRIPTIONS .......................................................................................8 
6. 
PHARMACODYNAMIC ANALYSIS ..............................................................................9 
6.1 
Gastric pH Monitoring ..............................................................................................9 
6.2 
Gastric pH Pharmacodynamic Parameters ................................................................9 
6.3 
Gastrin Sampling .....................................................................................................11 
6.4 
Gastrin Pharmacodynamic Parameters ...................................................................12 
6.5 
PD Data Summarization and Presentation ..............................................................12 
6.6 
Statistical Analysis of PD Parameters .....................................................................13 
6.6.1 Analysis of Variance ...................................................................................13 
7. 
PHARMACOKINETIC ANALYSIS ...............................................................................13 
7.1 
Measurements and Collection Schedule .................................................................13 
7.2 
Bioanalytical Methods ............................................................................................14 
7.3 
Investigational Product and PK Analyte Information .............................................15 
7.3.1 Vonoprazan .................................................................................................15 
7.3.2 Lansoprazole ...............................................................................................15 
7.4 
Pharmacokinetic Concentrations .............................................................................16 
7.5 
Non-Compartmental Pharmacokinetic Analysis and Parameter Calculation .........16 
7.5.1 Plasma Pharmacokinetic Parameters...........................................................16 
7.6 
PK Data Summarization and Presentation ..............................................................18 
8. 
SAFETY ...........................................................................................................................19 
8.1 
Subject Disposition .................................................................................................20 
8.2 
Demographics .........................................................................................................20 
8.3 
Adverse Events........................................................................................................20 
8.4 
Clinical Laboratory Tests (Serum Chemistry, Hematology, and Urinalysis) .........21 
8.5 
Vital Signs ...............................................................................................................21 
8.6 
Electrocardiogram ...................................................................................................22 


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8.7 
Concomitant Medications and Medical History .....................................................22 
8.8 
Physical Examination ..............................................................................................22 
9. 
SUMMARY OF CHANGES FROM PROTOCOL-PLANNED ANALYSIS ................22 
 


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1. INTRODUCTION 
The following statistical analysis plan (SAP) provides the framework for the 
summarization of the data from this study. Any changes made from the planned 
analysis, after locking of the database, will be documented in the clinical study report 
(CSR).   
2. OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
Primary Objective 
• To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of 
vonoprazan (20 mg) and lansoprazole (30 mg) following single (Day 1) and 
multiple doses (Day 7). 
 
Secondary Objective 
• To evaluate the safety and tolerability of vonoprazan (20 mg) following single 
(Day 1) and multiple doses (Day 7). 
2.2 
Endpoints 
Primary Endpoints 
• PD parameters: gastric pH >4 holding time ratio (HTR) and mean gastric pH 
over 24 hours on Days 1 and 7. 
• PK parameters as appropriate: following Day 1: AUC0-24, AUC0-inf, Cmax, 
and Tmax, and following Day 7: AUCtau, Cmax,ss, and Tmax,ss.  
 
Safety Assessments 
• Adverse events (AEs), 12-lead electrocardiograms (ECGs), vital signs, 
clinical laboratory tests, and physical examinations. 
3. STUDY DESIGN 
This is a Phase 1, open-label, randomized, 2-period, crossover study to evaluate the 
PK, PD, and safety and tolerability of vonoprazan in comparison to lansoprazole in 
healthy subjects. The study will be conducted at a single site. 
Forty (40), healthy, adult male and female subjects will be enrolled.  Subjects will be 
randomized to 1 of 2 treatment sequences in a 1:1 ratio, either AB or BA, where 
treatment A and treatment B are vonoprazan 20 mg QD and lansoprazole 30 mg QD, 
respectively.  
Screening of subjects will occur within 28 days prior to the first dosing. 


