Clinical trial NCT05319912
Conditions: Healthy
Keywords: ALXN1840 WTX101 Omeprazole
Sponsor: Alexion Pharmaceuticals, Inc.
Start date: 2014-04-07; Completion date: 2014-05-29
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This was single-center, open-label, randomized, 3-period, 3-treatment, 6-sequence crossover study evaluating the PK of single doses of WTX101 in healthy participants based on the measurement of plasma total Mo concentration.

Detailed description:

Arms: arm 1: Participants received each treatment on 1 occasion:

Period 1 (Treatment A): ALXN1840 tablets following an overnight fast. Period 2 (Treatment B): ALXN1840 tablets after the start of a high-fat breakfast, preceded by an overnight fast. Period 3 (Treatment C): Omeprazole once daily in the morning of Days -5 to -1 following an overnight fast, omeprazole at Hour -1 on Day 1 following an overnight fast, and ALXN1840 non-coated capsules at Hour 0 on Day 1.

There was a washout period of at least 14 days between each ALXN1840 dosing. arm 2: Participants received each treatment on 1 occasion:

Period 1 (Treatment A): ALXN1840 tablets following an overnight fast. Period 2 (Treatment C): Omeprazole once daily in the morning of Days -5 to -1 following an overnight fast, omeprazole at Hour -1 on Day 1 following an overnight fast, and ALXN1840 non-coated capsules at Hour 0 on Day 1. Period 3 (Treatment B): ALXN1840 tablets after the start of a high-fat breakfast, preceded by an overnight fast.

There was a washout period of at least 14 days between each ALXN1840 dosing. arm 3: Participants received each treatment on 1 occasion:

Period 1 (Treatment B): ALXN1840 tablets after the start of a high-fat breakfast, preceded by an overnight fast. Period 2 (Treatment A): ALXN1840 tablets following an overnight fast. Period 3 (Treatment C): Omeprazole once daily in the morning of Days -5 to -1 following an overnight fast, omeprazole at Hour -1 on Day 1 following an overnight fast, and ALXN1840 non-coated capsules at Hour 0 on Day 1.

There was a washout period of at least 14 days between each ALXN1840 dosing. arm 4: Participants received each treatment on 1 occasion:

Period 1 (Treatment B): ALXN1840 tablets after the start of a high-fat breakfast, preceded by an overnight fast. Period 2 (Treatment C): Omeprazole once daily in the morning of Days -5 to -1 following an overnight fast, omeprazole at Hour -1 on Day 1 following an overnight fast, and ALXN1840 non-coated capsules at Hour 0 on Day 1. Period 3 (Treatment A): ALXN1840 tablets following an overnight fast.

There was a washout period of at least 14 days between each ALXN1840 dosing. arm 5: Participants received each treatment on 1 occasion:

Period 1 (Treatment C): Omeprazole once daily in the morning of Days -5 to -1 following an overnight fast, omeprazole at Hour -1 on Day 1 following an overnight fast, and ALXN1840 non-coated capsules at Hour 0 on Day 1. Period 2 (Treatment A): ALXN1840 tablets following an overnight fast. Period 3 (Treatment B): ALXN1840 tablets after the start of a high-fat breakfast, preceded by an overnight fast.

There was a washout period of at least 14 days between each ALXN1840 dosing. arm 6: Participants received each treatment on 1 occasion:

Period 1 (Treatment C): Omeprazole once daily in the morning of Days -5 to -1 following an overnight fast, omeprazole at Hour -1 on Day 1 following an overnight fast, and ALXN1840 non-coated capsules at Hour 0 on Day 1. Period 2 (Treatment B): ALXN1840 tablets after the start of a high-fat breakfast, preceded by an overnight fast. Period 3 (Treatment A): ALXN1840 tablets following an overnight fast.

There was a washout period of at least 14 days between each ALXN1840 dosing.
Interventions: intervention 1: ALXN1840 Enteric-coated Tablet intervention 2: ALXN1840 Non-coated Capsule intervention 3: Omeprazole
Intervention descriptions: intervention 1: ALXN1840 (60 milligrams) was administered orally as EC tablets at Hour 0 on Day 1. intervention 2: ALXN1840 (60 milligrams) was administered orally as non-coated capsules at Hour 0 on Day 1. intervention 3: Omeprazole (20 milligrams) was administered orally as a delayed-release capsule in the morning of Days -5 to -1 and at Hour -1 on Day 1.

Protocol documents:
Prot_000.pdf: 
A Phase 1, Single-Center, Randomized, 3-Period Crossover 
Study in Healthy Volunteers to Evaluate the Absorption of 
WTX101 After Single Dose Administration of an Enteric 
Coated Formulation with and without food and a Non-
Coated Formulation Coadministered with a Proton Pump 
Inhibitor without Food 
Unique Protocol ID: 
NCT Number: 
Date of Protocol:  
WTX101-102 
NCT05319912 
24 February 2014 


 
16. 
Appendices 
16.1 
Study Information 
16.1.1 
Protocol and Protocol Amendments 
 
CA13895, 16.1.1 Protocol and Protocol Amendments
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CA13895, 16.1.1 Protocol and Protocol Amendments
1


 
 
 
 
 
 
 
 
 
Celerion Project No.:  CA13895 
 
Sponsor Project No.:  WTX101-102 
 
US IND No.:  119,006 
 
 
 
A Phase 1, Single-Center, Randomized, 3-Period Crossover Study in Healthy 
Volunteers to Evaluate the Absorption of WTX101 After Single Dose Administration of 
an Enteric Coated Formulation with and without food and a Non-Coated Formulation 
Coadministered with a Proton Pump Inhibitor without Food 
 
 
 
 
 
 
 
 
 
 
 
 
 
GCP Statement 
This study is to be performed in full compliance with the protocol, Good Clinical Practices (GCP), and 
applicable regulatory requirements. All required study documentation will be archived as required by 
regulatory authorities. 
 
Confidentiality Statement 
All information concerning the Investigational Product supplied by Wilson Therapeutics in connection 
with this study, and not previously published, is considered confidential and proprietary information. 
This information includes the Investigator’s Brochure, protocol and case report forms. This 
confidential information shall remain the sole property of Wilson Therapeutics, shall not be disclosed 
to others without prior written consent from Wilson Therapeutics, and shall not be used except in the 
performance of this study. 
The information developed during the conduct of this clinical study is also considered confidential and 
will be used by Wilson Therapeutics in connection with the development of the Investigational 
Product.  This information may be disclosed as deemed necessary by Wilson Therapeutics. 
The Investigator is obliged to provide Wilson Therapeutics with complete test results and all data 
derived from this study. Only Wilson Therapeutics may make information obtained during this study 
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Celerion Project No.:  CA13895 
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US IND No.: 119,006 
 
 
WTX101-102_CA13895_FINAL_Clinical Study Protocol_25 Feb 2014 
 
available to the physicians and to the regulatory agencies, except as required by regulation. 
1 
PROTOCOL REVISION HISTORY 
 
 
24 Feb 2014 By 
 
Final Version  
 
 
CA13895, 16.1.1 Protocol and Protocol Amendments
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EC Drug Absorption and Food Effect Study Protocol 
Celerion Project No.:  CA13895 
Wilson Therapeutics 
 
US IND No.: 119,006 
 
 
WTX101-102_CA13895_FINAL_Clinical Study Protocol_25 Feb 2014 
 
3 
ADDITIONAL KEY CONTACTS FOR THE STUDY 
 
Protocol Author 
 
 to 
Wilson Therapeutics AB 
Västra Trädgårdsgatan 15 
S-11153 Stockholm, Sweden 
Tel:  
 
E-mail:  
 
 
Clinical Contact 
 
Wilson Therapeutics AB 
Västra Trädgårdsgatan 15 
S-11153 Stockholm, Sweden 
Tel:  
 
Fax:  
 
E-mail:  
 
 
Certified Clinical Laboratory 
Celerion 
621 Rose Street 
Lincoln, Nebraska  68502, USA 
Contact:  
 
Tel.:  
 
Fax:  
 
 
Certified Bioanalytical Laboratory 
 
 
 
QPS Netherlands B.V. 
Petrus Campersingel 123 
NL-9713 AG Groningen 
The Netherlands 
Telephone: 
 
FAX: 
 
Email:
 
 
Pharmacokinetic and Statistical Analyses 
 
 
Kramer Consulting LLC 
14313 Outpost Way 
North Potomac, 
Maryland  20878-4352, USA 
 
 
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Celerion Project No.:  CA13895 
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US IND No.: 119,006 
 
 
WTX101-102_CA13895_FINAL_Clinical Study Protocol_25 Feb 2014 
 
4 
TABLE OF CONTENTS 
1 
PROTOCOL REVISION HISTORY ................................................................................ 2 
2 
PRINCIPAL INVESTIGATOR AND SPONSOR – SIGNATORIES ................................. 3 
3 
ADDITIONAL KEY CONTACTS FOR THE STUDY ....................................................... 4 
4 
TABLE OF CONTENTS ................................................................................................. 5 
5 
SYNOPSIS ..................................................................................................................... 8 
6 
STUDY EVENTS FLOW CHART ..................................................................................12 
7 
ABBREVIATIONS .........................................................................................................14 
8 
BACKGROUND AND RATIONALE ..............................................................................17 
8.1 Background ...........................................................................................................17 
8.1.1 
Non-clinical Safety and Toxicology Summary and Conclusion .................18 
8.1.2 
Summary of Safety in Oncology Studies with Bis-Choline 
Tetrathiomolybdate ..................................................................................19 
8.1.3 
Summary of Safety in Wilson Disease Studies with Ammonium 
Tetrathiomolybdate ..................................................................................20 
8.2 Rationale ...............................................................................................................20 
8.2.1 
Rationale for this Study and Study Design ...............................................20 
8.2.2 
Rationale for the Dose Selection .............................................................20 
8.2.3 
Rationale for Endpoints ...........................................................................21 
9 
STUDY OBJECTIVES, AND ENDPOINTS ...................................................................22 
9.1 Study Objectives ...................................................................................................22 
9.2 Study Endpoints ....................................................................................................22 
10 INVESTIGATIONAL PLAN ...........................................................................................22 
10.1 Overall Study Design and Plan..............................................................................22 
10.1.1 
Confinement and Return Visits ................................................................25 
10.1.2 
Study Duration .........................................................................................25 
10.2 Risks and/or Benefits to Subjects ..........................................................................25 
10.3 Selection of Study Population ...............................................................................26 
10.3.1 
Inclusion Criteria ......................................................................................26 
10.3.2 
Exclusion Criteria .....................................................................................27 
10.3.3 
Stopping Rules ........................................................................................28 
10.3.4 
Removal of Subjects from the Study ........................................................29 
10.4 Study Restrictions .................................................................................................29 
10.4.1 
Prohibitions and Concomitant Therapy ....................................................29 
10.4.2 
Meals .......................................................................................................30 
10.4.3 
Activity .....................................................................................................31 
10.5 Treatments ............................................................................................................31 
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Celerion Project No.:  CA13895 
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US IND No.: 119,006 
 
 
WTX101-102_CA13895_FINAL_Clinical Study Protocol_25 Feb 2014 
 
10.5.1 
Treatments Administered .........................................................................31 
10.5.2 
Method of Randomizing Subjects to Treatment Groups ...........................32 
10.5.3 
Blinding ...................................................................................................33 
10.5.4 
Treatment Compliance ............................................................................33 
10.5.5 
Diary ........................................................................................................33 
11 STUDY PROCEDURES ................................................................................................34 
11.1 Safety Assessment ...............................................................................................34 
11.1.1 
Screening ................................................................................................34 
11.1.2 
Physical Examination ..............................................................................34 
11.1.3 
Vital Signs ...............................................................................................34 
11.1.4 
ECG Monitoring .......................................................................................35 
11.1.5 
Blood Sampling for Safety and Pharmacokinetic Analyses ......................36 
11.1.5.1 Safety Laboratory Tests .............................................................36 
11.1.5.2 Pharmacokinetic Assessment Sampling and Processing ...........37 
11.1.5.3 Blood Volume Drawn for Study Assessments ............................38 
11.1.6 
Adverse Events .......................................................................................38 
11.1.6.1 Adverse Event Definition............................................................38 
11.1.6.2 Monitoring ..................................................................................38 
11.1.6.3 Reporting ...................................................................................39 
11.1.6.4 Reporting of Pregnancy and Lactation to the Sponsor ...............40 
11.1.6.5 Serious Adverse Event ..............................................................40 
12 DATA ANALYSIS .........................................................................................................41 
12.1 Pharmacokinetic Parameters ................................................................................41 
12.2 Statistical Methods ................................................................................................41 
12.2.1 
Determination of Sample Size .................................................................42 
12.2.2 
Descriptive Statistics ...............................................................................42 
12.2.3 
Analysis of Variance ................................................................................42 
12.2.4 
Ratios and Confidence Intervals ..............................................................42 
12.3 Safety Evaluation ..................................................................................................43 
13 STUDY ADMINISTRATION ..........................................................................................44 
13.1 Ethics ....................................................................................................................44 
13.1.1 
Institutional Review Board .......................................................................44 
13.1.2 
Ethical Conduct of the Study ...................................................................44 
13.1.3 
Subject Information and Consent .............................................................44 
13.2 Termination of the Study .......................................................................................44 
13.3 Study Documentation and Recordkeeping ............................................................45 
13.3.1 
Source Documents ..................................................................................45 
13.3.2 
Data Monitoring and Handling .................................................................45 
13.4 Data Quality Assurance.........................................................................................45 
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EC Drug Absorption and Food Effect Study Protocol 
Celerion Project No.:  CA13895 
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US IND No.: 119,006 
 
 
WTX101-102_CA13895_FINAL_Clinical Study Protocol_25 Feb 2014 
 
13.5 Direct Access to Source Data/Documents .............................................................46 
13.6 Drug Supplies, Packaging and Labeling ................................................................46 
13.6 Study Drug Handling, Storage and Return/Disposal ..............................................47 
13.7 Data Handling and Record Keeping ......................................................................48 
13.8 Training of Staff .....................................................................................................48 
13.9 Report Format .......................................................................................................48 
13.10 Publication Policy ...............................................................................................48 
14 REFERENCES ..............................................................................................................49 
 
 LIST OF FIGURES 
Figure 1 Study Diagram .................................................................................................23 
 
LIST OF TABLES 
Table 1 Blood Volume during the Study .........................................................................38 
 
 
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Sponsor Project No.: WTX101-102 
EC Drug Absorption and Food Effect Study Protocol 
Celerion Project No.:  CA13895 
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US IND No.: 119,006 
 
 
WTX101-102_CA13895_FINAL_Clinical Study Protocol_25 Feb 2014 
 
5 
SYNOPSIS 
Compound: 
WTX101 
Clinical Indication: 
Wilson Disease (WD) 
Study Phase and Type: 
Phase 1 – Drug absorption and food-effect  
Study Objectives: 
The primary objectives of the study are to evaluate: 
• The effect of dosing with an Enteric coated (EC) tablet 
versus dosing with the current non-coated capsule 
administered with a proton pump inhibitor (PPI; 
omeprazole) under fasting conditions on the absorption 
of WTX101. 
• The effect of dosing an EC tablet with and without food 
on the absorption of WTX101  
• The safety and tolerability of WTX101. 
 
Summary of Study 
Design: 
This will be a single-center, open-label, randomized, 3-period, 
3-treatment, 6-sequence crossover study evaluating the 
absorption of WTX101 after single doses in healthy subjects 
based on the measurement of plasma total molybdenum (Mo). 
This study consists of a screening phase, three periods with 
similar procedures, and an end-of-study (EOS) visit. Screening 
of subjects will occur within 28 days prior to the first WTX101 
dose. 
Subjects randomized to receive PPI in Period 1 (Treatment C) 
will report to the Clinical Research Unit (CRU) on Day -5, i.e. 5 
days prior to first dosing with WTX101, to receive a morning 
dose of omeprazole under fasting conditions. These subjects 
will be given a container with omeprazole doses and will 
continue once daily (QD) administration of omeprazole under 
fasting conditions on an outpatient basis, until their return to 
the CRU for check-in on Day -1. To ensure that the planned 
number of subjects are dosed with WTX101 on Day 1 of Period 
1, stand-by subjects will also receive QD doses of omeprazole, 
as described above. Should any subject withdraw from the 
study after omeprazole administration, but before receiving 
WTX101 in Period 1, they will be replaced with a stand-by 
subject. 
Subjects randomized to receive PPI in Periods 2 or 3 will 
receive the container with omeprazole doses prior to discharge 
from the CRU after the 192-hour post-dose procedures in 
Period 1 or Period 2, as appropriate. These subjects will initiate 
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Celerion Project No.:  CA13895 
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US IND No.: 119,006 
 
 
WTX101-102_CA13895_FINAL_Clinical Study Protocol_25 Feb 2014 
 
QD administration of omeprazole under fasting conditions at 
home the following day and continue until their return to the 
CRU for their next admission. 
In each of the 3 periods, all subjects (Treatments A, B, and C) 
will be admitted to the CRU on Day -1, and will receive 
WTX101 EC tablets alone under fasting conditions (Treatment 
A); WTX101 EC tablets alone under fed conditions (Treatment 
B); or, omeprazole under fasting conditions followed by 
WTX101 non-coated capsules under fasting conditions 
(Treatment C). Pharmacokinetic (PK) sampling (for the 
measurement of plasma concentrations of total elemental 
Molybdenum (Mo))  will be obtained at the following timepoints 
while subjects remain in the CRU:  Time 0 (within 1 hour 
predose), and then 1, 2, 3, 3.5, 4, 4.5, 5, 6, 7, 7.5, 8, 8.5, 9, 
9.5, 10, 12, 14, 16, 24, 36, and 48 hours postdose. Subjects 
will be discharged on Day 3 following the 48 hours postdose 
procedures, unless medically necessary to extend confinement 
to 72 hours.  
Subjects will be required to return to the CRU for outpatient  
visits on 6 consecutive days (Days 4, 5, 6, 7, 8 and 9) in each 
period, for subsequent PK sampling and procedures at: 72, 96, 
120, 144, 168, and 192 hours postdose. 
The exact time points for collection of PK samples may be 
amended following evaluation of the data from the ongoing 
Study WTX101-101. If this is required it will be confirmed prior 
to study start. However, the total volume of blood taken for PK 
sample analysis will not be increased from that stated in 
Section 11.1.5.3 
The washout between WTX101 doses in each period will be at 
least 14 days. 
Subjects will return to the CRU 14 days (+/-2 days) after the 
final study medication administration for an EOS visit with 
follow-up procedures, and to determine if any adverse event 
(AE) has occurred since the last study visit. Subjects who 
terminate the study early should be seen and assessed by an 
Investigator, whenever possible, to undergo the procedures 
associated with the EOS visit. 
Safety will be monitored throughout the study. 
Study Duration: 
Subjects who complete the study may be involved in the study 
for up to 48 days excluding screening (Day -5 of period one to 
the EOS visit). The study has a screening phase (Day -28 to 
Day -5 of Period 1); three study periods (Periods 1, 2, and 3 
comprised of Day -5 to Day 9); and, an EOS visit 14 days (+/- 2 
days) following the final administration of WTX101. Each 
period will be separated by a washout of at least 14 days 
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Celerion Project No.:  CA13895 
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US IND No.: 119,006 
 
 
WTX101-102_CA13895_FINAL_Clinical Study Protocol_25 Feb 2014 
 
between administrations of WTX101. 
The entire study is expected to last 48 days from the first 
subject dosed to last subject-last visit (LSLV). 
Blinding: 
This is an open-label study. 
Number of Subjects:  
Eighteen (18) healthy, non-tobacco using adult male and 
female subjects between 19 and 55 years of age (inclusive). 
Dosage, Dosage Form, 
Route, and Dose 
Regimen: 
WTX101 will be supplied as non-coated capsules or EC tablets 
for oral administration.  Each WTX101 non-coated capsule 
(hydroxypropyl methylcellulose [HPMC]) contains 30 mg of bis-
choline tetrathiomolybdate and the following excipients:  
anhydrous di-calcium phosphate and anhydrous sodium 
carbonate. Each WTX101 EC tablet contains 30 mg of bis-
choline tetrathiomolybdate and the following excipients: tri-
calcium 
phosphate, 
sodium 
carbonate, 
sodium 
starch 
glycolate, magnesium stearate. WTX101 EC Tablets are 
coated with Opadry 03K19229 Clear and Acryl-Eze White. 
Dose regimens are described as follows: 
Treatment A: 60 mg WTX101 (2 x WTX101 EC tablets, 30mg) 
at Hour 0 on Day 1 following an overnight fast. 
Treatment B: 60 mg WTX101 (2 x WTX101 EC tablets, 30mg) 
at Hour 0 on Day 1, 30 minutes after the start of 
a high-fat breakfast, preceded by an overnight 
fast. 
Treatment C: 20 mg omeprazole (1 x 20 mg delayed-release 
capsule) QD on the mornings of Days -5 to -1 
following an overnight fast, 20 mg omeprazole 
capsule at Hour -1 on Day 1 following an 
overnight fast, and 60 mg WTX101 (2 x WTX101 
non-coated capsules, 30mg) at Hour 0 on Day 1 
All study medications (WTX101 non-coated capsules, WTX101 
EC tablets and Omeprazole) should be administered orally with 
approximately 240 mL of room temperature water. The EC 
Tablets and non-coated capsules must be swallowed whole. 
Stopping Rules 
Safety-related individual- and study-specific stopping criteria 
are detailed below: 
Dosing will be discontinued for an individual subject 
experiencing any National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 
(CTCAE v. 4.0) Grade 3 or higher event that is assessed as 
treatment-related.*  
The study will be stopped if: 
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WTX101-102_CA13895_FINAL_Clinical Study Protocol_25 Feb 2014 
 
 
2 or more subjects experience an NCI CTCAE v. 4.0 
Grade 3 or higher event that is assessed as 
treatment-related*, or if  
 
1 or more subjects experience a Grade 4 or higher 
event that is assessed as treatment-related*. 
*Treatment-related is defined as likely, probably, or possibly 
related per Section 11.1.6.3 of the protocol. 
Key Assessments:  
Pharmacokinetics: 
The plasma concentrations of WTX101 will be measured by 
plasma concentrations of total elemental Mo. 
The following PK parameters will be calculated for total Mo in 
plasma:  AUC0-t, AUC0-inf, Cmax, tmax, z, t½, CL/F, and Vz/F. 
Descriptive statistics will be computed for all parameters.  The 
parameters Cmax, AUC0-t, and AUC0-inf will be compared among 
treatments using an analysis of variance (ANOVA) on the In-
transformed values.  Tmax will be compared among treatments 
using non-parametric statistic, i.e. Wilcoxon Rank Sum. 
Safety: 
Safety will be monitored through physical examinations, vital 
sign measurements, electrocardiograms (ECGs), AEs and 
clinical laboratory tests. Summary statistics for the laboratory 
safety tests, ECGs, and/or vital signs will be computed and 
provided. 
 