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In each period, multiple doses of either vonoprazan or lansoprazole will be 
administered QD for 7 consecutive days. Gastric pH will be measured continuously 
over a 24-hour period at Baseline (Day -1 of Period 1 only) and on Days 1 and 7 of 
Periods 1 and 2. PK samples will be collected at predose and for 24 hours following 
dosing on Days 1 and 7 of Periods 1 and 2. Gastrin samples will be collected over a 
24-hour period at Baseline (Day -1 of Period 1 only), at predose and for 24 hours 
following dosing on Days 1 and 7 of Period 1 only, and at predose (single sample) on 
Day 1 of Period 2. Safety will be monitored throughout the study by clinical safety and 
laboratory evaluations. 
Subjects will fast overnight for at least 10 hours prior to each dosing. On Days 1 and 7 
of Periods 1 and 2, subjects will continue the fast for 4 hours postdose when they will 
be given a meal, the next meal will be served at 9 hours postdose, and a snack will be 
served at 12 hours postdose. On Day -1 of Period 1, subjects will follow a similar time 
matched (± 15 minutes) food administration schedule as planned for Day 1.There will 
be a washout period of at least 7 days between the last dose in Period 1 and the first 
dose in Period 2. 
Discontinued subjects may be replaced at the discretion of the Sponsor. 
Blood sampling for PK of vonoprazan and lansoprazole in plasma will be obtained at 
the timepoints specified in Section 7.1. 
SAMPLE SIZE  
A total of 40 subjects, 20 subjects per sequence group (AB, BA) provides 90% power 
to detect a difference of at least 10% in the change from baseline in pH>4 HTR on 
Day 7 between the treatment groups, assuming a common standard deviation of 17% 
and that the correlation coefficient between periods is 0.5. This sample size allows for 
4 dropouts. 
 
 


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4. ANALYSIS POPULATIONS 
4.1 
Analysis Populations 
PD Population 
All subjects who received at least one dose of the study drug and have sufficient 
postdose pH measurements and absence of major protocol violations will be included 
in the PD analysis.  
PK Population 
All subjects who comply sufficiently with the protocol and display an evaluable PK 
profile (e.g., exposure to treatment, availability of measurements and absence of major 
protocol violations) will be included in the PK analysis.  
Safety Population 
All subjects who received at least one dose of the study drug will be included in the 
safety analysis. 
4.2 
Preliminary Data and Interim Analysis 
There are no interim analyses planned for this study. 
5. TREATMENT DESCRIPTIONS 
Treatments are described as follows: 
 
Treatment 
Short Description 
(text, tables, figures, 
listings, SAS output) 
Description 
A 
Vonoprazan  
Vonoprazan (1 x 20 mg tablet) administered 
QD on Days 1 through 7 
B 
Lansoprazole 
Lansoprazole (1 x 30 mg capsule) 
administered QD on Days 1 through 7 
 


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6. PHARMACODYNAMIC ANALYSIS 
6.1 
Gastric pH Monitoring 
Gastric pH will be measured continuously over a 24-hour period at Baseline on Day -1 
(Period 1 only) and on Days 1 and 7 of Periods 1 and 2, using a pH and pressure 
sensitive probe and ambulatory pH recording system (Sleuth/ZepHrTM Software from 
Sandhill Scientific). A pH recording will be taken every 5 seconds. After each 24-hour 
recording period, the flashcard will be removed from the recorder and transferred to 
the computer. It will then be placed back to start the next 24-hour collection, as 
appropriate. Once the recording is complete for Day -1 of Period 1 and Days 1 and 7 
of Periods 1 and 2, the data will be transferred on a SAS data file and sent for 
analyses. 
On Day -2 (Period 1) the lower esophageal sphincter (LES) will be identified and the 
distance from the upper border of LES to the nares will be recorded to facilitate the 
placement of the microelectrode probe for pH monitoring. 
Prior to pH monitoring, the pH probe will be inserted nasogastrically. The 
microelectrode will record pH values over a 24-hour time frame.  
Baseline pH monitoring will start in the morning of Day -1 of Period 1 and will 
continue for approximately 24 hours. On Days 1 and 7 of Periods 1 and 2, the 
continuous pH recording session will commence 30 to 60 minutes prior to treatment 
administration (Hour 0). Gastric pH will be sampled and recorded every 5 seconds and 
will conclude at the end of the 24-hour continuous monitoring period. Start time and 
stop time will be recorded. On Day -1 of Period 1, continuous pH recording will 
follow a similar time matched (± 15 minutes) scheduled as planned for Day 1. Any 
interruptions in pH monitoring will be captured. 
6.2 
Gastric pH Pharmacodynamic Parameters 
For each 15-minute interval within a pH collection time interval, the median pH, the 
mean pH, and the standard deviation of the pH values will be calculated for each 
subject using the pH values collected every 5 seconds. Nominal times will be used 
with dosing on Days 1 and 7 of each period being time 0. 
Using the 15-minute interval median pH values, the following PD parameters will be 
assessed (Day - 1 of Period 1 only and Days 1 and 7 for both treatments/periods): 