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6 
STUDY EVENTS FLOW CHART 
 
Study Proceduresa 
Sb 
 
C-Ic 
Study Days in Each Periodd 
EOS or 
ETe 
Days → -28 
-5 
-4  -3  -2 
-1  
1 
2 
3 4 5 
6 
7 
8 
9 
Hours → 
 
 
 
 
 
AM PM Pre 
dose 0f 1 2 3 3.
5 4 4.5 5 6 7 7.5 8 8.5 9 9.5 10 12 14 16g 24 36 48 72 96 120 144 168 192 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationh 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Evaluations / Others 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationi 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
12-Lead ECG 
x 
 
 
 
 
 
x 
x 
 
x 
 
 
 x 
 
   
 
x 
 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
x 
Vital Signs (HR, BP, RR & T) 
x 
 
 
 
 
 
x 
x 
 
x 
 
 
 x 
 
   
 
x 
 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
x 
Hem, Chem, UA, and Coagj 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
Serum Cp and Cu 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Preg (females  only) 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
FSH (postmen females only) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Alcohol and Drug Screen 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/Hepatitis Screen 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Monitoring 
 
<----------------------------------------------------------------------------------x-----------------------------------------------------------------------------> 
ConMeds 
<----------------------------------------------------------------------------------------x-----------------------------------------------------------------------------> 
Study Medication 
Administration / PK  samples 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPI Administrationk 
 
x 
x 
x 
x 
x 
 
x 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WTX101 Administration 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Plasma Total Mo 
(PK)l 
 
 
 
 
 
 
 
x 
 
x x x x x x x x x x x x x x 
x x x 
x 
x x x x x 
x 
x 
x 
x 
 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
High-Fat Breakfastm 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement in the CRU 
 
 
 
 
 
 
 
<---------------------------------------------x----------------------------------------------> 
 
 
 
 
 
 
 
Return Visits 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
x x 
x 
x 
x 
x 
x 
 
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Celerion Project No.:  CA13895 
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WTX101-102_CA13895_FINAL_Clinical Study Protocol_25 Feb 2014 
 
a. 
For details on study procedures, refer to Section 11. 
b. 
Within 28 days of WTX101 first administration. 
c. 
Subjects will be admitted to the CRU at least 10 hours prior to WTX101 dosing. 
d. 
Each period will be separated by a washout of at least 14 days between WTX101 doses. 
e. 
Subjects will be required to return to the CRU approximately 14 days (±2 days) following the final dose of study medication for an EOS evaluation. In the event of early 
termination, the procedures listed at the end of the study will be performed prior to subject discharge. 
f. 
Hour 0 corresponds to the time of WTX101 administration. Unless stated otherwise, times listed are in relation to WTX101 dosing. 
g. 
The 16-hour time point following WTX101 dosing on Day 1 will be either on Day 1 or Day 2, depending on the time of dosing on Day 1. 
h. 
Please refer to Section10.5.2 for randomization details. 
i. 
A full physical examination will be performed at screening, check-in, and at the end of the study or upon early termination. A symptom-driven physical examination may be 
performed at other times, at the Principal Investigator’s (PI) discretion. 
j. 
Samples for serum chemistry will be obtained following a fast of at least 8 hours at screening, and of at least 6 hours at check-in. In case of dropouts, rechecks and postdose 
serum chemistry, subjects may not have fasted for 6 or 8 hours before the serum chemistry sample is taken. 
k. 
Subjects randomized to receive Treatment C in Period 1 will be required to come to the CRU in the morning of Day -5 of Period 1 to receive their first dose of PPI (omeprazole). 
They will receive a properly labeled container which will contain omeprazole doses to be self-administered at home on Days -4 to -1. At the end of Periods 1 and 2, subjects will 
receive a container with omeprazole doses for self-administration of doses on Days -5 to -1, if they are randomized to receive Treatment C in the next period. Each omeprazole 
dose self-administered should be taken under fasting conditions, at a time corresponding to Hour -1 relative to the time of dosing WTX101 on Day 1 (Hour 0). Subjects will be 
given paper diaries to record their self-administered omeprazole doses and whether the dose was administered with food and must return the container (empty or not) and diary 
at the next visit. The data from the diary will then be transcribed into the eCRF. Home dosing will be monitored daily via attempted contacts (phone calls, texts or emails) 
whereupon subjects will be reminded to take their medication and queried about AE occurrence. 
l. 
The exact time points for collection of PK samples may be amended following evaluation of the data from the ongoing Study WTX101-101. If this is required it will be confirmed 
prior to study start. However, the total volume of blood taken for PK sample analysis will not be increased from that stated in Section 11.1.5.3  
m. Subjects randomized to receive Treatment B will receive breakfast, to be initiated at Hour -0.5 and consumed entirely within the 30 minutes prior to dosing. 
Abbreviations:  AE = Adverse Event, BP = Blood Pressure, Chem = Serum Chemistry, C-I = Check-in, Coag = Coagulation, ConMeds = Concomitant Medication Monitoring, Cp = 
Cerulplasmin, CRU = Clinical Research Unit, Cu = Copper, ECG = Electrocardiogram, EOS/ET = End of Study or Early Termination, FSH = Follicle Stimulating Hormone, 
Hem = Hematology, HIV = Human immunodeficiency virus, HR = Heart Rate, Mo = Molybdenum, PI = Principal Investigator, PK = Pharmacokinetics, Postmen = Postmenopausal, 
PPI = Proton Pump Inhibitor, RR = Respiration Rate, S = Screening, Serum Preg = Serum Pregnancy Test, T = Temperature, UA = Urinalysis. 
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7 
ABBREVIATIONS 
aPTT 
Activated partial thromboplastin time 
ADL 
Activity of daily living 
AE 
Adverse event 
ANOVA 
Analysis of variance 
AUC 
Area under the plasma concentration versus time curve 
AUC0-t 
Area under the plasma concentration versus time curve to the last 
measurable concentration (t) 
AUC0-inf 
Area under the plasma concentration versus time curve to infinity 
BMI 
Body Mass Index 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CL/F 
Apparent oral clearance 
cm 
Centimeter 
Cmax 
Maximum measured plasma concentration  
Cp 
Ceruloplasmin 
CRU 
Clinical research unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
Cu 
Copper 
CV 
Coefficient of variation 
EC 
Enteric Coated 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOS 
End-of-study 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
g 
gram 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GLSM 
Geometric least-squares means 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
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HIV 
Human immunodeficiency virus 
HPMC 
Hydroxypropyl methylcellulose 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
ICP-MS 
Inductively-coupled plasma mass spectrometry 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
z 
Apparent terminal elimination rate constant 
kg 
Kilogram 
LSLV 
Last subject-last visit 
µg 
Microgram 
mg 
Milligram 
mL 
Milliliter 
mmHg 
Millimeter of mercury 
Mo 
Molybdenum 
MTD 
Maximum tolerated dose 
N 
Number of subjects 
NCI 
National Cancer Institute 
No. 
Number 
NOAEL 
No observed adverse effect level 
oz 
Ounce 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PKAP 
Pharmacokinetic Analysis Plan 
PPI 
Proton pump inhibitor 
PT 
Prothrombin Time 
QA  
Quality assurance 
QD 
Once daily 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
tmax 
Time of the maximum measured plasma concentration 
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WTX101-102_CA13895_FINAL_Clinical Study Protocol_25 Feb 2014 
 
t½ 
Apparent terminal elimination half-life 
US 
United States 
USA 
United States of America 
Vz/F 
Apparent oral volume of distribution 
WD 
Wilson Disease 
 
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WTX101-102_CA13895_FINAL_Clinical Study Protocol_25 Feb 2014 
 
8 
BACKGROUND AND RATIONALE 
8.1 
Background 
WTX101 (bis-choline tetrathiomolybdate) is being developed by Wilson Therapeutics for the 
treatment of Wilson Disease (WD). WD is a rare autosomal-recessive disorder caused by 
mutations in the ATP7B gene, resulting in a disturbed copper (Cu) metabolism. In the 
affected patients, Cu accumulates in the liver and in other tissues including the central 
nervous system. Left untreated, morbidity is progressive and the condition is eventually 
fatal. 
The mechanism of action of tetrathiomolybdate differs in several aspects from currently 
existing WD therapeutics:  
• 
The tetrathiomolybdate anion binds Cu2+ with high affinity and has high selectivity to 
Cu compared with other divalent cations. 
• 
Thiomolybdates can enter hepatocytes and bind and remove Cu from 
metallochaperones (e.g., metallothionein). 
• 
Tetrathiomolybdate binds Cu via the formation of Cu-tetrathiomolybdate-protein 
complexes, which are rapidly excreted, primarily via bile.  
Published data suggest that this differentiated mechanism of action could translate into an 
improved clinical profile. Previous clinical studies with ammonium tetrathiomolybdate in WD 
patients indicate that tetrathiomolybdate might lower non-ceruloplasmin [Cp]-bound Cu 
faster than D penicillamine (Cuprimine®, Depen®) and trientine hydrochloride (Syprine®), 
which are orally administered chelating agents currently used to treat WD, as well as be 
associated with a reduced risk of neurologic deterioration after initiation of treatment in WD 
patients with neurologic disease.1, 2, 3 
Tetrathiomolybdate has previously been investigated in several clinical trials. Initially, 
researchers at University of Michigan used ammonium tetrathiomolybdate in trials in WD 
patients. In addition, there have been a number of clinical trials in other indications; mainly in 
oncology patients but also including patients with macular degeneration or primary biliary 
cirrhosis. Some of these studies in non-WD patients were conducted with ammonium 
tetrathiomolybdate, while some studies conducted by Attenuon LLC (later renamed to Tactic 
Pharma LLC) used bis-choline tetrathiomolybdate due to the stability issues identified with 
the ammonium salt form.  Based on its better stability, bis-choline tetrathiomolybdate is more 
suitable for clinical development and commercialization. 
The 
majority 
of 
the 
non-clinical 
studies 
were 
conducted 
using 
ammonium 
tetrathiomolybdate. To support the clinical use of the bis-choline salt form, the comparability 
of the two salt forms was established in both in vitro and in vivo non-clinical studies.  
Bridging data suggest that the cation has neither an influence on the mechanism of action of 
the drug nor any appreciable effect on its pharmacokinetics (PK). Therefore, studies 
performed with ammonium tetrathiomolybdate can support the use of bis-choline 
tetrathiomolybdate in the planned clinical development for WTX101. 
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8.1.1 Non-clinical Safety and Toxicology Summary and Conclusion 
The non-clinical package includes data collected using both ammonium and bis-choline 
tetrathiomolybdate, with the main toxicology studies being carried out with the ammonium 
tetrathiomolybdate. The active moiety, tetrathiomolybdate anion, is identical for both 
compounds, the chemical structure is well defined, and no substantial biological effect of the 
cationic moiety have been observed based on comparability studies in rodents and dogs. In 
summary, these studies show no substantial differences between the two salt forms that 
would indicate that non-clinical data obtained using the ammonium tetrathiomolybdate is 
different from data obtained using bis-choline tetrathiomolybdate. 
In accordance with regulatory guidelines, 6-month (rat) and 9-month (dog) repeated-dose 
studies were performed under Good Laboratory Practice (GLP) conditions. In these studies, 
ammonium tetrathiomolybdate was administered by gavage to normal rats up to the 
maximally tolerated dose (MTD). These repeated-dose toxicity studies as well as shorter 
term studies included separate groups including Cu supplementation of the diet of rats and 
dogs in an attempt to differentiate the effects induced by tetrathiomolybdate independent of 
the pharmacologic effects, namely, Cu depletion. Nevertheless, it is emphasized that Cu 
metabolism is not necessarily comparable between healthy animals, artificially Cu 
supplemented animals, and WD patients. It is assumed that short-term supplemented Cu is 
not handled in the same physiological way as long-term excess brought on by patients with 
WD. Thus, although the safety data collected in healthy animals or even in artificially Cu-
supplemented animals is useful in defining a toxicity profile for tetrathiomolybdate, the 
quantitative dose response extrapolation to humans, and particularly to WD patients, is of 
limited relevance.  
In rats, 4 mg/kg ammonium tetrathiomolybdate (i.e., equivalent to 6.8 mg/kg bis-choline 
tetrathiomolybdate) administered for 6 months caused minimal anemia, increases in total 
bilirubin, total bile acids, albumin, and cholesterol as well as degenerate spermatocytes and 
sperm granuloma in the epididymis, and tibial bone cysts. The anemia, changes in total 
bilirubin, albumin and cholesterol, as well as tibial cysts were reversible as they were not 
observed after a one-month recovery period. The increase in total bile acids was partially 
reversed at the end of the recovery period. Liver and pancreas histopathological changes 
were observed in a 90-day study without Cu supplements in males dosed at 10 mg/kg but 
was not accompanied by changes in plasma liver enzyme concentrations. 
Anemia, increases in total bile acids and cholesterol were not observed in Cu-supplemented 
(22 and 110 mg/kg) rats administered 4 mg/kg/day tetrathiomolybdate. Also, a lower 
incidence and/or severity of the degenerate spermatocytes and tibial cysts were observed in 
Cu-supplemented rats. These results are interpreted to indicate that these specific 
pathologic findings are secondary to Cu deprivation, i.e., secondary to the pharmacologic 
action of tetrathiomolybdate. In Cu-supplemented animals, the no-observed adverse effect 
level (NOAEL) was established at or above the highest tested dose (>10 mg/kg). 
In a 9-month repeat-dose toxicology study in dogs, no signs of local or systemic toxicity 
were noted up to the highest tested dose of 3 mg/kg. The initial pathology report further 
points to histopathological findings in the liver of mid and high dosed animals, defining the 
NOAEL at 0.3 mg/kg, the lowest tested dose. Since similar findings were not noted in rats 
and the findings were not correlated with any liver enzyme changes, Wilson Therapeutics 
requested a re-evaluation of the liver slides. According to the re-evaluation (conducted by 
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two independent pathologists) the only histologic finding in the liver that was attributed to the 
test item (with or without Cu supplementation), was hemosiderin deposition, which is 
considered non-adverse and not indicative of hepatocellular injury. 
In a shorter term study in dogs, ammonium tetrathiomolybdate at doses of 10 mg/kg and 
higher were lethal.  
Segment I (fertility) and II (developmental) reproductive toxicity studies were conducted in 
rats and rabbits. The results indicated effects on male fertility; no effects were observed in 
Cu-supplemented animals and thus, these effects on fertility were considered secondary to 
Cu deprivation rather than due to an intrinsic effect by the drug. Developmental toxicity was 
observed in rats and rabbits including malformations in rabbits at 20 mg/kg ammonium 
tetrathiomolybdate (equimolar to 34 mg/kg bis-choline tetrathiomolybdate); (human 
equivalent dose 5.5 mg/kg; 330 mg/subject [body weight 60 kg]). The NOAEL (6 mg/kg 
ammonium tetrathiomolybdate, equimolar to 10.2 mg/kg of bis-choline tetrathiomolybdate) 
based on teratogenicity and maternal toxicity is equivalent to 1.6 mg/kg bis-choline 
tetrathiomolybdate in humans (100 mg/human subject). 
The full standard package of genotoxicity studies as per regulatory guidance has been 
conducted. An Ames test was negative and excluded any mutagenic potential for bis-choline 
tetrathiomolybdate up to the highest tested concentration (5000 µg). An in vitro mouse 
lymphoma assay suggests genotoxic activity at high (cytotoxic) concentrations of ammonium 
tetrathiomolybdate. However, in vivo micronuclei evaluation of bone marrow cells were 
included in the rat chronic toxicity studies conducted with ammonium tetrathiomolybdate. 
There was no increase in micronuclei at the highest dose tested (with and without Cu 
supplementation); 4 mg/kg/day (equimolar to 6.8 mg/kg/day bis-choline tetrathiomolybdate) 
in rats or 3 mg/kg/day in dogs in vivo (equimolar to 5.1 mg/kg/day bis-choline 
tetrathiomolybdate); available data on bone marrow distribution and toxicity support that the 
drug reaches the bone marrow. 
In summary, the safety profile is acceptable for the proposed single dose healthy volunteer 
clinical study. 
8.1.2 Summary 
of 
Safety 
in 
Oncology 
Studies 
with 
Bis-Choline 
Tetrathiomolybdate 
Over 150 oncology patients have been treated with bis-choline tetrathiomolybdate, alone or 
in combination, at doses up to 330 mg/day, for periods of up to 6 months.  Overall, bis-
choline tetrathiomolybdate was well tolerated in this population. The most frequently 
reported (Adverse Events) AEs during bis-choline tetrathiomolybdate treatment (initial dose 
120-330 mg/day; maintenance dose titrated for toxicity and/or Cp) were fatigue, dizziness, 
myelosuppression 
(anemia, 
leukopenia, 
neutropenia, 
lymphocytopenia 
and/or 
thrombocytopenia), 
and 
gastrointestinal 
complaints 
(nausea, 
vomiting, 
diarrhea, 
constipation, flatulence, sulphur eructations, anorexia). Concomitant medication with a 
proton pump inhibitor (PPI) was found to overcome the gastrointestinal problems.4   
Dose-limiting toxicities were myelosuppression (anemia and/or neutropenia) and fatigue, 
and the MTD was defined as 300 mg/day. The degree of myelosuppression appears to be 
related to dose and duration of high-dose loading, but not to Cp level. Fatigue coincided 
often with anemia, and the degree of fatigue appeared to be loading dose-dependent and 
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only Grade 1-2 fatigue was seen at the MTD. Fatigue responded rapidly to dose reductions. 
These adverse effects are to be expected if copper levels are reduced to below-normal 
levels. As discussed by Lin et al,5 neutropenia has been described in copper-deficient 
patients and may be due to arrested development of granulocytes.6 It is also well 
established that copper deficiency is essential for iron metabolism and erythropoiesis and 
copper-deficient animals and humans develop iron deficiency anemia.   
8.1.3 Summary 
of 
Safety 
in 
Wilson 
Disease 
Studies 
with 
Ammonium 
Tetrathiomolybdate 
In the published, completed studies for ammonium tetrathiomolybdate treatment of WD 
(N=80), the most commonly reported AEs were changes in hematologic parameters (bone 
marrow suppression), attributed by the Investigators to overtreatment and resultant Cu 
deficiency. Also, transient and dose dependent elevation in liver transaminase levels, 
usually after 4 to 6 weeks, was reported.1, 2, 3. These two main side effects were readily 
reversible by decreasing the dose or giving a drug holiday (data on file at Wilson 
Therapeutics).  
8.2 
Rationale 
8.2.1 Rationale for this Study and Study Design 
This study is designed to meet the objectives outlined in Section 9. 
WTX101 is an oral de-coppering agent. It is a bis-choline salt of tetrathiomolybdate, bis[(2-
hydroxyethyl)trimethylammonium] tetrathiomolybdate.  
In previous studies, coadministration of PPIs has been shown to increase the bioavailability 
of tetrathiomolybdate (as a consequence of increased gastric pH) and to reduce 
gastrointestinal side effects.4  An Enteric Coated (EC) tablet formulation would be expected 
to offer the same benefits of increased bioavailability and reduced gastrointestinal side 
effects while avoiding the need to coadminister a PPI. 
This study will be conducted as a crossover study, aimed at evaluating the absorption of 
WTX101 from the EC tablet under fed and fasted conditions and compared to the current 
non-coated capsule administered with a proton pump inhibitor (under fasting conditions) in 
order to Confirm the in vivo performance characteristics, including the absorption profile, 
and food effect of the EC tablet in man.  
Subjects will be randomized to one of six treatment sequences to minimize assignment bias. 
A crossover design is used to control the variability between subjects. The washout period 
between WTX101 doses is considered sufficient to prevent carryover effects of the 
treatments. 
8.2.2 Rationale for the Dose Selection 
The 60 mg WTX101 dose selected for this healthy subject study is well within the dose 
range demonstrated to be safe in humans. In oncology indications, doses of up to 300 mg 
WTX101 coadministered with PPIs were well tolerated in studies of up to 6 months in 
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duration. The oncology patient experience, which identified appropriate measures for safety 
monitoring, is relevant to healthy subjects as both populations have normal baseline Cu 
conditions. For these reasons, single doses of 60 mg in healthy subjects are not anticipated 
to cause any safety issues in this Phase 1 study. 
The 60mg WTX101 dose has been used in the ongoing WTX101-101 Phase I study 
evaluating the bioavailability of WTX101 in healthy subjects after single dose administration 
of a non-coated capsule with and without a PPI and with a PPI with and without food. The 
WTX101-101 study is a 3 way cross-over study and healthy subjects have received 60mg 
doses of WTX101 on 3 occasions. Evaluation of interim safety data in this ongoing study 
has been performed and no safety concerns have been identified to date.  
A once daily (QD) dose of 20 mg omeprazole is consistent with the dosage and 
administration recommendations for various gastrointestinal conditions.7 
8.2.3 Rationale for Endpoints 
The primary endpoints will be the AUCs and Cmax, as these PK parameters are the most 
relevant to characterize the rate and extent of exposure following WTX101 administration - 
from the treatments to be tested. 
Other parameters will also be presented, including:  tmax, z, and t½, CL/F, and Vz/F. 
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9 
STUDY OBJECTIVES, AND ENDPOINTS 
9.1 
Study Objectives  
The primary objectives of the study are to evaluate: 
• 
The effect of dosing with an EC tablet versus dosing with the current non-coated 
capsule coadministered with a proton pump inhibitor (PPI; omeprazole) under 
fasting conditions, on the absorption of WTX101. 
• 
The effect of dosing an EC tablet with and without food on the absorption of 
WTX101. 
• 
The safety and tolerability of WTX101. 
9.2 
Study Endpoints 
The primary endpoints are: 
• 
Plasma concentrations and PK parameters (e.g., AUC0-inf, AUC0-t, Cmax, tmax, z, and 
t½, CL/F, and Vz/F) for total Molybdenum (Mo) following WTX101 EC tablet 
administration under fasting and fed conditions and WTX101 non coated capsule 
coadministered with a PPI under fasting conditions 
• 
Safety and tolerability will be evaluated based on physical examinations, vital sign 
measurements, Electrocardiogram (ECGs), AEs, and clinical laboratory tests. 
 
10 INVESTIGATIONAL PLAN 
10.1 Overall Study Design and Plan 
This will be a single-center, open-label, randomized, 3-period, 3-treatment, 6-sequence 
crossover study evaluating the PK of single doses of WTX101 in healthy subjects based on 
the measurement of plasma total Mo. 
Please refer to the next page for the Study Diagram. 
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       Celerion Project No.:  CA13895 
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US IND No.: 119,006 
 
WTX101-102_CA13895_FINAL_Clinical Study Protocol_25 Feb 2014 
 
Figure 1 Study Diagram 
Period 1
Study days 
Period 2
14 (2)
Omeprazole dose at CRU
(Treatment C only)
Period 3
1
3
4 to 9
-5 to -1
1
2
4 to 9
-5 to -1
1
2
4 to 9
-28 to -6
-4 to -1
3
2
3
-5
Check-out
Check-in
1
3
4 to 9
10 to 14
15
16
18 to 23 24 to 28
29
30
32 to 37
Screening
-4 to -1
17
2
31
-5
Calendar days 
43 (2)
Daily 
returns
Check-in
Check-in
Daily 
returns
Daily 
returns
End-of-study
visit
Washout (≥14 days)
Washout (≥14 days)
Daily omeprazole doses at home (Treatment C only)
WTX101 dose 
(Treatments  A, B, and C)
WTX101 dose 
(Treatments  A, B, and C)
WTX101 dose 
(Treatments  A, B, and C)
Check-out
Check-out
 
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Eighteen (18) healthy, non-tobacco using adult male and female subjects who complete the 
study screening assessments and meet all eligibility criteria will be enrolled. These subjects 
will receive the corresponding product, according to a randomization scheme generated at 
Celerion. To ensure that the planned number of subjects are dosed with WTX101 on Day 1 
of Period 1, additional ‘stand-by’ subjects (who also complete the study screening 
assessments and meet all eligibility criteria) will also be enrolled. Subjects will be considered 
randomized when they receive the first dose of WTX101 on Day 1 of Period 1. 
Subjects randomized to receive PPI in Period 1 (Treatment C) will report to the Clinical 
Research Unit (CRU) on Day -5, i.e. 5 days prior to first dosing with WTX101, to receive a 
morning dose of omeprazole under fasting conditions. These subjects will be given a 
container with omeprazole doses and continue QD administration of omeprazole under 
fasting conditions at home, until their return to the CRU for check-in on Day -1. To ensure 
that the planned number of subjects are dosed with WTX101 on Day 1 of Period 1, stand-by 
subjects will also receive QD doses of omeprazole, as described above.  Should any subject 
withdraw from the study after omeprazole administration, but before receiving WTX101 in 
Period 1, they will be replaced with a stand-by subject. 
Subjects randomized to receive PPI in Periods 2 or 3 will receive the container with 
omeprazole doses prior to discharge from the CRU after the 192-hour postdose procedures 
in Period 1 or Period 2, as appropriate. These subjects will initiate QD administration of 
omeprazole under fasting conditions at home the following day and continue until their 
return to the CRU for their next admission. For details on self-administration of omeprazole 
doses, see Section 10.5.1. 
In each of the 3 periods, all subjects (Treatments A, B, and C) will be admitted to the CRU 
on Day -1, and will receive WTX101 EC tablet alone under fasting conditions (Treatment A); 
WTX101 EC tablet under fed conditions (Treatment B); or, omeprazole under fasting 
conditions followed by WTX101 non-coated capsule under fasting conditions (Treatment C). 
PK sampling will be obtained at the following timepoints while subjects remain in the CRU:  
Time 0 (within 1 hour predose), and then 1, 2, 3, 3.5, 4, 4.5, 5, 6, 7, 7.5 8, 8.5, 9, 9.5,10, 12, 
14, 16, 24, 36, and 48 hours postdose. Subjects will be discharged on Day 3 following the 
48 hours postdose procedures, unless medically necessary to extend confinement to 72 
hours. 
Subjects will be required to return to the CRU for outpatient visits on 6 consecutive days 
(Days 4, 5, 6, 7, 8 and 9) in each period, for subsequent PK sampling and procedures at: 
72, 96, 120, 144, 168, and 192 hours postdose. 
Dose regimens are described as follows: 
Treatment A: 60 mg WTX101 (2 x WTX101 EC tablets, 30 mg) at Hour 0 on Day 1 
following an overnight fast. 
Treatment B: 60 mg WTX101 (2 x WTX101 EC tablets, 30 mg) at Hour 0 on Day 1, 30 
minutes after the start of a high-fat breakfast, preceded by an overnight fast. 
Treatment C: 20 mg omeprazole (1 x 20 mg delayed-release capsule) QD in the morning of 
Days -5 to -1 following an overnight fast, 20 mg omeprazole delayed-release 
capsule at Hour -1 on Day 1 following an overnight fast, and 60 mg WTX101 
(2 x WTX101 non-coated capsules, 30 mg) at Hour 0 on Day 1. 
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Appropriately trained employees of the study site will administer the study treatment. Each 
dose will be administered with approximately 240 mL of room temperature water. The date 
and time of administration will be recorded in the source notes and witnessed by a second 
person from the clinical facility. 
The washout between WTX101 doses in each period will be at least 14 days. 
Subjects will return to the CRU approximately 14 days (+/-2 days) after the final study 
medication administration for an end-of-study (EOS) visit with follow-up procedures, and to 
determine if any AE has occurred since the last study visit. Subjects who terminate the study 
early should be seen and assessed by an Investigator, whenever possible, to undergo the 
procedures associated with the EOS visit. 
Subjects may be replaced at the discretion of the Sponsor.  
10.1.1 Confinement and Return Visits 
During each of the 3 periods, subjects will be housed from at least 10 hours before dosing 
until after the 48-hour blood draw on Day 3. At all times, a subject may be required to 
remain at the CRU for longer at the discretion of the Principal Investigator (PI). Subjects will 
return for 6 consecutive days (Days 4, 5, 6, 7, 8 and 9) for the subsequent PK sampling. A 
final return visit will be required 14 days (+/-2 days) following the final administration of 
WTX101 for conduct of EOS procedures. 
10.1.2 Study Duration 
Subjects who complete the study may be involved in the study for up to 48 days excluding 
screening (Day -5 of period 1 to the EOS visit). The entire study is expected to last 
approximately 48 days from the first subject dosed (Omeprazole) to last subject-last visit 
(LSLV). 
The study has a screening phase (Day -28 to Day -5 of Period 1); three study periods 
(Periods 1, 2, and 3 comprised of Day -5 to Day 9); and an EOS visit 14 days (+/-2 days)  
following the final study medication administration. There is a 14 day minimum washout 
period between each dose of WTX101. 
10.2 Risks and/or Benefits to Subjects 
The dose of WTX101 administered in this study is not anticipated to induce any potential 
risk or benefit to subjects participating in this study. The single doses to be administered in 
each of the 3 periods are well within the dose range demonstrated to be safe in humans, 
(data on file at Wilson Therapeutics). The dose of omeprazole administered in this study 
corresponds to dosing recommendations found in the full prescribing information for 
Prilosec.7  
The safety monitoring practices employed by this protocol (i.e., physical examination, vital 
signs, 12-lead ECG, hematology, serum chemistry, urinalysis, and AE questioning) are 
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adequate to protect the subjects’ safety and should detect all expected treatment-emergent 
AEs.  
There will be no direct health benefit for study participants from receipt of study medication. 
An indirect health benefit to the healthy subjects enrolled in this trial is the free medical tests 
received at screening and during the study. 
10.3 Selection of Study Population 
10.3.1 Inclusion Criteria 
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in the 
study, unless otherwise specified: 
1. Healthy, adult, male or female, 19-55 years of age, inclusive.  
2. Continuous non-smoker who has not used nicotine-containing products for at least 3 
months prior to the first WTX101 dose. 
3. Medically healthy with no clinically significant laboratory profiles, vital signs or ECGs, as 
deemed by the PI. 
4. Body Mass Index (BMI) ≥ 18 and ≤ 32.0 kg/m2. 
5. Adequate venous access in the left or right arm to allow collection of a number of blood 
samples. 
6. Willing and able to fast per the study requirements. 
7. For a female of childbearing potential:  either be sexually inactive (abstinent) for 14 days 
prior to the first WTX101 dose and throughout the study or be using one of the following 
acceptable birth control methods:  
a. intrauterine device in place for at least 3 months prior to the first WTX101 dose and 
throughout the study. 
b. barrier methods (e.g., condom or diaphragm) with spermicide for at least 14 days 
prior to the first WTX101 dose and throughout the study. 
c. surgical sterilization of the partner (vasectomy for 6 months minimum). 
d. hormonal contraceptives for at least 3 months prior to the first WTX101 dose of the 
study and throughout the study.  
A female subject who claims to be sexually inactive, but becomes sexually active during 
the course of the study must agree to use a barrier method (e.g., condom, diaphragm) 
with spermicide from the time of the start of sexual activity through to the completion of 
the study. 
In addition, female subjects of childbearing potential will be advised to remain sexually 
inactive or to keep the same birth control method for at least 28 days following the last 
dose. 
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8. A female of non-childbearing potential must have undergone one of the following 
sterilization procedures at least 6 months prior to the first WTX101 dose: 
a. hysteroscopic sterilization; 
b. bilateral tubal ligation or bilateral salpingectomy; 
c. hysterectomy; 
d. bilateral oophorectomy; 
or be postmenopausal with amenorrhea for at least 1 year prior to the first WTX101 dose 
and follicle stimulating hormone (FSH) serum levels consistent with postmenopausal 
status. 
9. A non-vasectomized, male subject must agree to use a condom with spermicide or 
abstain from sexual intercourse during the study until 90 days beyond the last dose of 
study medication. (No restrictions are required for a vasectomized male provided his 
vasectomy has been performed 4 months or more prior to study start. A male who has 
been vasectomized less than 4 months prior to study start must follow the same 
restrictions as a non-vasectomized male). 
10. If male, must agree not to donate sperm from the first WTX101 dose until 90 days after 
the final WTX101 dosing. 
11. Understands the study procedures in the informed consent form (ICF), and willing and 
able to comply with the protocol. 
10.3.2 Exclusion Criteria 
Subjects must not be enrolled in the study if they meet any of the following criteria: 
1. Subject is mentally or legally incapacitated or has significant emotional problems at the 
time of screening visit or expected during the conduct of the study. 
2. History or presence of clinically significant medical or psychiatric condition or disease in 
the opinion of the PI. 
3. History of any illness that, in the opinion of the PI, might interfere with drug absorption 
(e.g., chronic diarrhea), might confound the results of the study or poses an additional 
risk to the subject by their participation in the study. 
4. History or presence of hypersensitivity or idiosyncratic reaction to the study medications, 
study medication excipients (including anhydrous di-calcium phosphate, anhydrous 
sodium carbonate, etc.), to PPIs, or to related compounds. 
5. History or presence of alcoholism or drug abuse within the past 2 years. 
6. Female subjects who are pregnant or lactating. 
7. Regularly drinks more than 2 units (1 unit = 265 mL beer, 100 mL wine, or 1 measure of 
spirits) of alcohol per day or may have difficulty abstaining from alcohol during the 
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48 hours prior to WTX101 administration and until completion of blood sampling in each 
period.   
8. Positive urine drug and alcohol results at screening or check-in. 
9. Positive results at screening for Human immunodeficiency virus (HIV), Hepatitis B 
surface antigen (HBsAg) or Hepatitis C virus (HCV). 
10. Seated blood pressure less than 90/60 mmHg or greater than 140/90 mmHg at 
screening. 
11. Serum Cp value outside of the normal range at screening. 
12. Serum Cu values outside of the normal range at screening. 
13. Unable to refrain from or anticipates the use of any drug, including recreational drugs,  
prescription and non-prescription (over-the-counter) medications, herbal remedies, or 
vitamin supplements beginning approximately 14 days prior to WTX101 first dosing and 
throughout the study. Hormonal contraceptives and hormone replacement therapy will 
not be excluded. Acetaminophen (up to 2 g per 24 hour period) may be permitted during 
the study. 
14. Have been on a diet incompatible with the on-study diet within the 28 days prior to the 
first WTX101 dose and throughout the study. 
15. Hemoglobin level below the lower limit of normal at screening. 
16. Unable to consume the contents of a high-fat breakfast. 
17. Donation of blood or significant blood loss within 56 days prior to the first WTX101 dose. 
18. Plasma donation within 7 days prior to the first WTX101 dose. 
19. Involvement in the planning or the conduct of the study. 
20. Participation in another clinical trial within 28 days prior to the first WTX101 dose. The 
28-day window will be derived from the date of the last study procedure (such as last 
blood collection or dosing) in the previous study to Day 1 of Period 1 of the current 
study. 
21. Participation in a previous clinical trial with WTX101. 
10.3.3 Stopping Rules 
Safety-related individual- and study-specific stopping criteria are detailed below: 
 
Dosing will be discontinued for an individual subject experiencing any National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v. 
4.0 Grade 3 or higher event that is assessed as treatment-related.*  
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 
The study will be stopped if 2 or more subjects experience an NCI CTCAE v. 4.0 
Grade 3 or higher event that is assessed as treatment-related*, or if 1 or more 
subjects 
experience 
a 
Grade 4 
or 
higher 
event 
that 
is 
assessed 
as 
treatment-related.*  
*Treatment-related is defined as likely, probably, or possibly related (see Section 11.1.6.3) 
10.3.4 Removal of Subjects from the Study 
Subjects are free to withdraw from the study at any time for any reason. Subjects who 
discontinue will be asked about the reason(s) for their discontinuation and the presence of 
any AEs. 
In addition, subjects may be withdrawn from the study by the PI or sub-Investigator in 
consultation with the Sponsor for the following reasons: 
 
NCI CTCAE v. 4.0 Grade 3 or higher event that is assessed as treatment-related 
(see Section 10.3.3.) 
 
AEs. 
 
Difficulties in blood collection. 
 
Safety reasons, as judged by the PI and/or the Sponsor. 
 
Protocol violation (may include severe non-compliance to the protocol or 
development of exclusion criterion). 
 
Incorrect enrollment (i.e., the subject does not meet the required inclusion/exclusion 
criteria). 
 
Subject lost to follow-up. 
Whenever possible, discontinued subjects should be seen and assessed by an 
Investigator.  Discontinued subjects should undergo the study procedures outlined at the 
end-of-study visit. AEs should be followed up as detailed in Section 11.1.6 
 
The clinical report will include reasons for subject withdrawals as well as details relevant to 
the subject withdrawal.  
10.4 Study Restrictions 
10.4.1 Prohibitions and Concomitant Therapy 
Consumption of foods and beverages containing the following substances will be prohibited 
as indicated: 
 
Xanthines/Caffeine:  24 hours before first dosing (PPI or WTX101) in each period 
and throughout the period of sample collection (small amounts of caffeine derived 
from normal foodstuffs e.g., 250 mL/8 oz. decaffeinated coffee or other decaffeinated 
beverage, per day, with the exception of espresso; 45 g/1.5 oz chocolate bar, per 
day, would not be considered a deviation to this restriction); 
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 
Alcohol:  48 hours before first dosing (PPI or WTX101) in each period and 
throughout the period of sample collection; 
 
Grapefruit/Seville orange:  14 days before first WTX101 dosing and throughout the 
period of sample collection. 
Subjects may not donate either blood or plasma throughout the duration of the study. 
No subject may take medication (including over-the-counter products), herbal products or 
vitamin supplements for 14 days prior to WTX101 first dosing and throughout the study, 
except as required for the study. Hormonal contraceptives and hormone replacement 
therapy are not part of this prohibition. 
During the study, acetaminophen (up to 2 g per 24 hours) may be administered at the 
discretion of the PI. The subjects will be instructed that no additional medication will be 
allowed without the prior consent of the Investigator. If deviations occur, the PI will decide on 
a case-by-case basis whether the subject may continue participation in the study based on 
the time the study medication was administered and its pharmacology. 
Any medication, which is considered necessary for the subject’s safety and well-being, may 
be given at the discretion of the Investigator(s). All medications taken by subjects during the 
course of the study will be recorded in the source documents and in the appropriate sections 
of the electronic Case Report Form (eCRF). If a medication is associated with an AE, the AE 
will also be recorded in the source documents and in the appropriate sections of the eCRF. 
Subjects may not participate in another clinical trial until they have completed their end-of-
study visit. 
10.4.2 Meals 
Days - 5 to -1: 
For Treatment C, subjects will be required to fast for at least 10 hours before, and for at 
least 1 hour following Omeprazole administration. 
Days -1 to 1: 
For Treatments A and C, subjects will be required to fast overnight for at least 10 hours 
before WTX101 dosing and for at least 4 hours thereafter.  
For Treatment B, subjects will be required to fast overnight for at least 10 hours until 
approximately 30 minutes prior to their scheduled dosing times (Hour -0.5), when they will 
be given a standard high-fat breakfast which will be entirely consumed within 30 minutes. An 
example of a high-fat breakfast would be 2 slices of buttered toast, 2 fried eggs, 2 strips of 
bacon, 1 serving of hash brown potatoes, and 240 mL of whole milk. Subjects will fast for at 
least 4 hours following dosing. 
All days: 
For Treatments A, B, and C, water will not be permitted from 1 hour before until 1 hour after 
WTX101 dosing, except for water and/or fluids given at dosing. Water will be allowed ad 
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libitum at all other times. On all days that subjects are confined to the CRU, standard meals 
will be provided at approximately 4 and 9 hours after dosing, and at appropriate times 
thereafter.  
Except for the high-fat breakfast in Treatment B, each meal and/or snack served at the CRU 
will be standardized and will be similar in caloric content and composition (especially for 
dietary Cu) and will be taken at approximately the same time in each period. 
10.4.3 Activity 
Subjects will remain ambulatory or seated upright for the first 4 hours following WTX101 
administration, except when they are supine or semi-reclined for study procedures.  
However, should AEs occur at any time, subjects may be placed in an appropriate position 
or will be permitted to lie down on their right side.  
Subjects will be instructed to refrain from strenuous physical activity which could cause 
muscle aches or injury, including contact sports, at any time from screening until completion 
of the study. 
10.5 Treatments 
10.5.1 Treatments Administered 
All subjects will be given properly labeled containers with the requisite number of 
omeprazole doses for at home administration. Subjects will be given paper diaries to record 
their self-administered omeprazole doses, and will be instructed in the CRU on: self-
administration under fasting conditions, and on recording of doses and timing of doses in 
their diary. Written instructions will be provided for the subjects to take home. Each 
omeprazole dose self-administered should be taken under fasting conditions, at a time 
corresponding to Hour -1 relative to the time of dosing WTX101 on Day 1 (Hour 0). Subjects 
must return the container (empty or not) and their diary at the next visit. Self-administered 
dosing will be monitored daily by attempted contacts (phone calls, texts, or emails) to remind 
subjects to take these doses.   
Subjects randomized to receive PPI in Period 1 (Treatment C) will report to the Clinical 
Research Unit (CRU) on Day -5, i.e. 5 days prior to first dosing with WTX101, to receive a 
morning dose of omeprazole under fasting conditions. Prior to release from the CRU on Day 
-5 of Period 1, subjects will receive a container with omeprazole doses which will be self-
administered by subjects at home. Subjects randomized to receive PPI in Periods 2 or 3 will 
receive the container with omeprazole doses prior to discharge from the CRU after the 192-
hour postdose procedures in Period 1 or Period 2, as appropriate. These subjects will 
initiate QD administration of omeprazole under fasting conditions at home the following day 
and continue until their return to the CRU for their next admission. Each self-administered 
dose of omeprazole should be taken under fasting conditions, at a time corresponding to 
Hour -1 relative to the time of dosing WTX101 on Day 1 (Hour 0). 
Treatments A, B, and C are described as follows: 
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Treatment A: 60 mg WTX101 (2 x WTX101 EC tablets, 30 mg) at Hour 0 on Day 1 
following an overnight fast. 
Treatment B: 60 mg WTX101 (2 x WTX101 EC tablets, 30 mg) at Hour 0 on Day 1, 30 
minutes after the start of a high-fat breakfast, preceded by an overnight fast. 
Treatment C: 20 mg omeprazole (1 x 20 mg delayed release capsule) QD in the morning of 
Days -5 to -1 following an overnight fast, 20 mg omeprazole capsule at Hour -
1 on Day 1 following an overnight fast, and 60 mg WTX101 (2 x WTX101 
non-coated capsules, 30mg) at Hour 0 on Day 1. 
 