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Table 6.1. 
Method of Determination of pH Parameters 
Parameter and Label 
Definition 
Method of Determination 
Integrated gastric 
acidity (IA): 
IA0-2 
IA0-4 
IA12-24 
IA0-24 
IA4-9 
IA9-12 
 
The acid concentration (mM) is 
calculated as 1000 x 10-pH.   
This parameter will be computed over the 
following time intervals: 
o Initial 2 hours after the start of each 
24-hour monitoring period (IA0-2); 
o Initial 4 hours after the start of each 
24-hour monitoring period (IA0-4); 
o From 12 hours after the start of each 
24-hour monitoring period (IA12-
24); 
o Overall 24-hour monitoring period 
(IA0-24). 
To measure Integrated acidity for food 
intake, Integrated acidity will also be 
computed over the following intervals: 
o From 4 hours to 9 hours after the start 
of each 24-hour monitoring period 
(IA4-9); 
o From 9 hours to 12 hours after the 
start of each 24-hour monitoring 
period (IA9-12). 
 
The IA is the time-weighted 
average of the acid concentration 
expressed as mmol×hr/L.  It is also 
the area under the acid 
concentration-time curve. The IA 
will be calculated using the linear 
trapezoidal with linear 
interpolation method. In case of 
missing data for an interval, no 
extrapolation will be used and the 
associated IA will be set to 
missing. 
Mean Gastric pH: 
pH0-2 
pH0-4 
pH12-24 
pH0-24 
pH4-9 
pH9-12 
The average gastric pH is a measure of 
the immediate effect on gastric pH and 
the duration of effect on gastric pH. 
The average gastric pH will be calculated 
over the following time intervals: 
o Initial 2 hours after the start of each 
24-hour monitoring period (pH0-2); 
o Initial 4 hours after the start of each 
24-hour monitoring period (pH0-4); 
o From 12 hours after the start of each 
24-hour monitoring period (pH12-
24); 
o Overall 24-hour monitoring period 
(pH0-24). 
To measure average gastric pH for food 
intake, gastric pH will also be computed 
over the following intervals: 
o From 4 hours to 9 hours after the start 
of each 24-hour monitoring period 
(pH4-9); 
o From 9 hours to 12 hours after the 
start of each 24-hour monitoring 
period (pH9-12). 
In case of missing data for an 
interval, no extrapolation will be 
used and the associated average 
gastric pH will be set to missing. 


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Parameter and Label 
Definition 
Method of Determination 
Time pH >4 
Calculated time that the gastric pH is >4 
over the course of the 24-hour monitoring 
period within the intervals described 
above 
Taken directly from the data 
(median values over 15-minute 
intervals) as the sum of 
intermittent times that pH > 4 
pH >4 HTR 
pH >4 holding time ratio: the percentage 
of time the gastric pH is >4 over the 
course of the 24-hour monitoring period 
within the intervals described above 
Calculated as: Time pH > 
4*100/total actual monitoring 
period time 
Time pH >5 
Calculated time that the gastric pH is >5 
over the course of the 24-hour monitoring 
period within the intervals described 
above 
Taken directly from the data 
(median values over 15-minute 
intervals) as the sum of 
intermittent times that pH > 5 
pH >5 HTR 
pH >5 holding time ratio: the percentage 
of time the gastric pH is >5 over the 
course of the 24-hour monitoring period 
within the intervals described above 
Calculated as: Time pH > 
5*100/total actual monitoring 
period time 
Time pH >6 
Calculated time that the gastric pH is >6 
over the course of the 24-hour monitoring 
period within the intervals described 
above 
Taken directly from the data 
(median values over 15-minute 
intervals) as the sum of 
intermittent times that pH > 6 
pH >6 HTR 
pH >6 holding time ratio: the percentage 
of time the gastric pH is >6 over the 
course of the 24-hour monitoring period 
within the intervals described above 
Calculated as: Time pH > 
6*100/total actual monitoring 
period time 
6.3 
Gastrin Sampling 
For all subjects, blood samples for determination of serum gastrin concentrations will 
be drawn at 0, 2, 4, 5, 9, 10, 12, 13, and 24 hours on Day -1 of Period 1 for baseline 
determination and on Days 1 and 7 of Period 1. Sampling times on Day -1 will be time 
matched to postdose sampling on Day 1 and Day 7. The samples collected at 4, 9, and 
12 hours postdose should be collected prior to starting meal/snack consumption. The 
0-hour (predose) sample on Day 1 of Period 1 will be the same as the 24-hour sample 
on Day -1; only one sample will be collected. A single gastrin sample will also be 
drawn in Period 2 at Day 1 predose. 
The 24-hour gastrin sample on Day -1 of Period 1 is to be taken approximately 
15 minutes prior to dosing on Day 1 of Period 1, and the 24-hour postdose gastrin 
sample on Day 1 and Day 7 of Period 1 is to be taken approximately 15 minutes prior 
to pH probe removal on Day 2 and Day 8 of Period 1, respectively. 