Subjects randomized to receive Treatment C in Period 1 will be required to come to the CRU 
in the morning of Day -5 of Period 1 to receive their first dose of PPI (omeprazole). They will 
receive a properly labeled container which will contain omeprazole doses to be self-
administered at home on Days -4 to -1. At the end of Periods 1 and 2, subjects will receive a 
container with omeprazole doses for self-administration of doses on Days -5 to -1, if they are 
randomized to receive Treatment C in the next period. Each self-administered dose of 
omeprazole should be taken under fasting conditions, at a time corresponding to Hour -1 
relative to the time of dosing WTX101 on Day 1 (Hour 0).  
The pharmacy at the CRU will provide each dose in individual unit dose containers for each 
subject and for each study period, as per the randomization scheme. 
All study medications should be taken orally with approximately 240 mL of water. 
Subjects will be instructed not to crush, split or chew the study medication, the WTX101 
non-coated capsules and WTX101 EC tablets should be swallowed whole. 
The date and exact clock time of dosing will be recorded on on-site dosing days.  
Home dosing will be monitored via attempted contacts (phone calls, texts or emails) as 
subjects will be reminded to take their omeprazole dose and queried about the occurrence 
of AEs. 
10.5.2 Method of Randomizing Subjects to Treatment Groups 
Each subject will be assigned a unique identification number upon screening. Subjects who 
complete the study screening assessments and meet all the eligibility criteria will receive the 
corresponding product, according to a randomization scheme generated at Celerion. To 
ensure that the planned number of subjects are dosed with WTX101 on Day 1 of Period 1, 
additional, stand-by subjects (who also complete the study screening assessments and 
meet all eligibility criteria) will also receive QD doses of omeprazole. Subjects will be 
considered randomized when they receive the first dose of WTX101 on Day 1 of Period 1. 
Subjects will receive each treatment on one occasion. The sequences to be used in the 
randomization will be ABC, ACB, BAC, BCA, CAB, and CBA. 
Subjects may be replaced at the discretion of the Sponsor. 
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10.5.3 Blinding 
This is an open-label study. The randomization scheme will not be available to bioanalytical 
laboratory personnel. 
10.5.4 Treatment Compliance  
A qualified designee will be responsible for monitoring the administration of the timed oral 
doses, for doses administered at the CRU. A mouth check will be performed by the qualified 
designee to ensure that the subjects have swallowed the study medication. Once a subject 
has finished the dosing water, the qualified designee will use a flashlight and a tongue 
depressor to check the subject’s mouth. Subjects’ hands will also be verified to ensure that 
the study medication was ingested. 
Compliance to at home omeprazole dosing will be reinforced by instructions and attempted 
daily contact with subjects. At home omeprazole dosing containers must be returned by the 
subjects to the CRU whether or not they are empty. A qualified designee will be responsible 
for accountability procedures. 
10.5.5 Diary 
Subjects will self-administer omeprazole at home on the days designated as home-dosing 
according to the Study Events Flow Chart (Section 6). 
A paper diary and omeprazole medication for at home dosing will be supplied to subjects 
before release from the CRU. The diary will capture subject identification, dose taken, actual 
date and time of dose taken, a check that the dose was accompanied or not by food, any 
missed doses, and a comment section should the subject have a comment. Subjects must 
return the diary when they return to the CRU at the next visit. The data will be transcribed 
from the patient diary into the eCRF.  
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11 STUDY PROCEDURES 
The Study Events Flow Chart (Section 6) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. 
Additional evaluations/testing may be deemed necessary by the PI and/or the Sponsor for 
reasons related to subject safety. 
For this study, the blood collection for total Mo is the critical parameter and needs to be 
collected as close to the exact time point as possible. All other procedures should be 
completed as close to the prescribed/scheduled time as possible, but can be performed 
prior or after the prescribed/scheduled time. 
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures. 
11.1 Safety Assessment 
11.1.1 Screening 
Within 28 days prior to WTX101 dosing, medical and surgical history and demographic data, 
including name, sex, date of birth, race, ethnicity, body weight (kg), height (cm), BMI, history 
of tobacco use, and alcohol use (including number drinks consumed per day) will be 
recorded. Each subject will have a physical examination, vital sign measurements (heart 
rate, blood pressure, temperature, and respiratory rate), 12-lead ECG and the laboratory 
tests of hematological, hepatic and renal function, as well as the additional tests as noted in  
Section 11.1.5.1. 
11.1.2 Physical Examination 
A full physical examination will be performed as per the Study Events Flow Chart 
(Section 6). The physical examination should include general appearance, skin, head and 
neck, lymph nodes, thyroid, musculoskeletal/extremities, cardiovascular system, respiratory 
system, abdomen and a neurological examination. A symptom driven physical examination 
may be performed at any time at the PI’s discretion. 
11.1.3 Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure and heart rate, 
will be measured as outlined in the Study Events Flow Chart (Section 6). 
Blood pressure and heart rate measurements will be performed on subjects after at least 2 
minutes in the supine position. Vital signs may be taken at any other times, if deemed 
necessary. Additional blood pressure and heart rate measurements will be performed with 
subjects in a supine position except when subjects are reclined, semi-reclined or in a seated 
position because of study procedures and/or AEs (e.g., nausea, dizziness) or if deemed 
necessary by the PI. 
Blood pressure and heart rate will be measured within 2 hours prior to Day 1 dosing of each 
period for the predose time point. Postdose vital signs will be performed within 
approximately 10 minutes of the scheduled time point.  
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11.1.4 ECG Monitoring 
Single 12-lead ECGs will be performed as outlined in the Study Events Flow Chart 
(Section 6). 
ECGs will be performed on subjects after at least 2 minutes in supine position. All ECG 
tracings will be reviewed by the Study Physician or his/her designee. The following ECG 
variables will be collected and transcribed into the eCRF; HR, PR interval, QRS duration, QT 
interval, QTcB interval, QTcF interval and overall interpretation 
ECGs will be measured within 2 hours prior to Day 1 dosing of each period for the predose 
time point. When scheduled, postdose ECGs will be performed within approximately 
20 minutes of the scheduled time point. 
A subject will be withdrawn from the study by the Study Physician if, in their medical 
judgment, ECG findings are present which make continued study participation not in the 
subject’s best interest.   
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11.1.5 Blood Sampling for Safety and Pharmacokinetic Analyses 
11.1.5.1 Safety Laboratory Tests 
All tests listed below will be performed as per Study Events Flow Chart (Section 6). Clinical 
laboratory results will be used during screening by the PI to establish eligibility for 
enrollment. Any deviation in laboratory values that are confirmed on re-examination to be 
clinically significant by the PI that would jeopardize the safety of the subject or impact the 
validity of the study results will result in exclusion of that subject.  In addition, laboratory 
safety tests may be performed at various unscheduled time points, if deemed necessary by 
the PI.  
Hematology 
 
Serum Chemistry* 
 
Hemoglobin 
 
Hematocrit  
 
Total and differential leukocyte 
count 
 
Red blood cell count 
 
Platelet count 
 
 
Blood urea nitrogen (BUN) 
 
Bilirubin (total and direct) 
 
Alkaline phosphatase 
 
Aspartate aminotransferase 
 
Alanine aminotransferase 
 
Albumin 
 
Sodium 
 
Potassium 
 
Chloride 
 
Glucose (fasting) 
 
Creatinine** 
 
Urinalysis 
 
Additional Tests 
 
pH 
 
Specific gravity 
 
Protein*** 
 
Glucose 
 
Ketones 
 
Bilirubin 
 
Blood*** 
 
Nitrite*** 
 
Urobilinogen 
 
Leukocyte esterase*** 
 
 
HIV test 
 
HBsAg 
 
HCV 
 
Urine drug screen 
 Opiates 
 Amphetamines 
 Barbiturates 
 Benzodiazepines 
 Cocaine 
 Cannabinoids 
 
Urine alcohol screen 
 
Serum pregnancy test (for females only) 
 
FSH (for post-menopausal females only) 
 
Prothrombin Time (PT) / International 
Normalized Ratio (INR), and activated 
Partial Thromboplastin Time (aPTT) 
 
Cp (Screening) 
 
Total Cu (Screening)  
 
* 
Samples for serum chemistry will be obtained following a fast of at least 8 hours at 
screening, and of at least 6 hours at check-in. In case of dropouts, rechecks and 
postdose serum chemistry, subjects may not have fasted for 6 or 8 hours before 
the serum chemistry sample is taken.  
**  
At screening, creatinine clearance will be calculated using Cockcroft-Gault formula. 
***  If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a 
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microscopic examination (for red blood cells, white blood cells, bacteria, casts, and 
epithelial cells) will be performed. 
11.1.5.2 Pharmacokinetic Assessment Sampling and Processing 
For all subjects, blood samples for the determination of plasma total Mo will be collected and 
processed at scheduled time points as delineated in the Study Events Flow Chart 
(Section 6). A total of approximately 1512 samples (84 per subject) will be collected for PK 
analysis as per the target sample times (times blood will be drawn in relation to dosing). 
The exact time points for collection of PK samples may be amended following evaluation of 
the data from the ongoing Study WTX101-101. If this is required it will be confirmed prior to 
study start. However, the total volume of blood taken for PK sample analysis will not be 
increased from that stated in Section 11.1.5.3. 
 
Details on the sample collection process will be included in the central laboratory manual. 
The predose blood sample should be taken within 60 minutes prior to dosing.  Samples up 
to and including the 8 hour postdose samples will be collected within 3 minutes of the 
scheduled time, thereafter all postdose samples will be collected within 30 minutes of the 
scheduled time. The actual blood collection date and time will be recorded in the source 
documents. All deviations outside the range allowed above will be documented as protocol 
deviations. In all such cases, appropriate time corrections, for the actual time of sample 
collection will be incorporated at the time of data analysis.  
 
The actual sample date and times (date and times samples actually taken) will be recorded 
in the source notes and will be entered at the time of or as soon as possible after sampling. 
All times must be recorded in the 24 hour format. An explanation must be given for any 
blood sample taken outside of the set sampling times.  
 
 
Sample Processing: The Sponsor will provide a laboratory manual that will detail the 
handling of PK blood samples.  
 
Analytical Methodology: Plasma samples will be assayed by a validated inductively 
coupled plasma mass spectrometry (ICP-MS) method, which is specific for the 
determination of Mo. A validation study will be conducted by the appointed bioanalytical 
laboratory to establish validity.  This study will be appended to the final report.  
 
Samples from all subjects enrolled in the study including drop-outs for AEs will be analyzed.  
The criteria for repeat analysis as defined in the respective in-house procedure will be 
followed. 
 
 
 
 
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WTX101-102_CA13895_FINAL_Clinical Study Protocol_25 Feb 2014 
 
11.1.5.3 Blood Volume Drawn for Study Assessments 
Table 1 Blood Volume during the Study 
Sample Type 
Number of 
Timepoints 
Approximate 
Volume per Time 
Point * (mL) 
Approximate Sample 
Volume Over Course 
of Study (mL) 
Screening laboratory safety tests 
(including hematology, serum 
chemistry, serology, Cp, and Cu), FSH 
(for postmenopausal female subjects 
only) and serum pregnancy (for female 
subjects only). 
1 
23 
23 
On-study hematology 
7 
4 
28 
On-study serum chemistry and serum 
pregnancy (for female subjects only) 
when scheduled at the same time 
7 
8.5 
59.5 
PT, INR, and aPTT 
8 
4.5 
36 
Blood for total Mo (PK) 
84 
6 
504 
Total Blood Volume (mL)→ 
650.5** 
** Additional volume, up to 50 mL may need to be collected due to unforeseen circumstances. 
11.1.6 Adverse Events  
11.1.6.1 
Adverse Event Definition 
Adverse Event (AE): Any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
11.1.6.2 
Monitoring 
Subjects will be monitored throughout confinement, and also during a home omeprazole 
dosing, for adverse reactions to the study formulations and/or procedures. At the time of 
release, subjects will be asked how they are feeling. At the time of subsequent sample 
collections in each study period and at the beginning of the second and third period subjects 
will be queried with an open-ended question such as: ‘How have you been feeling since 
your last visit?’  
All symptoms will be evaluated by the PI before the next dose is administered. 
Regardless of the relationship of the AE to the study drug the AE must be recorded in the 
eCRF. Any subject who reports an AE (whether serious or non-serious) or has a clinically 
significant abnormal laboratory test value(s) will be evaluated by the PI and will be treated 
and/or followed up until the symptoms or value(s) return to normal, or acceptable levels, as 
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judged by the PI. Treatment of serious adverse events (SAEs) will be performed by a 
physician, either at Celerion or at a nearby hospital emergency room. Where appropriate, 
medical test(s) and/or examination(s) will be performed to document resolution of event(s). 
Outcome may be classified as resolved, improved, unchanged, worse, fatal or unknown (lost 
to follow-up). 
11.1.6.3 
Reporting 
AEs (including SAEs) will be recorded beginning with the first dose of study medication, 
either omeprazole or WTX101 (as per randomization), and through the EOS visit.  AEs will 
be followed for 14 days after the last dosing with WTX101; or until the event resolves or 
stabilizes, whichever is earlier.  All AEs that occur during this period will be recorded.  
The PI will review each event and assess its relationship to drug treatment (likely, probably, 
possibly, unlikely or unrelated). Each sign or symptom reported will be graded on NCI 
CTCAE toxicity grading scale 5-point severity scale (Grade 1, 2, 3, 4 and 5).8 
The following definitions will be used for rating the severity of AEs: 
AE Severity 
Definition 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Grade 2  
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL* 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL** 
Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death related to AE 
Note 1: A semi-colon indicates ‘or’ within the description of the grade. 
Note 2: Activities of Daily Living (ADL)  
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
The date of onset, time of onset, and outcome of each event will be noted. Additional 
variables to be recorded are as follows:  
 
Date and time when the AE started and stopped 
 
Maximum intensity 
 
Action taken 
 
Whether or not the AE is serious 
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WTX101-102_CA13895_FINAL_Clinical Study Protocol_25 Feb 2014 
 
 
Whether or not the AE caused the subject to discontinue the study 
 
Outcome 
11.1.6.4 
Reporting of Pregnancy and Lactation to the Sponsor 
Although pregnancy and lactation are not considered AEs, it is the responsibility of PIs or 
their designees to report any pregnancy or lactation in a subject (spontaneously reported to 
them) that occurs during the trial or within 14 days of completing the trial. All subjects or 
female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes must be reported. 
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Sponsor Contact information can be found in the Investigator Trial File Binder. 
 
11.1.6.5 Serious Adverse Event 
If any of the above AEs are serious (SAEs), as defined by the Food and Drug Administration 
(FDA) Code of Federal Regulations (CFR), Chapter 21, special procedures will be followed. 
All SAEs will be reported to the Sponsor within one working day and followed by written 
reports within five working days for non-expedited reports and three working days for 
expedited reports, whether or not the serious events are deemed drug-related. All serious 
event reporting will adhere to 21 CFR 312.32 for Investigational New Drugs (IND) and 21 
CFR 314.80 for marketed drugs (15-day alerts). The institutional review board (IRB) will be 
notified by Celerion of the Alert Reports as per FDA regulations; FDA will be notified by the 
Sponsor or their designee. 
SAEs will be followed until either the event is considered stable or resolved. 
The following is the definition for a SAE as per FDA regulations: 
A Serious Adverse Event (SAE) is any adverse drug experience occurring at any dose that 
results in any of the following outcomes: death, a life-threatening adverse drug experience, 
in-patient hospitalization, a persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect. Important medical events that may or may not result in death, be life-
threatening, or require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
If a SAE occurs to a subject on this study, contact the Sponsor’s clinical representatives; 
 Tel.: 
 E-mail: 
 and 
 Tel:  
 E-mail: 
 
listed  in Section 2 and 3.  
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PPD
PPD
PPD
PPD
PPD
PPD
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WTX101-102_CA13895_FINAL_Clinical Study Protocol_25 Feb 2014 
 
12 DATA ANALYSIS 
Data will be handled and processed according to Celerion Standard Operating Procedures, 
which are written based on the principles of Good Clinical Practices. 
12.1 Pharmacokinetic Parameters 
PK parameters for plasma total Mo will be calculated as follows: 
 
AUC0-t: 
 
The area under the plasma concentration versus time curve, 
from time 0 to the last measurable concentration, as calculated 
by the linear trapezoidal method. 
AUC0-inf: 
The area under the plasma concentration versus time curve from 
time 0 to infinity. AUC0-inf is calculated as the sum of AUC0-t plus 
the ratio of the last measurable plasma concentration to the 
elimination rate constant. 
Cmax: 
Maximum measured plasma concentration over the time span 
specified. 
tmax: 
Time of the maximum measured plasma concentration. If the 
maximum value occurs at more than one time point, tmax is 
defined as the first time point with this value. 
z: 
Apparent first-order terminal elimination rate constant calculated 
from a semi-log plot of the plasma concentration versus time 
curve. The parameter will be 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), beginning with the last non-zero concentration. 
t½: 
Apparent first-order terminal elimination half-life will be calculated 
as 0.693/z. 
CL/F 
Apparent oral clearance 
Vz/F 
Apparent oral volume of distribution 
No value for z, AUC0-inf, t½, CL/F, or Vz/F will be reported for cases that do not exhibit a 
terminal log-linear phase in the concentration versus time profile. 
AUC and Cmax parameters will not be calculated for subjects with only 2 or less timepoints 
with detectable concentrations. 
12.2 Statistical Methods 
Detailed methodology for summary and statistical analyses of the data collected in this trial 
will be documented in a Statistical Analysis Plan (SAP). The SAP will be prepared by 
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WTX101-102_CA13895_FINAL_Clinical Study Protocol_25 Feb 2014 
 
Celerion and agreed upon with the Sponsor.  This SAP will not include any pharmacokinetic 
analysis. Additionally, a separate Pharmacokinetic Analysis Plan (PKAP) will be prepared by 
Kramer Consulting LLC and agreed upon with the Sponsor. This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoints 
definition and/or its analysis will also be reflected in a protocol amendment. Additional 
statistical analyses other than those described in this section may be performed if deemed 
appropriate and included in the SAP/PKAP.  
12.2.1 Determination of Sample Size 
The sample size chosen for this study was selected without statistical considerations. It has 
been determined adequate to meet the study objectives. 
12.2.2 Descriptive Statistics 
Arithmetic means, standard deviations (SD), sample size, coefficient of variation (CV), 
median, minimum and maximum values will be calculated for the plasma concentrations and 
the PK parameters listed in Section 12.1. Geometric means will be calculated only for AUC 
and Cmax parameters. 
12.2.3 Analysis of Variance 
An analysis of variance (ANOVA) will be performed on the ln-transformed AUC0-t, AUC0-inf 
and Cmax. The ANOVA model will include sequence, treatment, and period as fixed effects, 
and subject nested within sequence as a random effect. Sequence will be tested using 
subject nested within sequence as the error term at a 10% level of significance. Each 
ANOVA will include calculation of geometric least-squares means (GLSM), the difference 
between treatment GLSM, and the standard error associated with this difference. The above 
statistical analyses will be done using SAS® PROC GLM. 
12.2.4 Ratios and Confidence Intervals 
Ratios of GLSM will be calculated using the exponentiation of the difference between 
treatment GLSM from the analyses on the ln-transformed AUC0-t, AUC0-inf, and Cmax. These 
ratios will be expressed as a percentage relative to the reference treatment. 
Consistent with the two one-sided test for bioequivalence,9 90% (Confidence Interval) CIs for 
the ratios will be derived by exponentiation of the CIs obtained for the difference between 
treatment GLSM resulting from the analyses on the ln-transformed AUC0-t, AUC0-inf, and 
Cmax. The CIs will be expressed as a percentage relative to the reference treatment. 
The comparisons of interest are as follows: 
 
Treatment B compared with Treatment A 
 
Treatment A compared with Treatment C. 
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WTX101-102_CA13895_FINAL_Clinical Study Protocol_25 Feb 2014 
 
12.3 Safety Evaluation 
All subjects who receive at least one dose of WTX101 will be included in the safety 
evaluation, and safety data will be populated in individual eCRFs. All safety data will be 
listed by subject.   
Safety data including physical exams, ECGs, vital signs assessments, clinical laboratory 
evaluations, and AEs will be summarized by treatment group and point of time of collection, 
when applicable. 
Descriptive statistics (arithmetic mean, SD, sample size, CV, median, minimum, maximum, 
and number) will be calculated for quantitative safety data as well as for the difference to 
baseline, when appropriate. In addition, a shift table describing out of normal range shifts 
will be provided for clinical laboratory results. A normal-abnormal shift table will also be 
presented for physical exam results and ECGs. 
WTX101 and omeprazole dosing dates and times will be listed by subject. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) Version 
16.1 and summarized by treatment group for the number of subjects reporting the AE and 
the number of AEs reported. A by-subject AE data listing including (but not limited to) 
verbatim term, coded term, treatment group, severity, and relationship to treatment will be 
provided.  
All concomitant medications recorded during the study will be listed by subject and coded 
with the WHO Dictionary Version 01Sep2013.  Medical history will be listed by subject, and 
coded using the 16.1 version of MedDRA® dictionary. 
 
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WTX101-102_CA13895_FINAL_Clinical Study Protocol_25 Feb 2014 
 
13 STUDY ADMINISTRATION 
13.1 Ethics 
13.1.1 Institutional Review Board  
This protocol and ICF will be reviewed by an institutional review board and the study will not 
start until the Board has approved the protocol or a modification thereof. The Board is 
constituted and operates in accordance with the principles and requirements described in 
the US Code of Federal Regulations (21 CFR Part 56). The board is International 
Conference on Harmonisation (ICH) compliant. If it is necessary for the protocol to be 
amended, the amendment and/or a new version of the protocol, along with an updated ICF 
(if needed) must be provided to the IRB for approval, before implementation.   
13.1.2 Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, US Code of Federal 
Regulations, Good Clinical Practice (GCP), 21 CFR Parts 50, 56, and 312, the ethical 
principles set forth in the Declaration of Helsinki, and the ICH harmonized tripartite guideline 
regarding GCP (E6 Consolidated Guidance, April 1996). 
13.1.3 Subject Information and Consent 
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the subjects in non-technical terms. Subjects will be required to read, sign and 
date an informed consent form summarizing the discussion prior to screening, and will be 
assured that they may withdraw from the study at any time without jeopardizing their medical 
care. If a protocol amendment requires a change to the ICF, then subjects will be required to 
sign and date the updated ICF upon approval by the IRB. 
Subjects will be given a copy of their informed consent form(s). 
13.2 Termination of the Study 
Celerion reserves the right to terminate the study in the interest of subject welfare.  
The Sponsor reserves the right to terminate the study or a study site at any time. Reasons 
for terminating the study may include, but are not limited to, the following: 
 
The incidence and severity of AES in this or other studies with WTX101 indicates a 
potential health hazard to subjects. 
 
Subject enrollment is unsatisfactory. 
 
Data recording is inaccurate or incomplete. 
 
GCP is not being maintained and/or adequately followed. 
 
Administrative reasons. 
 
Reasons unrelated to the study. 
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WTX101-102_CA13895_FINAL_Clinical Study Protocol_25 Feb 2014 
 
13.3 Study Documentation and Recordkeeping 
13.3.1 Source Documents 
The Investigator must maintain detailed records of all study participants who are enrolled in 
the study or who undergo screening. Source documents include subject medical records 
and Investigator’s subject study files, as well as all test results. Information required for 
study purposes and any data recorded in the eCRF must be supported by appropriate 
source documentation. 
 