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6.4 
Gastrin Pharmacodynamic Parameters 
PD parameters for serum gastrin will be calculated as follows: 
Gastrin 
AUC0-24:  
The area under the curve over the 24-hour postdose period 
(AUC0-24) for Day -1 of Period 1 (Baseline) and Days 1 and 7 of 
Period 1, as calculated by the linear trapezoidal method. 
6.5 
PD Data Summarization and Presentation 
SAS® software Version 9.4 will be used for all PD data presentation and 
summarization including statistical analyses, summary tables, and data listings. 
Descriptive statistics of pH PD parameters, gastrin concentrations, and gastrin PD 
parameters will be generated using SAS®. 
For each 15-minute interval within a pH collection time interval, the median pH, the 
mean pH, and the standard deviation of the pH values will be calculated and listed for 
each subject. 
Summary statistics, including sample size (n), arithmetic mean (mean), standard 
deviation (SD), coefficient of variation (CV%), median, minimum, and maximum will 
be calculated for all gastrin serum concentrations.  
Summary statistics, including n, mean, SD, CV%, median, minimum, maximum, 
geometric mean (Geom Mean), and geometric CV% (Geom CV%) will be calculated 
for all PD parameters (for gastric pH and gastrin). Where a PD parameter cannot be 
reported, the parameter record will display “NA” for not available. Means will only be 
calculated based on the available subject data (i.e., if a parameter is “NA”, that result 
will be excluded from the mean calculation). 
Mean gastric pH (based on median pH values of each 15-minute interval) over time on 
Day 7 will be presented graphically for vonoprazan and lansoprazole on one graph; 
similar graphs will also be presented for Days -1 and 1. 
Mean gastric pH (based on median pH values of each 15-minute interval) versus time 
for vonoprazan will be presented for baseline, Day 1 and Day 7 on the same graph; a 
similar graph will be presented for lansoprazole. 
In addition, individual plots for gastric pH (based on median pH values of each 
15-minute interval) over time will be presented for each subject including Day -1 and 
Day 1 and Day 7 for both periods. 


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6.6 
Statistical Analysis of PD Parameters  
6.6.1 Analysis of Variance 
For gastric pH >4, pH >5, and pH >6 HTRs and mean gastric pH on Days 1 and 7, the 
point estimate of the difference in changes from baseline between the study 
medications (vonoprazan - lansoprazole) will be calculated along with the 2-sided 
95% CI, using an ANOVA with treatment, sequence, and period as fixed effects and 
subject within sequence as a random effect. The data for these endpoints will be 
evaluated for gross departures from normality and transformations may be 
considered.  
The statistical analyses will be performed using the following SAS® code: 
Proc Mixed data=< >; 
By day; 
Class subject sequence period treatment; 
Model parameter = sequence period treatment/ddfm=KR; 
Random subject(sequence); 
Estimate “vonoprazan vs lansoprazole” treatment 1 -1/CL alpha=0.05; 
LSMeans treatment; 
Run; 
 