13.3.2 Data Monitoring and Handling 
Data collection and maintenance will be conducted through Electronic Data Capture. 
Celerion standard eCRFs will be supplied. Validation checks will be built into the live system 
to capture data errors, and data clarification queries will be generated at the time of data 
monitoring. One hundred percent source data verification against the source documents at 
the site will be performed prior to locking of the study database.  Following the completion of 
source data verification, a thorough review of data will be completed manually by the clinical 
data managers to ensure data consistency and to identify and request correction of any 
remaining data errors. All queries will be resolved or closed with written documentation 
providing reasons for irresolvable queries. Additional manual validation checks will be 
performed as needed. Statistical analysis will be performed based on a predefined statistical 
analysis plan. 
The study site will be monitored according to GCP and standard operating procedures. Prior 
to initiation of the study, representatives from the Sponsor or its designee will review with 
the site personnel information about the investigational product, protocol requirements, 
randomization procedures, training on data collection and entry, monitoring requirements, 
and reporting of AEs. During and after the study, periodic site visits will be made to monitor 
for compliance, including verification of the accuracy and completeness of data recorded on 
the eCRFs, source documents, and drug accountability records. 
The eCRFs for each subject must be reviewed and signed by the Investigator. This should 
be done as soon as possible after the subject has completed the study and all data queries 
have been resolved.  
13.4 Data Quality Assurance 
Standard operating procedures are available for all activities performed at Celerion relevant 
to the quality of this study. Designated personnel of Celerion will be responsible for 
implementing and maintaining quality assurance and quality control systems to ensure that 
the trial is conducted, and that data are generated, documented and reported in compliance 
with the study protocol, GCP and Good Laboratory Practice requirements as well as 
applicable regulatory requirements and local laws, rules and regulations relating to the 
conduct of the clinical study. 
The Clinical Study Report will be audited by the quality assurance (QA) department and the 
QA audit certificate will be included in the study report. 
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WTX101-102_CA13895_FINAL_Clinical Study Protocol_25 Feb 2014 
 
13.5 Direct Access to Source Data/Documents 
Celerion will ensure that the Sponsor, IRB and inspection by domestic and foreign 
regulatory authorities will have direct access to all trial-related sites, source data/documents, 
and reports for the purpose of monitoring and auditing (ICH[E6] 5.1.2 & 6.10). Celerion will 
contact the Sponsor immediately if contacted by a regulatory agency about an inspection at 
his or her center. The purpose of Sponsor audit or inspection is to systematically and 
independently examine all study-related activities and documents to determine whether 
these activities were conducted, and data were recorded, analyzed, and accurately reported 
according to the protocol, ICH/GCP guidelines, and any applicable regulatory requirements.  
In the event that other trial-related monitoring should be done by other parties, they will be 
required to sign a confidentiality agreement prior to any monitoring and auditing. 
13.6 Drug Supplies, Packaging and Labeling 
The Sponsor will supply sufficient quantities of WTX101 to allow completion of this study. 
WTX101 will be supplied in two different formulations: 
WTX101 non-coated capsule, 30 mg: 
A size 1 white opaque hydroxypropyl methylcellulose (HPMC) capsule, each capsule 
contains 30 mg of bis-choline tetrathiomolybdate and the following excipients:  475 mg 
anhydrous di-calcium phosphate and 25 mg anhydrous sodium carbonate. 
The capsules are manufactured in accordance with the principles of cGMP at:  
Pharmatek Laboratories, Inc. 
7330 Carroll Road, Suite 200 
San Diego, CA 92121 
USA 
WTX101 30 mg non-coated capsule will be supplied by the Sponsor in blisters containing 
capsules in accordance with all applicable regulatory requirements. Labels will be in 
accordance with all applicable regulatory requirements for the labeling of active 
pharmaceutical ingredients and with Annex 13 of GMP.  Labels will contain the drug name 
(Capsules of WTX101, 30mg), protocol number, lot number, storage conditions and a 
caution that the drug is for clinical investigational use only. 
WTX101 EC tablets, 30 mg: 
A white round tablet containing 30 mg of WTX101 and the following excipients: tri-calcium 
phosphate, sodium carbonate, sodium starch glycolate, magnesium stearate, Opadry clear 
coat, Acryl-eze white enteric coat. 
The WTX101 EC tablets, 30 mg are manufactured in accordance with the principles of 
cGMP at:  
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Pharmatek Laboratories, Inc. 
7330 Carroll Road, Suite 200 
San Diego, CA 92121 
USA 
WTX101 EC tablet, 30 mg will be supplied by the Sponsor in amber glass bottles containing 
tablets and dessicant in accordance with all applicable regulatory requirements. Labels will 
be in accordance with all applicable regulatory requirements for the labeling of active 
pharmaceutical ingredients and with Annex 13 of GMP.  Labels will contain the drug name; 
(Tablets of WTX101, 30 mg), protocol number, lot number, storage conditions and a caution 
that the drug is for clinical investigational use only. 
Omeprazole will be sourced by Celerion. The lot numbers and expiration dates (where 
available) of the study medications supplied will be recorded in the final report. 
13.6 Study Drug Handling, Storage and Return/Disposal 
All material supplied is for use only in this clinical study and should not be used for any other 
purpose. Only subjects enrolled in the study may receive study drug, in accordance with all 
applicable regulatory requirements. Only authorized site staff may supply or administer 
study drug. All study drug supplies will be stored refrigerated at 2-8oC (36-46oF), and in a 
secure area with access limited to the Investigator and authorized staff and under the 
physical conditions that are consistent with the study drug–specific requirements.  
Study drug supplies will be stored securely under the appropriate conditions at the clinical 
study facility according to the State and Commonwealth Laws.   
Standard Operating Procedures will be followed for the receipt, handling and accountability 
of the study formulations. 
The Investigator is responsible for the investigational product accountability, reconciliation 
and record maintenance. In accordance with all applicable regulatory requirements, the 
Investigator or designated site staff must maintain investigational product accountability 
records throughout the course of the study. This person will document the amount of 
investigational product received from the Sponsor, the amount supplied and/or administered 
to and returned by subjects, if applicable. 
A Drug Dispensing Log must be kept current and will contain the following information: 
 
the identification of the subject to whom the drug was dispensed. 
 
the date(s), time(s) and quantity of the drug dispensed to the subject. 
 
the identification of the dispenser. 
Doses will be dispensed in accordance with the study-specific randomization schedule. 
At the conclusion of the study, any unused study medications will be retained by Celerion, 
returned to the Sponsor or designee, or destroyed, as per Sponsor instructions. Records 
shall be maintained by the Investigator of any such alternate disposition of the test drug.  
These records must show the identification and quantity of each unit disposed of, the 
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method of destruction (taking into account the requirements of local law), and the person 
who disposed of the test substance. Such records must be submitted to the Sponsor. If no 
supplies remain, this fact will be documented in the pharmacy product accountability 
records. 
 
13.7 Data Handling and Record Keeping 
All raw data generated in connection with this study, together with the original copy of the 
final report, will be retained by Celerion until at least 5 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in a ICH region or at least 5 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period however if required by the applicable regulatory 
requirements or by an agreement with the sponsor. It is the responsibility of the Sponsor to 
inform the PI/Institution as to when these documents no longer need to be retained. 
13.8 Training of Staff 
The PI is responsible for the conduct of the study at this study site, including delegation of 
specified study responsibilities, and training of study staff. The PI shall ensure that the study 
is carried out in accordance with the protocol, ICH/GCP guidelines, and regulations. 
The PI will maintain a record of all individuals involved in the study (medical, nursing and 
other staff). He or she will ensure that appropriate training relevant to the study is given to all 
of these staff, and that any new information of relevance to the performance of this study is 
forwarded to the staff involved. 
13.9 
Report Format 
According to the ICH Harmonized Tripartite Guideline (Organization of the Common 
Technical Document for the Registration of Pharmaceuticals for Human Use M4 and the ICH 
M2 Expert Working Group), the final report will be written according to the ICH E3 Guideline 
(Structure and Content of Clinical Study Reports).  
13.10 Publication Policy 
All unpublished information given to Celerion by the Sponsor shall not be published or 
disclosed to a third party without the prior written consent of the Sponsor.   
The data generated by this study are considered confidential information and the property of 
the Sponsor. This confidential information may be published only in collaboration with 
participating personnel from the Sponsor or upon Sponsor’s written consent to publish the 
article. 
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14 REFERENCES 
1 Brewer GJ, Hedera P, Kluin KJ, Carlson M, Askari F, Dick RB, Sitterly J, Fink JK, 2003. 
Treatment of Wilson disease with ammonium tetrathiomolybdate: III. Initial therapy in a 
total of 55 neurologically affected patients and follow-up with zinc therapy. Arch Neurol 
60, 379-385. 
2 Brewer GJ, Askari F, Lorincz MT, Carlson M, Schilsky M, Kluin KJ, Hedera P, Moretti P, 
Fink JK, Tankanow R, Dick RB, Sitterly J, 2006a. Treatment of Wilson disease with 
ammonium tetrathiomolybdate: IV. Comparison of tetrathiomolybdate and trientine in a 
double-blind study of treatment of the neurologic presentation of Wilson disease. Arch 
Neurol 63, 521-527 
3 Brewer GJ, Askari F, Dick RB, Sitterly J, Fink JK, Carlson M, Kluin KJ, Lorincz MT, 
2009. Treatment of Wilson's disease with tetrathiomolybdate: V. Control of free copper 
by tetrathiomolybdate and a comparison with trientine. Transl Res 154, 70-77. 
4 Lowndes SA, Adams A, Timms A, Fisher N, Smythe J, Watt SM, Joel S, Donate F, 
Hayward C, Reich S, Middleton M, Mazar A, Harris AL, 2008. Phase I study of copper-
binding agent ATN-224 in patients with advanced solid tumors. Clin Cancer Res 14, 
7526-7534. 
5 Lin J, Zahurak M, Beer TM, Ryan CJ, Wilding G, Mathew P, Morris M, Callahan JA, 
Gordon G, Reich SD, Carducci MA, Antonarakis ES, 2011. A non-comparative 
randomized phase II study of 2 doses of ATN-224, a copper/zinc superoxide dismutase 
inhibitor, in patients with biochemically recurrent hormone-naive prostate cancer. 
Urologic oncology. 
6 Karimbakas J, Langkamp-Henken B, Percival SS, 1998. Arrested maturation of 
granulocytes in copper deficient mice. J Nutr 128, 1855-1860. 
7 Prilosec® 
(omeprazole 
magnesium) 
delayed-release 
capsules, 
full 
prescribing 
information (electronic monograph) published on the FDA website (document issued 
May 2013). Available at:  
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019810s097,022056s013lbl.
pdf, accessed on: 20 Sep 2013. 
8 National Cancer Institute. Common Terminology Criteria for Adverse Events v4.0. NCI, 
NIH, DHHS. May 29, 2009. NIH publication # 09-7473. Available online at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm The quick 
reference guide is available online at: 
 http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf accessed on: 18 Dec 2013 
9 Schuirmann DJ. A comparison of the two one-sided tests procedure and the power 
approach for assessing the equivalence of average bioavailability. J Pharmacokinet 
Biopharm 1987;15: 657-680. 
CA13895, 16.1.1 Protocol and Protocol Amendments
50

SAP_001.pdf: 
A Phase 1, Single-Center, Randomized, 3-Period Crossover 
Study in Healthy Volunteers to Evaluate the Absorption of 
WTX101 After Single Dose Administration of an Enteric 
Coated Formulation with and without food and a Non-
Coated Formulation Coadministered with a Proton Pump 
Inhibitor without Food 
Unique Protocol ID: 
NCT Number: 
Date of SAP:  
WTX101-102 
NCT05319912 
22 May 2014 


 
16.1.9 
Documentation of Statistical Methods 
16.1.9.1 
Pharmacokinetic Analysis 
16.1.9.1.1 Pharmacokinetic Analysis Plan 
 
 
CA13895, 16.1.9 Documentation of Statistical Methods
1


A Phase 1, Single-Center, Randomized, 3-Period Crossover 
Study in Healthy Volunteers to Evaluate the Absorption of 
WTX101 After Single Dose Administration of an Enteric 
Coated Formulation with and without food and a Non-Coated 
Formulation Coadministered with a Proton Pump Inhibitor 
without Food 
 
Protocol WTX101-102 
 
 
Pharmacokinetic Analysis Plan 
 
 
Version 1 
May 22, 2014 
 
 
Prepared for: 
WilsonTherapeutics USA, Inc. 
P.O. Box 17757 
Urbana, Illinois 61803 
USA 
 
Wilson Therapeutics, AB 
Västra Trädgårdsgatan 15 
11453 Stockhold 
Sweden 
 
 
Prepared by: 
Kramer Consulting LLC 
14313 Outpost Way 
North Potomac, MD  20878 
 
CA13895, 16.1.9 Documentation of Statistical Methods
2


CA13895, 16.1.9 Documentation of Statistical Methods
3
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WilsonTherapeutics USA, Inc. — Protocol WTX101-102 
Pharmacokinetic Analysis Plan 
May 22, 2014 
Table of Contents 
Page 
Version 1 
Page ii 
Signature Page ..................................................................................................... i 
Table of Contents ................................................................................................ ii 
List of Abbreviations ......................................................................................... iii 
1.0 
Introduction ......................................................................................................... 1 
2.0 
Study Overview .................................................................................................. 1 
3.0 
Pharmacokinetic Sampling Schedule .................................................................. 2 
4.0 
Blinding and Unblinding..................................................................................... 3 
5.0 
Interim Analysis .................................................................................................. 3 
6.0 
Pharmacokinetic Analysis ................................................................................... 3 
6.1 
Analysis Population ............................................................................................ 3 
6.2 
Pharmacokinetic Analysis ................................................................................... 3 
6.2.1 Pharmacokinetic Parameters ............................................................................... 3 
7.0 
Statistical Analyses ............................................................................................. 4 
7.1 
Primary Analysis ................................................................................................. 5 
7.2 
Secondary Analysis ............................................................................................. 5 
7.3 
Exploratory Analysis .......................................................................................... 5 
8.0 
Quality Control Procedures................................................................................. 6 
9.0 
Tables, Figures, Appendices ............................................................................... 6 
9.1 
Tables .................................................................................................................. 6 
9.2 
Figures................................................................................................................. 6 
9.3 
Appendices .......................................................................................................... 7 
 
CA13895, 16.1.9 Documentation of Statistical Methods
4


WilsonTherapeutics USA, Inc. — Protocol WTX101-102 
Pharmacokinetic Analysis Plan 
May 22, 2014 
List of Abbreviations 
Version 1 
Page iii 
Term 
Definition 
 
 
ANOVA 
Analysis of Variance 
AUC(0-t) 
Area under the plasma concentration-time curve from 0 to the final 
time with a concentration ≥ LOQ 
AUC(inf) 
Area under the plasma concentration-time curve from 0 to infinity 
BMI 
Body Mass Index 
CI 
Confidence interval 
CL/F 
Clearance uncorrected for bioavailability 
Cmax 
Maximum plasma concentration 
EC 
Enteric coated 
F 
Bioavailability 
GMR 
Geometric mean ratio 
h 
Hour 
IM 
Intramuscular 
kg 
Kilogram 
LOQ 
Validated lower limit of the bioanalytical method 
m² 
Squared meter 
mg 
Milligram 
mL 
Milliliter 
Mo 
Molybdenum 
MSE 
Mean squared error 
ng 
Nanogram 
PK 
Pharmacokinetic 
PKAP 
Pharmacokinetic analysis plan 
PPI 
Proton pump inhibitor 
SAP 
Statistical analysis plan 
t½ 
Elimination half-life 
Tmax 
Time of maximum plasma concentration 
Vz/F 
Volume of distribution uncorrected for bioavailability 
WSCV 
Within-subject coefficient of variation 
λz 
Elimination rate constant 
CA13895, 16.1.9 Documentation of Statistical Methods
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WilsonTherapeutics USA, Inc. — Protocol WTX101-102 
Pharmacokinetic Analysis Plan 
May 22, 2014 
 
Version 1 
Page 1 
1.0 
Introduction 
This pharmacokinetic analysis plan (PKAP) summarizes the planned presentation and 
analysis of the clinical pharmacokinetic data from WilsonTherapeutics USA, Inc. 
Protocol WTX101-102, “A Phase 1, Single-Center, Randomized, 3-Period Crossover 
Study in Healthy Volunteers to Evaluate the Absorption of WTX101 After Single Dose 
Administration of an Enteric Coated Formulation with and without food and a Non-
Coated Formulation Coadministered with a Proton Pump Inhibitor without Food”. 
Some of the analyses detailed here may be more detailed or in some aspects slightly 
different than those described in the protocol.  In case of differences, this PKAP would 
supersede the pharmacokinetic sections in the protocol. 
Only the pharmacokinetic analyses are described in this PKAP.  The summaries of 
demographics, baseline characteristics, and safety are detailed in a separate statistical 
analysis plan (SAP) for this study. 
2.0 
Study Overview 
This is an open-label, 3-treatment, 3-period, 6-sequence, single-dose, randomized 
crossover study of the pharmacokinetics and comparative bioavailability of WTX101 
after administration of an enteric coated (EC) tablet versus an uncoated capsule with a 
proton pump inhibitor (PPI) and after administration of the EC tablet under fed and fasted 
conditions. 
The treatments to be administered are as follows: 
Treatment A: WTX101 EC tablets, 60 mg (2 × 30mg) on Day 1 after an overnight fast. 
Treatment B: WTX101 EC tablets, 60 mg (2 × 30mg) on Day 1, 30 minutes after the 
start of a high calorie / high fat breakfast, preceded by an overnight fast. 
Treatment C: Omeprazole 20 mg (1 × 20 mg delayed-release capsule) once-daily (QD) 
on the mornings of Days -5 to -1 after an overnight fast, omeprazole 
20 mg delayed-release capsule at Hour -1 on Day 1 after an overnight fast, 
and WTX101 uncoated capsules, 60 mg (2 × 30mg) at Hour 0 on Day 1. 
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WilsonTherapeutics USA, Inc. — Protocol WTX101-102 
Pharmacokinetic Analysis Plan 
May 22, 2014 
 
Version 1 
Page 2 
Eighteen (18) healthy adult male and female volunteers will be randomly assigned to 1 of 
6 treatment sequences, as shown in Table 1. 
Table 1: Treatment Sequences. 
 
Treatment* 
Sequence 
Period 1 
Period 2 
Period 3 
 
 
 
 
1 
A 
B 
C 
2 
B 
C 
A 
3 
C 
A 
B 
4 
B 
A 
C 
5 
A 
C 
B 
6 
C 
B 
A 
*A = WTX101 EC tablets, 60 mg (2 × 30mg) on Day 1 after an overnight fast; B = 
WTX101 EC tablets, 60 mg (2 × 30mg) on Day 1, 30 minutes after the start of a 
high calorie / high fat breakfast, preceded by an overnight fast; C = Omeprazole 20 
mg (1 × 20 mg delayed-release capsule) once-daily (QD) on the mornings of Days 
-5 to -1 after an overnight fast, omeprazole 20 mg delayed-release capsule at Hour 
-1 on Day 1 after an overnight fast, and WTX101 uncoated capsules, 60 mg (2 × 
30mg) at Hour 0 on Day 1. 
Serial blood samples for the measurement of the plasma concentrations of total 
molybdenum (Mo) will be obtained over a 192-hour period after each dose.  There will 
be a minimum 14-day washout between the dosing in each period. 
3.0 
Pharmacokinetic Sampling Schedule 
On Study Days 1, 15, and 29 (Periods 1, 2, and 3, respectively), blood samples for the 
determination of total Mo concentrations will be collected before and at 1, 2, 3, 3.5, 4, 
4.5, 5, 6, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12, 14, 16, 24, 36, 48, 72, 96, 120, 144, 168, and 192 
hours after dosing.  Samples collected through 48 hours will be on an inpatient basis and 
from 72 through 192 hours on an outpatient basis.  There will be a minimum 14-day 
washout between the dosing in each period. 
There will be a total of 84 blood samples for pharmacokinetics per subject, 28 per 
treatment. 
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WilsonTherapeutics USA, Inc. — Protocol WTX101-102 
Pharmacokinetic Analysis Plan 
May 22, 2014 
 
Version 1 
Page 3 
4.0 
Blinding and Unblinding 
This is an objective study and blinding is not required. 
5.0 
Interim Analysis 
No interim analysis will be conducted. 
6.0 
Pharmacokinetic Analysis 
6.1 
Analysis Population 
The analysis population will consist of all subjects who complete at least 2 periods of the 
study and have data sufficient for the determination of PK parameters.  Any subjects that 
are excluded from the analysis will be listed along with the reason for the exclusion. 
6.2 
Pharmacokinetic Analysis 
Actual blood sampling times will be used in all PK analyses.  Per protocol times will be 
used to calculate mean plasma concentrations for tabular and graphical displays.  All PK 
calculations and generation of individual subject plasma concentration vs. time graphs 
will be done using SAS for Windows Version 9.3 or higher under Windows XP 
Professional or higher.  Graphs of mean plasma concentration will be prepared using 
SigmaPlot for Windows Version 12.5 or higher. 
6.2.1 Pharmacokinetic Parameters 
Pharmacokinetic parameters for total Mo will be calculated using non-compartmental 
analysis.  Only plasma concentrations equal to or greater than the validated lower limit 
(LOQ) of the assay will be used in the pharmacokinetic analysis.  Plasma concentrations 
< LOQ will be taken as 0 for the calculation of the descriptive statistics for plasma 
concentrations at each sampling time.  For the PK analysis, plasma concentrations < LOQ 
that occur from pre-dose to the first concentration ≥ LOQ will be taken as 0 and those 
that occur thereafter will be taken as missing. 
Cmax and Tmax will be taken directly from the data.  The elimination rate constant, λz, 
will be calculated as the negative of the slope of the terminal log-linear segment of the 
CA13895, 16.1.9 Documentation of Statistical Methods
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WilsonTherapeutics USA, Inc. — Protocol WTX101-102 
Pharmacokinetic Analysis Plan 
May 22, 2014 
 