Gastric pH >4, pH >5, and pH >6 HTRs, mean gastric pH, and their changes from 
baseline will be summarized with descriptive statistics and 2-sided 95% CIs for each 
study treatment. 
7. PHARMACOKINETIC ANALYSIS 
7.1 
Measurements and Collection Schedule 
Blood samples for the determination of plasma vonoprazan and lansoprazole 
concentrations will be obtained on Days 1 and 7 of Periods 1 and 2 at the following 
time points: predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 9, 10, 12, 13, 16, and 24 
hours postdose. 
All concentration data will be included in the calculation of the individual PK 
parameters, the individual concentration-time plots (based on actual sample times), 
and in the mean concentration-time plots (based on nominal sample times). However, 


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if there are any significant deviations from nominal sample times, some concentration 
data may be excluded from mean concentration-time plots and/or additional 
concentration-time plots of the mean data may be provided. All deviations and 
excluded data will be provided and discussed in the CSR. 
7.2 
Bioanalytical Methods 
The analyses of vonoprazan and lansoprazole in plasma samples will be performed at 
 and 
 respectively 
using validated liquid chromatography-mass spectrometry/mass spectrometry 
methods. The analytical ranges (lower limit of quantitation [LLOQ] – upper limit of 
quantitation [ULOQ]) for vonoprazan and lansoprazole are expected to be 0.1 – 
100 µg/mL and 2.00 – 2000 ng/mL, respectively.  
Samples from all subjects will be assayed even if the subjects do not complete the 
study. The Bioanalytical Reports for the determinations of vonoprazan and 
lansoprazole will be included in the CSR. 
 


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7.3 
Investigational Product and PK Analyte Information 
7.3.1 Vonoprazan 
The chemical structure of vonoprazan fumarate is shown below. 
 
Chemical name: 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-
methylmethanamine monofumarate 
Molecular formula: C17H16FN3O2S•C4H4O4 
Molecular weight (salt): 461.46 
Molecular weight (free base): 345.39 
Dose correction for the administered salt formulation will be made for the calculation 
of dose-dependent parameters if free base is measured, while no correction is needed if 
the salt is measured. 
Dosecorrected = (MWfreebase/MWsaltform) x Doseadministered  
7.3.2 Lansoprazole 
The chemical structure of lansoprazole is shown below. 
 
Chemical name: 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]- 
benzimidazole  
Molecular formula: C16H14F3N3O2S 
Molecular weight: 369.37 


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7.4 
Pharmacokinetic Concentrations 
Plasma concentrations of vonoprazan and lansoprazole as determined at the collection 
times and per the bioanalytical methods described in Section 7.1 and Section 7.2, 
respectively, will be used for the calculation of the plasma vonoprazan and 
lansoprazole PK parameters. 
7.5 
Non-Compartmental Pharmacokinetic Analysis and Parameter Calculation 
7.5.1 Plasma Pharmacokinetic Parameters  
The appropriate non-compartmental PK parameters will be calculated from the plasma 
vonoprazan and lansoprazole concentration-time data using Phoenix® WinNonlin® 
Version 8.1 or higher. Actual sample times will be used in the calculations of the PK 
parameters. The calculation of the actual time for vonoprazan and lansoprazole will be 
in respect to the start of the respective dose administration time. All PK parameters 
included in the protocol are listed in Table 7.1. 
Table 7.1. Noncompartmental Pharmacokinetic Parameters to be Calculated 
Day 1 
Parameter  
Definition 
Method of Determination 
AUC0-t: 
 
The area under the 
concentration time curve, 
from time 0 to the last 
observed non-zero 
concentration 
Calculated using the Linear Trapezoidal 
with Linear Interpolation Method  
AUC0-24: 
The area under the 
concentration time curve, 
from time 0 to the 24hour 
time point 
Calculated using the Linear Trapezoidal 
with Linear Interpolation Method  
AUC0-inf: 
The area under the 
concentration time curve from 
time 0 extrapolated to infinity 
AUC0-inf = AUC0-t + (Clast/kel) 
where Clast is the last observed/measured 
concentration 
Cmax: 
The maximum observed 
concentration 
Taken directly from bioanalytical data 
Tmax: 
The time to reach Cmax 
Taken from clinical database as the 
difference in the time of administration and 
the time of the blood draw which is 
associated with the Cmax 
If the maximum value occurs at more than 
one time point, Tmax is defined as the first 
time point with this value. 


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Parameter  
Definition 
Method of Determination 
Kel: 
Apparent first-order terminal 
elimination rate constant 
calculated from a semi-log 
plot of the plasma 
concentration versus time 
curve 
Calculated by linear least-squares regression 
analysis using the maximum number of 
points in the terminal log-linear phase (e.g., 
three or more non-zero plasma 
concentrations excluding Cmax) 
t½: 
Apparent first-order terminal 
elimination half-life 
Calculated as 0.693/Kel 
CL/F 
Apparent total plasma 
clearance after oral 
(extravascular) administration  
Calculated as Dose/AUC0-inf 
Vz/F: 
Apparent volume of 
distribution during the 
terminal elimination phase 
after oral (extravascular) 
administration 
Calculated as Dose/(AUC0-inf x Kel) 
Day 7 
Parameter  
Definition 
Method of Determination 
AUCtau: 
 
The area under the 
concentration-time curve 
during a dosing interval (tau) 
at steady state 
Calculated using the Linear Trapezoidal 
with Linear Interpolation Method  
Cmax,ss: 
The maximum observed 
concentration at steady state 
Taken directly from bioanalytical data 
Cavg: 
Average concentration at 
steady state 
Ratio of AUCtau to the dosing interval, tau 
Tmax,ss: 
The time to reach Cmax at 
steady state 
Taken from clinical database as the 
difference in the time of administration and 
the time of the blood draw which is 
associated with the Cmax,ss 
RA,AUC 
AUC accumulation ratio  
 
Calculated at steady-state, as:  
RA,AUC = AUCtau/AUC0-24 
Note: AUC0-24 is from Day 1 dosing. 
RA,Cmax 
Cmax accumulation ratio  
 
Calculated at steady-state, as: 
RA,Cmax = Cmax,ss/Cmax 
Note : Cmax is from Day 1 dosing 
Note: Additionally, Kel may be calculated for Day 7. 
For the calculation of the PK parameters, plasma concentrations below the limit of 
quantification (BLQ) prior to the first quantifiable concentration will be set to 0 and 
plasma concentrations BLQ after the first quantifiable concentration will be treated as 
missing. 


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The Kel will be determined using linear regressions composed of least 3 data points. 
The Kel will not be assigned if 1) the terminal elimination phase is not apparent, 2) if 
Tmax is one of the 3 last data points, or 3) if the R2 value is less than 0.8. In cases 
where the Kel interval is not assigned, the values of t½, AUC0-inf, CL/F, and Vz/F are 
considered not calculable and will not be reported. Wherever the resulting T½ is more 
than half as long as the sampling interval, the Kel values and associated parameters 
(t½, AUC0-inf, CL/F, and Vz/F) may not be presented as judged appropriate and in 
accordance with Celerion SOPs. 
No PK parameters will be calculated for subjects with 2 or fewer consecutive time 
points with detectable concentrations. 
AUC0-24 will be calculated for plasma vonoprazan and lansoprazole concentration 
versus time profiles containing measurable concentrations up to 24 hours postdose. 
If the last measurable concentration occurs prior to 24 hours postdose, or the 
concentration at 24 hours is missing, the Kel may be used to extrapolate a 
concentration value at 24 hours postdose in order to calculate AUC0-24h. If the Kel is 
not reportable, but the actual time of the 24-hour sample is within 1% of the nominal 
sample time and the sample is not missing or BLQ, the AUC0-24h will be calculated 
based on the area under the curve from 0 through the actual time of the 24-hour 
sample. Otherwise, AUC0-24h will not be reported. 
7.6 
PK Data Summarization and Presentation 
SAS® software Version 9.4 will be used for all data presentation and summarization 
including statistical analyses, summary tables, graphs, and data listings. Plasma 
concentrations and PK parameters descriptive statistics will be generated using SAS®. 
Plasma vonoprazan and lansoprazole concentrations will be presented with the same 
precision as received from the bioanalytical laboratory based on number of decimal 
places or significant figures. They will be listed by nominal sample time for each 
subject, tabulated by treatment, and summarized using descriptive statistics, including 
sample size (n), arithmetic mean (Mean), standard deviation (SD), coefficient of 
variation (CV%), standard error of the mean (SEM), minimum, maximum and median. 
Concentrations from excluded subjects will be included in the plasma concentration 
tables, but will be excluded from the summary statistics and noted as such in the 
tables. All BLQ values will be presented as “BLQ” in the plasma concentration table 
listings and footnoted accordingly. 
Parameter values for Cmax, Cmax,ss, and Cavg will be presented with the same 
precision as per the bioanalytical data. Exposure parameters (i.e., AUC0-t, AUC0-24, 
AUC0-inf, and AUCtau) will be presented with, at maximum, the precision of the 
bioanalytical data, and, at minimum, 3 significant figures (will be determined by the 
pharmacokineticist). Values for time-based parameters (i.e., Tmax, Tmax,ss, and t½) 
will be presented with 2 decimals. All other PK parameters will be presented with 3 
significant figures.  