Version 1 
Page 4 
plasma concentration-time curve.  The slope will be determined from a plot of the natural 
log of the terminal plasma concentrations against time; at least 3 terminal plasma 
concentration time points, beginning with the final concentration ≥ LOQ, will be selected 
for the determination of λz and the regression will have a coefficient of determination (r²) 
≥ 0.9000.  The range of data to be used for each subject and treatment will be determined 
by visual inspection of a semi-logarithmic plot of concentration vs. time.  Elimination 
half-life (t½) will be calculated according to the following equation: 
z
t
λ
693
.0
½ =
. 
Area under the curve to the final sample with a concentration ≥ LOQ [AUC(0-t)] will be 
calculated using the linear trapezoidal method and extrapolated to infinity [AUC(inf)] 
using 
z
C
t
AUC
AUC
tf
λ
+
−
=
)
0
(
(inf)
 
where Ctf is the final concentration ≥ LOQ. 
Clearance (CL/F) and volume of distribution (Vz/F), uncorrected for bioavailability (F), 
will be calculated according to 
(inf)
/
AUC
Dose
F
CL
=
 and 
z
AUC
Dose
F
Vz
λ
×
=
(inf)
/
, 
respectively. 
7.0 
Statistical Analyses 
Individual subject plasma total Mo concentrations, blood sampling times, and PK 
parameters will be listed by treatment group.  Plasma concentrations and PK parameters 
will be summarized by treatment group using descriptive statistics.  Summaries for 
plasma concentrations will include number, arithmetic mean, standard error, and 
coefficient of variation, geometric mean and coefficient of variation, and minimum, 
CA13895, 16.1.9 Documentation of Statistical Methods
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WilsonTherapeutics USA, Inc. — Protocol WTX101-102 
Pharmacokinetic Analysis Plan 
May 22, 2014 
 
Version 1 
Page 5 
median and maximum.  Summaries for PK parameters will include number, arithmetic 
mean, standard deviation, and coefficient of variation, geometric mean and coefficient of 
variation, and minimum, median, maximum. 
7.1 
Primary Analysis 
The PK parameters for total Mo — Cmax, AUC(0-t), and AUC(inf) —will be compared 
among treatments using an Analysis of Variance (ANOVA) statistical model with 
sequence, treatment, and period as the fixed effects and subject within sequence as a 
random effect, using the natural logarithms of the data. 
Confidence intervals (90%) will be constructed for the least squares geometric treatment 
ratios (GMR) — Treatment B (WTX101 EC Tablet + Food)-to-Treatment A (WTX101 
EC Tablet Fasted) and Treatment A (WTX101 EC Tablet Fasted)-to-Treatment C 
(WTX101 Uncoated Capsule + PPI Fasted) — of all 3 parameters using the natural 
log-transformed data and the two one-sided t-tests procedure.  The GMRs and associated 
90% confidence limits (CI) will be exponentiated back to the original scale. 
7.2 
Secondary Analysis 
The within-subject coefficient of variation (WSCV) of Cmax, AUC(0-t), and AUC(inf) 
will be estimated using 
1
%
100
−
×
=
MSE
e
WSCV
 
where MSE is the mean squared error from the ANOVA. 
7.3 
Exploratory Analysis 
Relationships between CL/F and Vz/F and body size — weight (kg) and BMI (kg/m² — 
will be examined graphically for each treatment.  If suggested by the graphs, regression 
models may be fit to the data. 
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WilsonTherapeutics USA, Inc. — Protocol WTX101-102 
Pharmacokinetic Analysis Plan 
May 22, 2014 
 
Version 1 
Page 6 
8.0 
Quality Control Procedures 
All data — random code*, plasma concentrations, dosing and sampling dates and times 
— will be received electronically, either as SAS datasets or Excel workbooks; no data, at 
any time, will be entered by hand.  The creation of the analysis data sets will be quality 
controlled by a visual inspection of a graph of each subject’s plasma concentration vs. 
time data to ensure that there are no errors. 
The data used to construct summary figures and tables will be created by the SAS 
programs used to either create the analysis data sets or to perform the pharmacokinetic 
analyses.  Data will be transferred electronically to Excel workbooks, e.g. there will be no 
data transcription, from which the figures and tables will then be constructed.  Figures 
and tables will be hyperlinked to Appendix listings containing the source data. 
As a final check, data from a minimum of two subjects will be selected, analyzed 
manually in an Excel workbook, and the results verified against those created by the SAS 
programs. 
9.0 
Tables, Figures, Appendices 
9.1 
Tables 
Table 1: 
Summary of total Mo pharmacokinetic parameters after administration of a 
single 60 mg (2 × 30 mg) dose of WTX101 EC tablets to healthy volunteers 
under fasted and fed conditions and a single 60 mg (2 × 30 mg) dose of 
WTX101 uncoated capsules with a PPI under fasted conditions. 
Table 2: 
Statistical analysis of total Mo pharmacokinetic parameters after 
administration of a single 60 mg (2 × 30 mg) dose of WTX101 EC tablets to 
healthy volunteers under fasted and fed conditions and a single 60 mg (2 × 30 
mg) dose of WTX101 uncoated capsules with a PPI under fasted conditions. 
9.2 
Figures 
Figure 1: 
Mean plasma concentrations of total Mo administration of a single 60 mg 
(2 × 30 mg) dose of WTX101 EC tablets to healthy volunteers under fasted 
and fed conditions — linear axes (left panel) and semi-logarithmic (right 
panel). 
                                                 
* If not created by Kramer Consulting LLC. 
CA13895, 16.1.9 Documentation of Statistical Methods
11


WilsonTherapeutics USA, Inc. — Protocol WTX101-102 
Pharmacokinetic Analysis Plan 
May 22, 2014 
 
Version 1 
Page 7 
Figure 2: 
Mean plasma concentrations of total Mo administration of a single 60 mg (2 
× 30 mg) dose of WTX101 EC tablets and a single 60 mg (2 × 30 mg) dose 
of WTX101 uncoated capsules with a PPI to healthy volunteers under fasted 
conditions conditions — linear axes (left panel) and semi-logarithmic (right 
panel). 
9.3 
Appendices 
Appendix I: 
Randomization Code 
Appendix II: 
Individual Subject Plasma Total Mo Concentrations 
Appendix III: 
Individual Subject Blood Sampling Times 
Appendix IV: 
Mean ± Standard Deviation Plasma Total Mo Concentrations 
(ng/mL) 
Appendix V: 
Individual Subject Total Mo Pharmacokinetic Parameters 
Appendix VI: 
Descriptive Statistics for Total Mo Pharmacokinetic Parameters 
Appendix VII: 
Statistical Analysis of Total Mo Pharmacokinetic Parameters 
Appendix VIII: 
Individual Subject Plasma Total Mo Concentration vs. Time 
Graphs — Linear Axes 
Appendix IX: 
Individual Subject Plasma Total Mo Concentration vs. Time 
Graphs — Semi-Logarithmic Axes† 
 
                                                 
† Graphs include line segments indicating the range of data used to estimate λz. 
CA13895, 16.1.9 Documentation of Statistical Methods
12


16.1.9.1.2 Pharmacokinetic Report 
CA13895, 16.1.9 Documentation of Statistical Methods
2


A Phase 1, Single-Center, Randomized, 3-Period Crossover Study in 
Healthy Volunteers to Evaluate the Absorption of WTX101 After Single 
Dose Administration of an Enteric Coated Formulation with and 
without food and a Non-Coated Formulation Coadministered with a 
Proton Pump Inhibitor without Food
Study WTX101-102
Pharmacokinetic and Statistical Report
Prepared for:
Wilson Therapeutics USA, Inc.
P.O. Box 17757
Urbana, IL  61803
USA
Wilson Therapeutics, AB
Västra Trädgårdsgatan 15
111 53 Stockholm
Sweden
Prepared by:
Kramer Consulting LLC
14313 Outpost Way
North Potomac, MD  20878-4352
Signature:
Date:
July 14, 2014
CA13895, 16.1.9 Documentation of Statistical Methods
14
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Wilson Therapeutics USA, Inc. 
Page i 
Study WTX101-102 
July 14, 2014 
Table of Contents 
 
 
Page 
 
Table of Contents .....................................................................................................i 
List of Tables  ........................................................................................................ ii 
List of Figures ....................................................................................................... iii 
List of Abbreviations .............................................................................................iv 
1.0 
Synopsis of Pharmacokinetic Results ....................................................................1 
2.0 
Introduction ...........................................................................................................2 
3.0 
Objective ................................................................................................................2 
4.0 
Study Conduct .......................................................................................................3 
4.1 
Clinical ................................................................................................................... 3 
4.2 
Bioanalytical .......................................................................................................... 3 
4.3 
Pharmacokinetic and Statistical Analyses ............................................................. 3 
5.0 
Overview of the Study Design ...............................................................................3 
6.0 
Pharmacokinetic and Statistical Methods ..............................................................4 
6.1 
Pharmacokinetic Methods ..................................................................................... 4 
6.2 
Statistical Methods ................................................................................................ 6 
6.2.1 Primary Analysis ................................................................................................... 6 
6.2.2 Secondary Analysis ............................................................................................... 7 
6.2.3 Exploratory Analysis ............................................................................................. 7 
7.0 
Results ...................................................................................................................7 
7.1 
Subjects with a Pre-Dose Concentration ≥ LOQ ................................................... 7 
7.2 
Pharmacokinetic Analysis Population ................................................................... 8 
7.3 
Pharmacokinetics ................................................................................................... 8 
7.3.1 Results ................................................................................................................... 8 
7.3.2 Discussion ............................................................................................................ 16 
8.0 
Conclusions .........................................................................................................16 
9.0 
References ...........................................................................................................17 
Appendix I  
Random Code ........................................................................... 18 
Appendix II 
Subject Height, Weight, and BMI ............................................ 19 
Appendix III 
Individual Subject Plasma Concentrations .............................. 20 
Appendix IV 
Individual Subject Blood Sampling Times .............................. 26 
Appendix V 
Descriptive Statistics for Plasma Concentrations .................... 32 
Appendix VI 
Individual Subject Pharmacokinetic Parameters ...................... 35 
Appendix VII 
Descriptive Statistics for Pharmacokinetic Parameters ........... 38 
Appendix VIII 
Statistical Analysis of Pharmacokinetic Parameters ................ 39 
Appendix IX 
Individual Subject Total Mo Plasma Concentration vs. 
Time Graphs — Linear Axes ................................................... 46 
Appendix X 
Individual Subject Total Mo Plasma Concentration vs. 
Time Graphs — Semi-Logarithmic Axes ................................ 51 
CA13895, 16.1.9 Documentation of Statistical Methods
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Wilson Therapeutics USA, Inc. 
Page ii 
Study WTX101-102 
July 14, 2014 
List of Tables 
 
 
Page 
 
Table 1: 
Treatment Sequences. .................................................................................... 4 
Table 2: 
Subjects with a pre-dose concentration ≥ LOQ. ............................................ 8 
Table 3: 
Summary of total Mo PK parameters after administration of a single 
60 mg (2 × 30 mg) dose of WTX101 EC Tablets under fasted and 
fed conditions and UC + PPI under fasted conditions. ................................ 12 
Table 4: 
Statistical analysis of total Mo PK parameters after administration of 
a single 60 mg (2 × 30 mg) dose of WTX101 EC Tablets under 
fasted and fed conditions and UC + PPI under fasted conditions................ 13 
Table 5: 
Summary of between-subject coefficients of variation of total Mo 
Cmax, AUC(0-t), and AUC(inf) after administration of a single 
60 mg (2 × 30 mg) dose of WTX101 EC Tablets under fasted and 
fed conditions and UC + PPI under fasted conditions. ................................ 15 
 
CA13895, 16.1.9 Documentation of Statistical Methods
16


Wilson Therapeutics USA, Inc. 
Page iii 
Study WTX101-102 
July 14, 2014 
List of Figures 
 
 
Page 
 
Figure 1: 
Mean ± standard error plasma concentrations of total Mo after 
administration of a single 60 mg (2 × 30 mg) dose of WTX101 EC 
Tablets under fasted and fed conditions and UC + PPI under fasted 
conditions — linear axes (left panel) and semi-logarithmic (right 
panel). .......................................................................................................... 11 
Figure 2: 
Individual subject CL/F vs. body weight (left panel) and BMI (right 
panel) of total Mo after administration of a single 60 mg (2 × 30 mg) 
dose of WTX101 EC Tablets fasted to healthy volunteers.......................... 14 
Figure 3: 
Individual subject CL/F vs. body weight (left panel) and BMI (right 
panel) of total Mo after administration of a single 60 mg (2 × 30 mg) 
dose of WTX101 uncoated capsules + PPI fasted to healthy 
volunteers. .................................................................................................... 15 
 
CA13895, 16.1.9 Documentation of Statistical Methods
17


Wilson Therapeutics USA, Inc. 
Page iv 
Study WTX101-102 
July 14, 2014 
List of Abbreviations 
 
 
Term 
Definition 
λz 
Elimination rate constant 
AUC(0-t) 
Area under the plasma concentration-time curve from 0 to the final 
time with a concentration ≥ LOQ. 
AUC(inf) 
Area under the plasma concentration-time curve to infinity 
BMI 
Body Mass Index 
CL/F 
Total clearance uncorrected for bioavailability (F) 
cm 
Centimeter 
Cmax 
Maximum plasma concentration 
Cu 
Copper 
EC 
Enteric coated 
F 
Bioavailability 
h 
hour 
ICP-MS 
Inductively coupled plasma mass spectrometry 
kg 
Kilogram 
LOQ 
Validated lower limit of the bioanalytical method(s) 
m² 
Meter Squares 
mg 
Milligram 
mL 
Milliliter 
Mo 
Molybdenum 
MW 
Molecular weight 
ng 
nanogram 
PK 
Pharmacokinetics 
PPI 
Proton Pump Inhibitor 
QD 
Once daily 
r² 
Coefficient of determination 
t½ 
Elimination half-life 
Tlag 
Absorption lag time 
Tmax 
Time of maximum plasma concentration 
UC 
Uncoated Capsule 
Vz/F 
Volume of distribution uncorrected for bioavailability (F) 
 
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Wilson Therapeutics USA, Inc. 
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Study WTX101-102 
July 14, 2014 
 
1.0 
Synopsis of Pharmacokinetic Results 
Protocol WTX101-102 was an open-label, 3-treatment, 3-period, 6-sequence, 
single-dose, randomized crossover study of the pharmacokinetics and comparative 
bioavailability of WTX101 after administration of an Enteric Coated (EC) Tablet versus 
dosing with the current uncoated capsule (UC) coadministered with a proton pump 
inhibitor (PPI; omeprazole) under fasting conditions and the effect of dosing an EC 
Tablet with and without food on the absorption of WTX101.  Subjects received, 
according to a randomization schedule (Appendix I), 1 of the WTX101 treatments.  
Dosing occurred after an overnight fast (Treatments A and C) or 30 minutes after 
ingesting a high calorie / high fat meal (Treatment B) and there was a minimum 14-day 
washout between the dosing in successive periods. 
Eighteen (18) subjects were enrolled into and completed the study.  One (1) subject had a 
pre-dose plasma concentration after administration of the EC Tablet Fed that was ≥ LOQ 
and ≥ 5% of the corresponding Cmax and was excluded from the descriptive statistics 
and statistical analyses for that treatment.  The PK analysis population was therefore 
comprised of 18 subjects for the EC Tablet Fasted and the UC + PPI Fasted and 
17 subjects for the EC Tablet Fed. 
• Based on total Mo, administration of the EC Tablet Fasted results in comparable 
exposure to the UC + PPI Fasted in most subjects. 
• Based on total Mo, administration of the EC Tablet Fed results in a 60% to 75% 
decrease in exposure compared to the EC Tablet Fasted in the majority of subjects. 
• The mean t½ for total Mo was essentially the same for all 3 treatments, with an 
overall mean of ~48 h or 2 days. 
• There were no apparent relationships between CL/F and body size (weight, BMI), 
suggesting that a fixed dose, rather than a dose based on body size, i.e. mg/kg or 
mg/m², may be appropriate for WTX101. 
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Study WTX101-102 
July 14, 2014 
 
• The lowest between-subject coefficients of variation (BSCV) for Cmax, AUC(0-t), 
and AUC(inf) were observed for the UC + PPI Fasted, with an ~2-fold increase when 
the EC Tablet was administered under fasted conditions and an ~4-fold increase, 
based on the AUCs, when the EC Tablet was administered under fed conditions. 
• Administration of WTX101 either as the UC + PPI or the EC Tablet under fasted 
conditions should result in comparable plasma concentrations of total Mo in most 
subjects.  However, administration of the EC Tablet under fed conditions results in a 
large decrease in exposure with increased between-subject variability. 
2.0 
Introduction 
WTX101 is an oral de-coppering agent. It is a bis-choline salt of tetrathiomolybdate, 
bis[(2-hydroxyethyl)trimethylammonium] tetrathiomolybdate.  WTX101 is being 
developed by Wilson Therapeutics for the treatment of Wilson Disease (WD).  WD is a 
rare autosomal-recessive disorder caused by mutations in the ATP7B gene, resulting in a 
disturbed copper (Cu) metabolism.  In the affected patients, Cu accumulates in the liver 
and in other tissues including the central nervous system.  Left untreated, morbidity is 
progressive and the condition is eventually fatal. 
In previous studies, coadministration of proton pump inhibitors (PPI) has been shown to 
increase the bioavailability of tetrathiomolybdate and to reduce gastrointestinal side 
effects.  An Enteric Coated (EC) tablet formulation would be expected to offer the same 
benefits of increased bioavailability and reduced gastrointestinal side effects while 
avoiding the need to coadminister a PPI. 
This study was conducted as a crossover study, aimed at evaluating the absorption of 
WTX101 from the EC tablet under fed and fasted conditions and compared to the current 
uncoated capsule (UC) administered with a proton pump inhibitor (PPI; omeprazole) 
under fasting conditions. 
3.0 
Objective 
The primary objectives of the study were to evaluate: 
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• The effect of dosing with an EC tablet versus dosing with the current UC 
coadministered with a PPI  under fasting conditions, on the absorption of WTX101. 
• The effect of dosing an EC Tablet with and without food on the absorption of 
WTX101. 
• The safety and tolerability of WTX101. 
4.0 
Study Conduct 
4.1 
Clinical 
This study was conducted at Celerion, 621 Rose Street, Lincoln, NE 68502, under the 
direction of 
 
A copy of the protocol is included in the clinical summary that accompanies this report. 
4.2 
Bioanalytical 
Plasma concentrations of total molybdenum (Mo) were measured using an Inductively 
coupled plasma mass spectrometry (ICP-MS) method by QPS Netherlands B.V., Petrus 
Campersingel 123, 9713 AG Groningen, The Netherlands.  A detailed report of the 
bioanalytical methodology and results accompanies this report. 
4.3 
Pharmacokinetic and Statistical Analyses 
The PK and statistical analyses were done by 
 Kramer 
Consulting LLC, 14313 Outpost Way, North Potomac, MD  20878, and are the subject of 
this report. 
5.0 
Overview of the Study Design 
This was an open-label, 3-treatment, 3-period, 6-sequence, single-dose, randomized 
crossover study of the pharmacokinetics and comparative bioavailability of WTX101 
after administration of an EC Tablet versus dosing with the current UC + PPI under 
fasting conditions and the effect of dosing an EC Tablet with and without food on the 
absorption of WTX101. 
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The treatments to be administered were as follows: 
Treatment A: WTX101 EC Tablets, 60 mg (2 × 30 mg) at Hour 0 on Day 1 following an 
overnight fast. 
Treatment B: WTX101 EC Tablets, 60 mg (2 × 30 mg) at Hour 0 on Day 1, 30 minutes 
after the start of a high-fat breakfast, preceded by an overnight fast. 
Treatment C: WTX101 UC, 60 mg (2 × 30 mg), after an overnight fast, preceded by 
omeprazole 20 mg (1 × 20 mg delayed-release tablet) once-daily the 
mornings of Day -5 to Day -1. 
Eighteen (18) healthy adult male and female volunteers were randomly assigned 
(Appendix I) to 1 of 6 treatment sequences, as shown in Table 1. 
Table 1: Treatment Sequences. 
 
Treatment* 
Sequence 
Period 1 
Period 2 
Period 3 
 
 
 
 
1 
A 
B 
C 
2 
B 
C 
A 
3 
C 
A 
B 
4 
B 
A 
C 
5 
A 
C 
B 
6 
C 
B 
A 
*A = WTX101 EC Tablets, 60 mg (2 × 30 mg) fasted; B = WTX101 EC Tablets, 
60 mg (2 × 30 mg) fed; C = WTX101 UC 60 mg (2 × 30 mg) + PPI fasted 
On Study Days 1, 15, and 29 (Periods 1, 2, and 3, respectively), blood samples for the 
determination of total Mo concentrations were collected before and at 1, 2, 3, 3.5, 4, 4.5, 
5, 6, 7, 8, 10, 12, 16, 24, 36, 48, 72, 96, 120, 144, 168, and 192 hours after dosing.  
Samples collected through 48 hours were on an inpatient basis and from 72 through 192 
hours on an outpatient basis.  There was a minimum 14-day washout between the dosing 
in each period. 
6.0 
Pharmacokinetic and Statistical Methods 
6.1 
Pharmacokinetic Methods 
All PK parameters were calculated using non-compartmental analysis.  Only those 
plasma concentrations equal to or greater than the respective LOQ (total Mo – 
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0.1 ng/mL) were used in the analysis.  Plasma concentrations < LOQ were taken as 0 for 
the calculation of the descriptive statistics for plasma concentrations at each sampling 
time.  For the pharmacokinetic analysis, plasma concentrations < LOQ that occurred from 
pre-dose to the first concentration ≥ LOQ were treated as 0 and those that occur thereafter 
were treated as missing.  Actual sampling times were used for all pharmacokinetic 
analyses.  Protocol times were used to calculate mean plasma concentrations for 
graphical displays. 
The maximum plasma concentration (Cmax) and time to Cmax (Tmax) were taken 
directly from the data.  If the plasma concentration at the 1st sample after drug 
administration — 1 h — was < LOQ, then the absorption lag time (Tlag) was taken as the 
1st succeeding sampling time with a concentration ≥ LOQ.  The elimination rate constant, 
λz, was calculated as the negative of the slope of the terminal log-linear segment of the 
plasma concentration-time curve.  The slope was determined from a plot of the natural 
log of the terminal plasma concentrations against time; at least 3 terminal plasma 
concentration time points, beginning with the final concentration ≥ LOQ, were selected 
for the determination of λz and the regression will have a coefficient of determination (r²) 
≥ 0.9000.  The range of data used for each subject and treatment was determined by 
visual inspection of a semi-logarithmic plot of concentration vs. time.  Elimination half-
life (t½) was calculated according to the following equation. 
z
t
λ
693
.0
½ =
 
Area under the curve from zero to the final sample with a concentration ≥ LOQ 
[AUC(0-t)] was calculated using the linear trapezoidal method and extrapolated to 
infinity [AUC(inf)] using 
z
tf
C
t
AUC
AUC
λ
+
−
=
)
0
(
(inf)
 
where Ctf is the final concentration ≥ LOQ. 
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The clearance (CL/F) and volume of distribution (Vz/F) of Mo, uncorrected for 
bioavailability (F), were calculated according to 
(inf)
/
AUC
Dose
F
CL
=
 and 
z
AUC
Dose
F
Vz
λ
×
=
(inf)
/
, 
respectively, where Dose represents the dose of Mo.  The molecular weights (MW) of 
WTX101 and Mo are 432.52 and 95.94, respectively, and thus 60 mg of WTX101 
represents 13.3 mg of Mo. 
All pharmacokinetic calculations were done and individual subject plasma concentration-
time graphs were prepared using SAS® for Windows® Version 9.3.  Graphs of mean 
plasma concentration vs. time and other in-text graphs were prepared using SigmaPlot for 
Windows Version 12.5. 
6.2 
Statistical Methods 
Plasma concentrations, actual blood sampling times, and pharmacokinetic parameters are 
listed; concentrations and pharmacokinetic parameters are summarized using descriptive 
statistics. 
All statistical analyses were done using SAS® for Windows® Version 9.3. 
6.2.1 
Primary Analysis 
The PK parameters for total Mo — Cmax, AUC(0-t), and AUC(inf) — were compared 
between treatments using an Analysis of Variance (ANOVA) statistical model with 
sequence, treatment, and period as the fixed effects and subject within sequence as a 
random effect, using the natural logarithms of the data. 
Confidence intervals (90%) were constructed for the least squares geometric mean ratios 
(GMR) — Treatment B (EC Tablet Fed)-to-Treatment A (EC Tablet Fasted) and 
Treatment A (EC tablet Fasted)-to-Treatment C (UC + PPI Fasted) — of all 3 parameters 
using the natural log-transformed data and the two one-sided t-tests procedure.  The 
GMRs and associated 90% confidence limits (CI) were exponentiated back to the original 
scale. 
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6.2.2 
Secondary Analysis 
The within-subject coefficient of variation (WSCV) of Cmax, AUC(0-t), and AUC(inf) 
were estimated using 
1
%
100
−
×
=
MSE
e
WSCV
 
where MSE is the mean squared error from the ANOVA. 
6.2.3 
Exploratory Analysis 
Relationships between CL/F and body size — weight (kg) and BMI (kg/m² — were 
examined graphically for each treatment.  If suggested by the graphs, regression models 
could be fit to the data. 
7.0 
Results 
The random code is shown in Appendix I and the individual subject body size — weight 
and body mass index (BMI) — are listed in Appendix II.  The individual subject plasma 
total Mo concentrations, actual blood sampling times, and descriptive statistics for 
plasma concentrations are listed in Appendix III, Appendix IV, and Appendix V 
respectively.  Individual subject PK parameters are listed in Appendix VI and the 
associated descriptive statistics for the PK parameters are in Appendix VII.  The 
statistical analysis of the total Mo PK parameters is in Appendix VIII.  Individual subject 
graphs of plasma total Mo concentration vs. time on linear axes can be found in 
Appendix IX and on semi-logarithmic axes in Appendix X.  The latter contains line 
segments indicating the range of data used to estimate λz for those datasets for which it 
could be estimated. 
7.1 
Subjects with a Pre-Dose Concentration ≥ LOQ 
Two (2) subjects had a plasma total Mo concentration prior to dosing in Period 2 that was 
≥ LOQ (0.1 ng/mL) (Table 2).  For Subject 
 the pre-dose concentration was 40.60% 
of the corresponding Cmax and the data for this treatment — EC Tablet Fed — for this 
subject was excluded from the descriptive statistics and statistical analyses.1  For Subject 
 the pre-dose concentration after administration of the UC + PPI Fasted was < 5% of 
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the corresponding Cmax (Table 2) and the data were therefore included in the descriptive 
statistics and the PK and statistical analyses.1 
Table 2: Subjects with a pre-dose concentration ≥ LOQ. 
C(0)
Cmax
Ratio*
Subject
Period
Treatment
(ng/mL)
(ng/mL)
(%)
2
EC Tablet Fed
12.34
30.39
40.60
2
UC + PPI Fasted
10.28
375.17
2.74
 
*Ratios ≥ 5% are shown in red. 
Source:  C(0) – Appendix III; Cmax – Appendix VI. 
7.2 
Pharmacokinetic Analysis Population 
Eighteen (18) subjects were enrolled into and all completed the study.  As discussed in 
Section 7.1, the data for Subject 
 for the EC Tablet Fed were excluded from the 
descriptive statistics and statistical analyses.  The PK analysis population was therefore 
comprised of 18 subjects for the EC Tablet Fasted and the UC + PPI Fasted and 
17 subjects for the EC Tablet Fed. 
7.3 
Pharmacokinetics 
7.3.1 
Results 
The mean ± standard error plasma concentrations of total Mo are shown in.   
As shown in Figure 1, the mean ± standard error plasma concentrations of total Mo were 
slightly lower after administration of the EC Tablet Fasted compared to the UC + PPI 
Fasted.  There was, however, variability among subjects with 3 of the 18 showing much 
lower concentrations for the EC Tablet, 5 showing the same pattern as the mean data, and 
10 showing more comparable or superimposable concentrations for both treatments 
(Appendix IX). 
Consistent with the mean plasma concentrations, the arithmetic (Table 3) and geometric 
(Table 4) mean values for Cmax, AUC(0-t), and AUC(inf) were lower for the EC Tablet 
Fasted than for the UC Capsule + PPI Fasted.  The GMRs ranged from 75.81% to 
87.16% with lower limits of the associated 90% CIs < 80.00% (Table 4), indicating a 
decrease in exposure on the average.  The median Tmax was comparable for both 
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treatments, 4.54 h and 4.50 h, respectively, with comparable ranges (Table 3).  Four (4) 
of the 18 subjects had an absorption lag time after administration of the EC Tablet fasted 
with a median (range) of 2.00 h (2.00 h to 3.00 h) (Table 3). 
Administration of the EC Tablet with food resulted in a large decrease in the mean 
plasma total Mo concentrations (Figure 1).  This was also observed in all but 2 of the 
17 subjects evaluable for this treatment (Appendix IX).  Cmax, AUC(0-t), and AUC(inf) 
were lower after administration of the EC Tablet with food (Table 3, Table 4) with GMRs 
ranging from 25.20% to 40.49%, indicating a substantial decrease in absorption.  The 
median Tmax was comparable with and without food, 4.55 h and 4.54 h, respectively, 
with comparable ranges (Table 3).  Compared to the EC Tablet Fasted, more subjects (6) 
had an absorption lag time an increase in the median (range) to 3.00 h (2.00 h to 5.00 h) 
(Table 3). 
The mean t½ was essentially the same for all 3 treatments (Table 3), with an overall mean 
of ~48 h or 2 days. 
The relationships between Mo CL/F and body size, expressed as weight and BMI, are 
illustrated in Figure 2 (Treatment A — EC Tablet Fasted) and Figure 3 (Treatment C — 
UC + PPI Fasted).1  There are no apparent relationships between CL/F and either 
measure of body size.  This suggests that a fixed dose, rather than a dose based on body 
size, i.e. mg/kg or mg/m², may be appropriate for WTX101. 
The lowest between-subject coefficients of variation (BSCV) for Cmax, AUC(0-t), and 
AUC(inf) were observed for the UC capsule + PPI Fasted, with values ranging from 
15.8% to 19.1% (Table 5).  Administration of the EC Tablet Fasted resulted in higher 
BSCVs (26.1% to 35.2%; Table 5).  The BSCVs were much higher, particularly for 
AUC(0-t) and AUC(inf) — 81.5% and 72.6%, respectively (Table 5) — when the EC 
Tablet was administered after the high calorie / high fat meal.  Compared to the EC 
                                                 
1 Due to the slight but apparent differences in bioavailability among the treatments, the 
relationships between CL/F and body size are shown separately for the 2 fasted 
treatments.  As a consequence of the low bioavailability after administration of the EC 
Tablet Fed, it was excluded from this analysis. 
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Tablet Fasted, the BSCVs for the AUCs were ~2.2-fold higher when the EC Tablet was 
administered under fed conditions. 
 
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Figure 1: 
Mean ± standard error plasma concentrations of total Mo after administration of a single 60 mg (2 × 
30 mg) dose of WTX101 EC Tablets under fasted and fed conditions and UC + PPI under fasted 
conditions — linear axes (left panel) and semi-logarithmic (right panel). 
Linear Axes
Time (h)
0
24
48
72
96
120
144
168
192
Conc (ng/mL)
0
100
200
300
400
500
Semi-Logarithmic Axes
Time (h)
0
24
48
72
96
120
144
168
192
Conc (ng/mL)
0.1
1
10
100
1000
EC Tablet Fasted
EC Tablet Fed
Uncoated Capsule + PPI Fasted
 
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Table 3: Summary of total Mo PK parameters after administration of a single 60 mg (2 × 30 mg) 
dose of WTX101 EC Tablets under fasted and fed conditions and UC + PPI under fasted 
conditions. 
Parameter*
EC Tablet Fasted
EC Tablet Fed
UC + PPI Fasted
Tlag (h)
2.00 (4)
3.00 (6)
—†
[2.00 – 3.00]
[2.00 – 5.00]
Cmax (ng/mL)
376 ± 98.0 (18)
187 ± 118 (17)
442 ± 69.6 (18)
Tmax (h)
4.54 (18)
4.55 (17)
4.50 (18)
[3.00 – 9.53]
[3.52 – 9.51]
[2.99 – 10.0]
AUC(0-t) (h×ng/mL)
16,026 ± 5,635 (18)
5,740 ± 4,681 (17)
19,809 ± 3,509 (18)
AUC(inf) (h×ng/mL)
17,258 ± 5,955 (18)
6,973 ± 5,065 (15)
21,047 ± 4,022 (17)
λz (1/h)
0.0140 ± 0.0023 (18)
0.0258 ± 0.0303 (15)
0.0145 ± 0.0014 (17)
t½ (h)
51.0 ± 8.87 (18)
43.5 ± 20.9 (15)
48.2 ± 4.86 (17)
CL/F (L/h)
0.92 ± 0.51 (18)
6.34 ± 11.9 (15)
0.66 ± 0.13 (17)
Vz/F (L)
66.6 ± 34.0 (18)
175 ± 98.1 (15)
45.2 ± 8.31 (17)
Treatment
 
*Arithmetic mean ± standard deviation (N) except for Tmax for which the median (N) [Range] is reported.  Additional descriptive 
statistics can be found in Appendix VII. 
†Parameter could not be estimated for any subject for this treatment. 
Source:  Appendix VII. 
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Table 4: Statistical analysis of total Mo PK parameters after administration of a single 60 mg (2 × 30 mg) dose of 
WTX101 EC Tablets under fasted and fed conditions and UC + PPI under fasted conditions. 
Within-Subject
Parameter
Test
Reference
Estimate
CV (%)
EC Tablet Fasted vs. UC + PPI Fasted
Cmax
360.88
436.61
82.65
63.91
→
106.90
47.98
AUC(0-t)
14,790.84
19,511.14
75.81
52.23
→
110.02
73.76
AUC(inf)
15,997.76
18,353.45
87.16
64.59
→
117.63
55.30
EC Tablet Fed vs. EC Tablet Fasted
Cmax
146.11
360.88
40.49
31.12
→
52.68
47.98
AUC(0-t)
3,726.71
14,790.84
25.20
17.21
→
36.89
73.76
AUC(inf)
5,071.14
15,997.76
31.70
23.12
→
43.47
55.30
90% Confidence Interval
Geometric Mean Ratio (%)*
Least Squares Geometric Means
 
*Based on analysis of natural log-transformed data. 
Source:  Appendix VIII. 
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Figure 2: 
Individual subject CL/F vs. body weight (left panel) and BMI (right panel) of total Mo after 
administration of a single 60 mg (2 × 30 mg) dose of WTX101 EC Tablets fasted to healthy volunteers. 
Weight
Weight (kg)
50
60
70
80
90
100
110
120
CL/F (L/h)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
BMI
BMI (kg/m²)
15
20
25
30
35
CL/F (L/h)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
 
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Figure 3: 
Individual subject CL/F vs. body weight (left panel) and BMI (right panel) of total Mo after 
administration of a single 60 mg (2 × 30 mg) dose of WTX101 uncoated capsules + PPI fasted to healthy 
volunteers. 
Weight
Weight (kg)
50
60
70
80
90
100
110
120
CL/F (L/h)
0.0
0.2
0.4
0.6
0.8
1.0
BMI
BMI (kg/m²)
15
20
25
30
35
CL/F (L/h)
0.0
0.2
0.4
0.6
0.8
1.0
 
Table 5: Summary of between-subject coefficients of variation of total Mo Cmax, AUC(0-t), and 
AUC(inf) after administration of a single 60 mg (2 × 30 mg) dose of WTX101 EC Tablets 
under fasted and fed conditions and UC + PPI under fasted conditions. 
Parameter*
EC Tablet Fasted
EC Tablet Fed
UC + PPI Fasted
Cmax (ng/mL)
26.1
39.9
15.8
AUC(0-t) (h×ng/mL)
35.2
81.5
17.7
AUC(inf) (h×ng/mL)
34.5
72.6
19.1
Treatment
 
*Between-subject coefficient of variation (%). 
Source:  Appendix VII. 
 
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7.3.2 
Discussion 
As illustrated in Figure 1, there was a slight decrease in the mean ± standard error plasma 
concentrations of total Mo after administration of the EC Tablet Fasted compared to the 
UC + PPI fasted.  Similar trends were observed with respect to Cmax, AUC(0-t), and 
AUC(inf) (Table 3 and Table 4).  Nevertheless, examination of the individual subject 
data (PK parameters — Appendix VI; graphs of plasma concentrations — Appendix IX) 
indicates that while a similar pattern was observed with some of the individual subjects, 
the majority had a total Mo concentration-time profile that was comparable for the 
EC Tablet and UC + PPI when both were administered under fasted conditions.  
However, administration of the EC Tablet fed resulted in a 60% to 75% decrease in 
absorption which was consistent among the majority of subjects (Appendix IX). 
Administration of WTX101 as the EC Tablet increased the between-subject variability 
compared to the UC + PPI, ~2-fold when administered under fasted conditions and 
~4-fold, based on the AUCs, when administered under fed conditions. 
8.0 
Conclusions 
• Based on total Mo, administration of the EC Tablet Fasted results in comparable 
exposure to the UC + PPI Fasted in most subjects. 
• Based on total Mo, administration of the EC Tablet Fed results in a 60% to 75% 
decrease in exposure compared to the EC Tablet Fasted in the majority of subjects. 
• The mean t½ for total Mo was essentially the same for all 3 treatments, with an 
overall mean of ~48 h or 2 days. 
• There were no apparent relationships between CL/F and body size (weight, BMI), 
suggesting that a fixed dose, rather than a dose based on body size, i.e. mg/kg or 
mg/m², may be appropriate for WTX101. 
• The lowest between-subject coefficients of variation (BSCV) for Cmax, AUC(0-t), 
and AUC(inf) were observed for the UC + PPI Fasted, with an ~2-fold increase when 
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the EC Tablet was administered under fasted conditions and an ~4-fold increase, 
based on the AUCs, when the EC Tablet was administered under fed conditions. 
• Administration of WTX101 either as the UC + PPI or the EC Tablet under fasted 
conditions should result in comparable plasma concentrations of total Mo in most 
subjects.  However, administration of the EC Tablet under fed conditions results in a 
large decrease in exposure with increased between-subject variability. 
9.0 
References 
1. Bioavailability and Bioequivalence Studies for Orally Administered Drug Products 
— General Considerations.  U.S. Department of Health and Human Services, Food 
and Drug Administration, Center for Drug Evaluation and Research (CDER), March, 
2003. 
 
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                                                                      Appendix I 
                                                                     Random Code 
 
                                                                        —————————— Treatment —————————— 
                                                                        Period      Period      Period 
                                               Subject     Sequence        1           2           3 
                                               ———————————————————————————————————————————————————————— 
 
                                               
        BCA           B           C           A 
                                               
        BAC           B           A           C 
                                               
        ABC           A           B           C 
                                               
        CAB           C           A           B 
                                               
        ACB           A           C           B 
                                               
        CBA           C           B           A 
                                               
        BCA           B           C           A 
                                               
        ABC           A           B           C 
                                               
        CBA           C           B           A 
                                               
        CAB           C           A           B 
                                               
        ACB           A           C           B 
                                               
        BAC           B           A           C 
                                               
        BAC           B           A           C 
                                               
        CBA           C           B           A 
                                               
        ABC           A           B           C 
                                               
        BCA           B           C           A 
                                               
        CAB           C           A           B 
                                               
        ACB           A           C           B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                       Treatment A - EC Tablet Fasted; Treatment B - EC Tablet Fed; Treatment C - Uncoated Capsule + PPI Fasted 
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                                                                     Appendix II 
                                                         Subject Sex, Height, Weight, and BMI 
 
                                                                       Height     Weight        BMI 
                                                Subject     Sex        (cm)*      (kg)*      (kg/m²)§ 
                                                —————————————————————————————————————————————————————— 
 
                                                
  179        66.7        20.82 
                                                
  179        92.4        28.84 
                                                
  168        80.4        28.49 
                                                
  170        85.3        29.52 
                                                
  180        80.2        24.75 
                                                
  173        90.7        30.31 
                                                
  161        80.0        30.86 
                                                
  182        91.4        27.59 
                                                
  165        74.3        27.29 
                                                
  159        62.2        24.60 
                                                
  176        92.6        29.89 
                                                
  168        66.1        23.42 
                                                
  182        99.7        30.10 
                                                
  165        83.9        30.82 
                                                
  181       104.7        31.96 
                                                
  159        69.5        27.49 
                                                
  168        65.1        23.07 
                                                
  178        72.0        22.72 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                  *Screening values. 
                                                         §Calculated from height and weight. 
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                                                                     Appendix III 
                                                       Individual Subject Plasma Concentrations 
                                                            Treatment A - EC Tablet Fasted 
 
                            ————————————————————————————————————————————— Scheduled Time (h) ————————————————————————————————————————————— 
           Subject  Period    0       1       2       3      3.5      4      4.5      5       6       7      7.5      8      8.5      9 
           ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— 
 
           
     3       0.00   98.18  125.71  138.32  134.78  134.68  147.29  144.71  127.97  115.04  116.83  112.36  117.64  105.05 
           
     2       0.00  131.56  181.29  254.30  259.03  265.79  259.69  236.91  232.83  236.22  249.49  258.13  269.11  261.36 
           
     1       0.00  103.85  123.14  201.11  228.55  235.67  278.51  254.12  233.12  222.06  218.52  208.76  211.79  210.42 
           
     2       0.00  216.94  291.58  441.89  426.36  384.91  386.73  359.17  343.18  348.62  329.94  328.22  314.16  314.27 
           
     1       0.00    0.00    0.00  137.20  178.68  193.81  264.12  256.91  361.37  391.14  397.87  390.01  349.42  366.02 
           
     3       0.00   51.16  230.61  322.23  381.35  396.83  450.27  407.18  395.63  430.82  417.64  441.73  420.96  416.72 
           
     3       0.00   34.22  218.85  366.40  401.36  399.91  445.21  434.97  459.26  466.89  471.67  460.54  443.90  406.51 
           
     1       0.00  103.97  215.77  372.46  411.20  361.31  393.54  339.88  335.44  342.55  335.99  340.47  338.79  350.50 
           
     3       0.00    0.00  176.32  250.96  285.75  323.16  378.18  421.52  450.94  422.34  419.15  410.65  384.26  396.16 
           
     2       0.00  126.94  224.27  325.68  389.12  407.87  424.72  377.99  345.06  340.38  350.33  350.58  347.63  346.22 
           
     1       0.00   85.14  207.71  291.54  329.85  325.93  362.73  359.79  333.19  350.12  342.13  345.30  346.02  363.13 
           
     2       0.00   47.05  284.76  348.80  429.67  445.57  445.60  392.73  363.19  352.16  346.38  364.62  361.13  345.61 
           
     2       0.00  131.22  232.84  309.63  288.91  283.82  337.12  313.26  295.05  268.31  272.14  301.30  293.73  328.17 
           
     3       0.00  164.45  281.99  344.07  366.83  392.60  349.50  317.17  313.08  295.65  312.10  314.15  288.54  308.53 
           
     1       0.00   41.02   58.40   56.51   62.06  121.48  185.29  226.50  355.54  296.63  297.73  296.64  277.83  292.64 
           
     3       0.00    0.00   51.89  143.01  145.26  166.39  213.74  212.31  218.93  217.18  219.93  198.39  207.42  205.77 
           
     2       0.00  137.79  182.76  224.62  252.50  271.86  312.57  298.54  298.64  289.98  286.18  279.42  273.04  268.70 
           
     1       0.00    0.00  195.53  337.83  413.32  478.14  533.87  483.43  483.92  461.07  460.39  464.76  484.69  467.48 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                 Assay LOQ = 10 ng/mL 
                                                       (. = no sample analyzed and/or reported) 
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                                                                     Appendix III 
                                                       Individual Subject Plasma Concentrations 
                                                            Treatment A - EC Tablet Fasted 
 
                            ————————————————————————————————————————————— Scheduled Time (h) ————————————————————————————————————————————— 
           Subject  Period   9.5      10      12      14      16      24      36      48      72      96     120     144     168     192 
           ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— 
 