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PK parameters will be listed by subject, tabulated by treatment, and summarized 
using summary statistics (n, mean, SD, CV%, SEM, minimum, median, and 
maximum). In addition, geometric mean (Geom Mean) and geometric mean 
coefficient of variation (Geom CV%) will be calculated for AUC, Cmax, and Cavg 
parameters. Excluded subjects will be included in the PK parameter tables and 
listings, but will be excluded from the summary statistics and noted as such in the 
tables.  
The level of precision for the summary statistics on plasma concentrations and PK 
parameters will be presented as follows: 
• n: no decimal; 
• Minimum, Maximum: same precision as in individual values 
• Mean, Median, Geom Mean: one more level of precision than the individual 
values; 
• SD, SEM: one more level of precision than the Mean; 
• CV% and Geom CV%: one decimal place. 
 
The following graphical presentations will be made for vonoprazan and lansoprazole: 
• Linear and semi-log scale of mean plasma concentrations versus nominal time 
points with all treatments plotted in the same figure. Linear mean plots will be 
presented with and without ± SD. 
• Individual plasma concentration versus time profiles on linear and semi-log 
scales with all treatments plotted in the same figure. 
• Individual plasma concentration versus time profiles on semi-log scale for 
each treatment showing the points and regression line used to determine Kel. 
8. SAFETY  
All safety endpoints will be reported for the observed data by treatment group for the 
Safety Population. No imputation will be made for the missing safety data. All case 
report form (CRF) safety data will be summarized by treatment group and listed by 
subject and chronologically by assessment time points including rechecks, 
unscheduled assessments, and early termination visits.  
Continuous variables will be summarized using n, arithmetic mean, SD, minimum, 
median, and maximum for each treatment. Categorical variables will be summarized 
by frequencies and percentage by treatment group.   
The level of precision will be presented as follows: minimum/maximum in the same 
precision as in the database, mean/median in one more precision level than 
minimum/maximum, SD in one more precision level than mean/median, and n will be 
presented as an integer. 


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8.1 
Subject Disposition 
Subject disposition will be summarized by number of subjects enrolled, completed, 
and discontinued the study with discontinuation reasons by treatment sequence and 
overall. Subjects’ dosing status will also be tabulated by treatment and presented with 
discontinuation reason and date of discontinuation. The total number of subjects 
exposed to each treatment will also be displayed. 
In addition, the number and percentage of subjects who signed the informed consent 
form and who screen failed will be presented along with the reason for screen failure. 
8.2 
Demographics 
Descriptive statistics will be calculated for continuous variables (age, weight, height, 
and body mass index [BMI]) by treatment sequence and overall. Age will be derived 
by subtracting the year of birth from the year of informed consent.  If year of informed 
consent – year of birth is less than the protocol minimum age then the age derivation 
will be year of informed consent – year of birth +1.    
Frequency counts will be provided for categorical variables (race, ethnicity, and sex) 
by treatment sequence and overall.  
8.3 
Adverse Events 
All AEs occurring during this clinical trial will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA®), Version 23.0.  
All AEs captured in the database will be listed in by-subject data listings including 
verbatim term, MedDRA preferred term, treatment, severity, relationship to study 
medication, action taken with study drug, and outcome; however, only treatment-
emergent AEs (TEAEs) will be summarized.  
A TEAE is defined as an AE that is starting or worsening at the time of or after study 
drug administration. Each TEAE will be attributed to a treatment based on the onset 
date and time of the AE.  
If the onset time of an AE is missing and the onset date is the same as the treatment 
dosing date, then the AE will be considered treatment emergent for the current 
treatment. If onset time of an AE is missing and the onset date does not fall on a 
dosing date, then the AE will be considered treatment emergent for the last treatment 
administered. If the onset date of an AE is missing, then the AE will be considered 
treatment emergent to the treatment of that period. 
TEAEs will be tabulated by System Organ Class (SOC) and Preferred Term. Summary 
tables will include number (%) of subjects reporting the AEs by treatment and overall. 
The number of AEs will be tabulated in a similar manner. Tables which tabulate the 


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number of TEAEs by severity and relationship to study treatment will also be 
included. 
8.4 
Clinical Laboratory Tests (Serum Chemistry, Hematology, and Urinalysis) 
Clinical laboratory data will be performed at screening, at Check-in of each period, 
and Day 8 of Period 2 or upon early termination. 
Out-of-normal range flags will be recorded as follows: high (H) and low (L) for 
numerical results and did-not-match (*) for categorical results. Out-of-range values 
and corresponding recheck results will be listed.  
For all numeric laboratory values, descriptive statistics will be presented for each 
laboratory test by assessment time point and randomized treatment sequence. Change 
from baseline will be summarized in a similar manner. Baseline is defined as the latest 
assessments prior to the first dose at Period 1 which may include unscheduled or 
recheck results. This will typically be the result collected at Day -2 of Period 1. 
Postdose unscheduled events, rechecks and early termination results will not be 
included in summaries. 
For each laboratory test, a shift table will be developed to compare the frequency of 
the results at baseline (above normal, normal, or below normal) with the respective 
postdose results. For urinalysis tests, the categories are normal and outside normal.  
8.5 
Vital Signs  
Vital signs (temperature, heart rate and blood pressure) will be measured at screening, 
check in, approximately 1 hour before and after pH probe placement on Day -1 (Period 
1 only) and on Days 1 and 7 of Periods 1 and 2, and approximately 1 hour prior to 
each dose on Days 2 through 6 of Periods 1 and 2. The vital signs assessment 
following removal of the pH probe used for monitoring on Day -1 of Period 1 will be 
the same as the vital signs assessment prior to dosing on Day 1 of Period 1. 
Respiration rate will be collected at screening and at the end of Period 2 or prior to 
early termination from the study only. 
Descriptive statistics will be presented for each vital sign measurement by assessment 
time point and treatment. Change from baseline will be summarized in a similar 
manner. Baseline is defined as the result closest and prior to the first dose at each 
period which may include unscheduled or recheck results. This will typically be the 
result collected at Day 1 predose of each period. Postdose unscheduled events, 
rechecks and early termination results will not be included in summaries. 


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8.6 
Electrocardiogram  
Safety ECGs (heart rate, PR, QRS, QT, QTcF [Fridericia correction], and RR) will be 
measured at screening, at Check-in of each period, and Day 8 of Period 2 or upon 
early termination. 
Descriptive statistics will be presented for each ECG parameter by assessment time 
point and randomized treatment sequence. Change from baseline will be summarized 
in a similar manner. Baseline is defined as the result closest and prior to the first dose 
at Period 1 which may include unscheduled or recheck results. This will typically be 
the result collected at Day -2 of Period 1. Postdose unscheduled events, rechecks and 
early termination results will not be included in summaries. 
QTcF values that are > 450 msec and increase from baseline > 30 msec will be flagged 
in the data listing.  
8.7 
Concomitant Medications and Medical History 
All concomitant medications recorded during the study will be coded with the WHO 
Dictionary 01SEP2020-b3 and listed. Medical history will be listed. 
8.8 
Physical Examination 
Physical examination will be performed at screening and Day 8 of Period 2 or upon 
early termination. Symptom-driven physical examinations may be performed at other 
times, at the PI’s or designee’s discretion. Abnormal findings will be reported as 
medical history or adverse events. All data found in the CRF will be listed.  
9. SUMMARY OF CHANGES FROM PROTOCOL-PLANNED ANALYSIS 
The analyses described in this SAP are aligned with those analyses described in the 
protocol.