           
     3     112.76   99.92   95.51   88.90   79.60   60.92   47.59   35.30   21.94   14.71   10.78    0.00    0.00    0.00 
           
     2     260.79  236.14  227.19  204.69  185.09  147.11  107.47   82.48   50.55   33.55   22.31   16.23   12.86    0.00 
           
     1     225.06  205.92  176.43  157.93  152.88   97.47   69.32   51.19   30.31   17.98   12.76    0.00    0.00    0.00 
           
     2     304.71  319.67  285.85  255.60  259.52  192.44  142.28  110.57   67.51   44.77   32.70   23.54   16.08   14.88 
           
     1     352.32  348.76  335.61  316.58  294.79  225.15  173.69  129.75   93.38   63.95   47.64   32.45   22.88   17.83 
           
     3     430.28  386.82  365.13  309.13  300.81  241.06  184.14  153.41  115.16   82.92   65.42   48.90   36.43   29.78 
           
     3     483.93  439.16  412.80  380.54  356.82  278.09  197.75  165.38  109.70   71.94   48.97   35.21   26.33   21.32 
           
     1     355.05  318.66  307.43  284.51  268.49  217.31  179.06  143.01  103.58   64.34   43.22   32.54   21.89   15.20 
           
     3     402.79  381.36  343.25  336.71  312.59  229.49  170.57  139.00   83.68   56.87   38.65   25.64   19.56   14.94 
           
     2     336.90  322.15  306.96  257.42  249.45  195.73  142.86  104.51   66.33   49.72   37.37   30.10   23.43   19.41 
           
     1     382.79  339.11  336.56  305.76  284.98  218.45  176.12  142.62   94.04   69.13   48.73   36.28   27.56   23.57 
           
     2     359.32  337.47  337.98  301.69  289.11  214.49  175.84  142.55   85.27   59.90   37.70   28.21   20.62   15.45 
           
     2     370.37  353.17  322.89  323.13  300.35  232.70  184.84  148.69   95.31   63.80   47.80   32.00   26.70   19.35 
           
     3     293.83  282.71  253.88  236.86  215.28  171.24  128.20   93.85   54.15   38.16   27.71   18.25   16.10   13.73 
           
     1     283.95  262.86  235.97  217.67  179.96  139.98  108.75   80.09   49.45   31.58   24.04   17.77   14.03   10.97 
           
     3     210.84  187.51  161.23  143.24  127.83   88.49   59.00   40.87   24.61   16.68   13.42   10.12    0.00    0.00 
           
     2     288.20  266.03  263.01  249.57  231.03  170.63  135.96  115.92   72.60   47.06   37.47   27.27   21.64   15.26 
           
     1     471.19  445.84  441.49  397.88  371.79  294.46  217.24  177.90  115.12   78.30   52.94   37.19   27.53   21.02 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                 Assay LOQ = 10 ng/mL 
                                                       (. = no sample analyzed and/or reported) 
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                                                                     Appendix III 
                                                       Individual Subject Plasma Concentrations 
                                                             Treatment B - EC Tablet Fed 
 
                            ————————————————————————————————————————————— Scheduled Time (h) ————————————————————————————————————————————— 
           Subject  Period    0       1       2       3      3.5      4      4.5      5       6       7      7.5      8      8.5      9 
           ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— 
 
           
     1       0.00    0.00    0.00    0.00    0.00    0.00    0.00   12.85   21.31   26.61   27.15   26.70   24.40   23.84 
           
     1       0.00    0.00   19.53   73.01  103.86  122.75  144.33  144.19  136.16  125.60  124.38  118.22  112.11  109.29 
           
     2       0.00    0.00    0.00   55.41   64.64   62.62   71.48   63.85   63.03   63.23   64.01   60.00   63.17   59.68 
           
     3       0.00   17.63  163.84  295.07  338.70  365.88  386.35  369.95  362.28  355.71  357.16  362.04  351.14  361.03 
           
     3       0.00   18.50   31.04   40.99   50.52   55.02   64.10   64.88   69.05   75.27   73.47   69.96   67.68   64.73 
           
     2      12.34   11.91   11.82   16.32   18.79   20.68   24.66   26.31   27.81   29.98   30.06   30.39   29.06   29.90 
           
     1       0.00   10.56   10.90   14.69   17.40   21.24   29.16   33.80   41.03   45.72   45.31   44.84   44.00   42.00 
           
     2       0.00  100.70  223.00  270.10  278.69  250.68  246.98  224.48  203.37  186.22  177.73  170.61  172.76  163.03 
           
     2       0.00    0.00    0.00    0.00    0.00    0.00    0.00   41.25  152.93  264.01  313.69  315.30  303.47  293.78 
           
     3       0.00    0.00   69.44  155.16  180.68  214.36  231.05  226.73  247.67  250.60  228.21  235.55  231.30  213.13 
           
     3       0.00   12.76   60.13   65.00   68.49   68.42   72.27   69.50   73.25   67.49   68.82   65.18   61.54   61.15 
           
     1       0.00    0.00    0.00   95.61  269.48  294.17  314.87  298.13  290.46  298.33  265.11  265.05  236.01  264.11 
           
     1       0.00   93.68  185.96  206.87  224.37  240.28  256.51  249.79  234.39  215.20  196.05  200.88  183.31  187.43 
           
     2       0.00  122.88  116.09  123.52  127.48  125.11  137.05  130.62  120.55  120.76  114.42  121.14  112.86  118.34 
           
     2       0.00   43.93   71.15   74.60   81.63   79.24   87.43   81.91   75.72   72.43   69.18   65.51   66.65   64.04 
           
     1       0.00   63.64  174.22  232.66  264.35  262.92  272.07  264.48  257.48  228.43  234.69  218.01  208.02  202.39 
           
     3       0.00   34.52   62.27   81.62   84.74   93.57   99.11  101.54  100.88  108.85  106.91  102.02   95.32   96.57 
           
     3       0.00   48.89  176.75  273.72  293.40  309.80  325.45  298.39  290.22  270.46  254.53  258.93  244.79  238.98 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                 Assay LOQ = 10 ng/mL 
                                                       (. = no sample analyzed and/or reported) 
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                                                                     Appendix III 
                                                       Individual Subject Plasma Concentrations 
                                                             Treatment B - EC Tablet Fed 
 
                            ————————————————————————————————————————————— Scheduled Time (h) ————————————————————————————————————————————— 
           Subject  Period   9.5      10      12      14      16      24      36      48      72      96     120     144     168     192 
           ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— 
 
           
     1      22.74   20.35   15.83   12.49    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00    0.00 
           
     1     102.40   93.88   83.54   70.40   58.36   41.73   28.68   20.40   12.26    0.00    0.00    0.00    0.00    0.00 
           
     2      61.95   54.64   44.48   40.03   36.43   27.97   14.59   11.88    0.00    0.00    0.00    0.00    0.00    0.00 
           
     3     387.75  361.80  336.48  287.92  271.27  205.55  164.40  123.25   81.51   46.99   31.11   22.42   16.87   14.10 
           
     3      62.74   58.63   44.76   36.19   31.43   19.73   13.19   12.01   11.41    0.00    0.00    0.00    0.00    0.00 
           
     2      29.11   29.40   27.63   25.66   23.05   20.66   17.83   16.93   14.94   13.13   12.08   10.85   10.26    0.00 
           
     1      40.88   38.50   31.95   25.93   22.45   15.08   10.09    0.00    0.00    0.00    0.00    0.00    0.00    0.00 
           
     2     144.14  150.50  129.38  116.44  104.83   77.62   56.59   44.71   33.05   20.90   16.58   12.05   11.52    0.00 
           
     2     282.58  266.41  253.46  220.59  198.89  148.90  111.04   87.57   53.12   32.67   27.06   20.49   14.68   14.61 
           
     3     209.67  197.77  166.45  161.87  135.22   99.25   73.16   49.52   34.18   27.16   20.07   14.23   12.49   11.45 
           
     3      59.32   54.39   51.61   47.20   40.48   33.12   22.31   19.44   14.26   11.45   11.03    0.00    0.00    0.00 
           
     1     243.44  217.27  206.65  202.29  168.90  124.03   88.83   70.95   40.85   26.10   19.04   12.84   10.08    0.00 
           
     1     184.59  164.35  151.38  133.58  114.28   81.36   60.24   45.75   27.43   20.26   14.02   10.87    0.00    0.00 
           
     2     119.70  112.78  104.55   95.49   83.22   59.42   36.81   28.19   17.43   12.95    0.00    0.00    0.00    0.00 
           
     2      63.03   53.90   47.35   42.35   38.05   24.95   15.97   13.13    0.00    0.00    0.00    0.00    0.00    0.00 
           
     1     214.18  193.12  165.25  148.12  122.52   86.84   53.00   39.10   22.72   16.69   12.37    0.00    0.00    0.00 
           
     3      95.97   87.71   70.99   58.05   48.75   33.42   22.46   20.53   15.56   11.45   10.51    0.00    0.00    0.00 
           
     3     241.80  217.08  199.77  170.73  155.83  118.87   82.46   60.69   42.21   29.73   22.87   17.90   15.04   12.28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                 Assay LOQ = 10 ng/mL 
                                                       (. = no sample analyzed and/or reported) 
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July 14, 2014 
 
                                                                     Appendix III 
                                                       Individual Subject Plasma Concentrations 
                                                     Treatment C - Uncoated Capsule + PPI Fasted 
 
                            ————————————————————————————————————————————— Scheduled Time (h) ————————————————————————————————————————————— 
           Subject  Period    0       1       2       3      3.5      4      4.5      5       6       7      7.5      8      8.5      9 
           ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— 
 
           
     2       0.00  224.42  321.57  445.77  415.87  396.83  438.76  395.75  384.80  374.79  372.45  347.23  374.22  356.89 
           
     3       0.00  192.87  226.09  306.50  353.87  320.33  313.55  293.74  303.75  302.48  291.78  296.67  303.73  303.22 
           
     3       0.00  191.87  283.68  347.63  351.11  377.14  447.08  416.43  397.65  383.91  363.62  352.14  366.16  347.99 
           
     1       0.00  177.57  327.32  409.25  399.03  418.87  460.34  386.95  375.68  381.60  356.53  374.77  378.81  367.19 
           
     2       0.00  292.36  344.86  361.71  347.34  349.25  366.44  390.67  392.11  375.63  393.39  403.71  398.74  402.12 
           
     1       0.00  146.44  297.86  371.24  367.63  392.13  402.97  375.76  394.88  376.46  383.51  388.41  393.68  381.60 
           
     2       0.00  187.04  278.25  391.55  411.06  417.43  459.34  433.49  416.44  417.04  410.70  400.32  402.69  403.65 
           
     3       0.00  172.51  302.15  346.64  366.56  359.30  367.72  327.67  327.51  320.73  303.08  300.30  304.80  299.41 
           
     1       0.00  284.76  414.18  444.73  477.57  439.41  445.33  408.90  406.91  398.53  388.18  385.06  381.33  386.98 
           
     1       0.00  217.16  347.86  421.06  422.30  504.29  566.16  508.98  494.04  484.56  453.48  454.36  462.01  460.35 
           
     2      10.28  127.23  233.36  300.54  317.84  318.92  353.98  375.17  343.82  347.99  330.78  337.38  332.99  314.67 
           
     3       0.00  238.80  391.08  496.93  456.00  405.66  403.10  354.45  341.59  332.72  335.86  356.96  386.74  369.44 
           
     3       0.00  178.85  238.61  261.60  313.19  405.34  378.42  354.16  335.74  343.32  331.76  360.85  338.15  341.49 
           
     1       0.00  229.28  307.83  378.54  423.01  514.24  567.10  511.19  455.47  445.27  460.56  434.12  452.59  433.62 
           
     3       0.00  243.79  263.93  343.30  356.25  351.84  396.79  395.00  383.28  379.15  406.78  368.15  386.99  406.89 
           
     2       0.00  244.56  331.66  430.38  525.94  487.14  506.36  522.42  500.18  466.81  490.01  457.84  466.42  469.08 
           
     1       0.00  177.70  226.93  274.26  281.36  286.07  313.14  285.64  278.19  281.49  303.36  296.99  288.49  283.64 
           
     2       0.00  214.52  303.38  375.11  434.78  460.50  460.65  389.43  389.19  384.06  384.60  392.86  392.85  387.66 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                 Assay LOQ = 10 ng/mL 
                                                       (. = no sample analyzed and/or reported) 
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Study WTX101-102 
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                                                                     Appendix III 
                                                       Individual Subject Plasma Concentrations 
                                                     Treatment C - Uncoated Capsule + PPI Fasted 
 
                            ————————————————————————————————————————————— Scheduled Time (h) ————————————————————————————————————————————— 
           Subject  Period   9.5      10      12      14      16      24      36      48      72      96     120     144     168     192 
           ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— 
 
           
     2     378.12  340.38  329.38  307.77  300.02  227.34  182.73  136.12   96.11   59.37   39.66   84.79   21.57   13.58 
           
     3     304.27  276.50  273.22  237.39  221.39  168.44  134.43   95.76   56.85   35.40   24.03   16.75   12.92   10.21 
           
     3     375.62  333.90  311.55  266.46  254.40  191.91  139.42  113.03   70.17   42.16   30.55   18.82   15.27   11.38 
           
     1     380.14  360.12  352.32  319.54  283.43  216.70  160.60  123.93   77.34   49.76   33.11   21.40   15.51   12.34 
           
     2     387.36  420.63  400.83  371.53  354.52  282.20  210.81  177.45  125.29   86.81   66.86   49.56   36.86   28.30 
           
     1     377.46  368.36  346.78  314.09  296.17  244.65  184.02  156.60  116.31   82.97   55.69   45.11   36.09   27.35 
           
     2     424.07  374.84  345.94  312.07  295.06  243.41  180.78  140.31   88.17   59.81   42.41   29.24   23.50   17.56 
           
     3     312.16  276.55  257.41  245.59  227.29  178.21  146.10  112.61   73.32   47.69   36.56   25.66   18.57   14.14 
           
     1     397.37  381.58  356.53  325.10  310.16  242.30  195.76  155.76  100.31   66.04   45.65   34.75   27.27   18.52 
           
     1     476.75  475.05  483.18  444.36  411.71  331.55  248.04  191.50  123.79   86.90   60.70   45.69   35.64   27.27 
           
     2     341.95  331.05  310.17  306.04  280.37  222.50  169.94  137.93   89.31   65.79   43.28   36.66   29.13   20.96 
           
     3     371.57  362.27  326.69  303.20  273.45  217.46  179.13  132.44   87.33   51.20   36.17   26.28   19.93   13.58 
           
     3     342.72  331.49  323.28  292.50  285.39  226.62  189.29  150.77  106.33   73.72   51.86   37.92   30.21   22.81 
           
     1     425.94  411.98  383.88  339.51  300.50  227.74  171.68  125.20   82.82   54.73   36.22   26.31   21.26   17.41 
           
     3     371.30  362.04  349.01  289.32  269.58  212.02  166.18  127.70   85.14   59.30   41.62   30.95   22.13   16.00 
           
     2     479.68  447.22  399.67  423.13  370.26  278.32  208.34  156.94  102.21   67.16   45.48   32.12   25.40   21.03 
           
     1     289.70  273.28  251.68  227.71  210.72  158.07  128.40  107.16   69.18   42.79   31.00   22.05   15.82   13.40 
           
     2     427.60  411.21  373.99  342.50  315.24  262.80  197.64  160.18  108.44   76.12   51.59   38.53   28.04   20.71 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                 Assay LOQ = 10 ng/mL 
                                                       (. = no sample analyzed and/or reported) 
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                                                                     Appendix IV 
                                                       Individual Subject Blood Sampling Times 
                                                            Treatment A - EC Tablet Fasted 
 
                            ————————————————————————————————————————————— Scheduled Time (h) ————————————————————————————————————————————— 
           Subject  Period    0       1       2       3      3.5      4      4.5      5       6       7      7.5      8      8.5      9 
           ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— 
 
           
     3      -0.75    1.00    2.00    3.00    3.50    4.00    4.50    5.00    6.00    7.00    7.50    8.00    8.50    9.00 
           
     2      -0.75    1.00    2.00    3.00    3.50    4.00    4.50    5.00    6.00    7.00    7.50    8.00    8.50    9.00 
           
     1      -0.66    1.00    2.00    3.00    3.51    4.01    4.50    5.00    6.01    7.00    7.50    8.00    8.50    9.00 
           
     2      -0.75    1.00    2.00    3.00    3.50    4.00    4.50    5.00    6.00    7.02    7.50    8.00    8.50    9.01 
           
     1      -0.75    1.00    2.00    3.00    3.50    4.00    4.50    5.00    6.00    7.00    7.50    8.00    8.52    9.00 
           
     3      -0.75    1.00    2.00    3.00    3.50    4.00    4.50    5.00    6.00    7.00    7.50    8.03    8.51    9.00 
           
     3      -0.74    1.00    2.00    3.00    3.50    4.00    4.50    5.00    6.00    7.00    7.50    8.00    8.50    9.00 
           
     1      -0.75    1.00    2.00    3.00    3.52    4.00    4.50    5.00    6.00    7.00    7.50    8.01    8.50    9.00 
           
     3      -0.75    1.00    2.00    3.01    3.50    4.00    4.52    5.00    6.00    7.02    7.50    8.00    8.50    9.00 
           
     2      -0.53    1.01    2.12    3.01    3.52    4.00    4.55    5.01    6.00    7.01    7.51    8.11    8.55    9.01 
           
     1      -0.74    1.00    2.00    3.04    3.52    4.04    4.52    5.00    6.00    7.00    7.50    8.02    8.56    9.01 
           
     2      -0.73    1.01    2.01    3.01    3.53    4.00    4.53    5.00    6.00    7.01    7.51    8.01    8.51    9.00 
           
     2      -0.73    1.01    2.01    3.01    3.50    4.00    4.50    5.00    6.00    7.01    7.52    8.01    8.51    9.03 
           
     3      -0.75    1.09    2.01    3.00    3.50    4.00    4.50    5.00    6.00    7.00    7.52    8.01    8.51    9.01 
           
     1      -0.75    1.00    2.00    3.00    3.52    4.00    4.50    5.00    6.00    7.00    7.50    8.03    8.51    9.01 
           
     3      -0.75    1.00    2.00    3.00    3.50    4.00    4.50    5.00    6.00    7.00    7.52    8.01    8.52    9.02 
           
     2      -0.72    1.03    2.00    3.00    3.50    4.00    4.50    5.00    6.00    7.00    7.50    8.03    8.50    9.01 
           
     1      -0.75    1.00    2.00    3.00    3.51    4.00    4.50    5.00    6.00    7.00    7.50    8.01    8.51    9.00 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                       (. = no sample analyzed and/or reported) 
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                                                                     Appendix IV 
                                                       Individual Subject Blood Sampling Times 
                                                            Treatment A - EC Tablet Fasted 
 
                            ————————————————————————————————————————————— Scheduled Time (h) ————————————————————————————————————————————— 
           Subject  Period   9.5      10      12      14      16      24      36      48      72      96     120     144     168     192 
           ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— 
 
           
     3       9.50   10.00   12.00   14.00   16.00   24.00   36.00   48.00   72.00   96.00  120.00  144.00  168.00  192.00 
           
     2       9.50   10.00   12.14   14.00   16.00   24.01   36.00   48.06   72.00   96.00  120.09  144.00  168.00  192.00 
           
     1       9.52   10.00   12.00   14.00   16.00   24.00   36.01   48.00   72.01   96.00  120.00  144.00  168.00  192.00 
           
     2       9.50   10.01   12.00   14.00   16.00   24.00   36.00   48.01   72.00   96.01  120.09  144.01  168.01  192.01 
           
     1       9.52   10.00   12.00   14.00   16.00   24.00   36.02   48.07   72.00   96.00  120.00  144.00  168.01  192.00 
           
     3       9.50   10.00   12.00   14.05   16.00   24.00   36.05   48.00   72.00   96.00  120.01  144.00  168.00  192.00 
           
     3       9.50   10.00   12.00   14.00   16.00   24.00   36.00   48.00   72.00   96.00  120.00  144.00  168.00  192.00 
           
     1       9.52   10.00   12.00   14.00   16.00   24.00   36.03   48.00   72.00   96.00  120.00  144.00  168.00  192.00 
           
     3       9.50   10.00   12.01   14.00   16.00   24.00   36.00   48.00   72.00   96.00  120.00  144.00  168.00  192.00 
           
     2       9.50   10.01   12.01   14.01   16.01   24.05   36.07   48.11   72.03   96.07  120.09  144.00  168.08  192.51 
           
     1       9.53   10.01   12.00   14.02   16.03   24.01   36.06   48.01   72.00   96.00  120.00  144.00  168.01  192.00 
           
     2       9.50   10.00   12.02   14.01   16.00   24.01   36.02   48.01   72.01   96.02  120.09  144.00  168.01  192.03 
           
     2       9.51   10.03   12.03   14.01   16.00   24.01   36.01   48.01   72.01   96.02  120.09  144.00  168.01  192.03 
           
     3       9.50   10.01   12.00   14.00   16.01   24.02   36.08   48.00   72.01   96.00  120.00  144.00  168.00  192.00 
           
     1       9.53   10.01   12.00   14.02   16.02   24.00   36.00   48.01   72.00   96.00  120.00  144.00  168.01  192.01 
           
     3       9.50   10.00   12.00   14.00   16.00   24.01   36.10   48.00   72.01   96.00  120.00  144.00  168.00  192.00 
           
     2       9.51   10.01   12.15   14.01   16.00   24.04   36.02   48.03   72.01   96.02  120.10  144.00  168.01  192.03 
           
     1       9.53   10.00   12.00   14.02   16.01   24.00   36.10   48.01   72.00   96.00  120.00  144.00  168.03  192.00 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                       (. = no sample analyzed and/or reported) 
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                                                                     Appendix IV 
                                                       Individual Subject Blood Sampling Times 
                                                             Treatment B - EC Tablet Fed 
 
                            ————————————————————————————————————————————— Scheduled Time (h) ————————————————————————————————————————————— 
           Subject  Period    0       1       2       3      3.5      4      4.5      5       6       7      7.5      8      8.5      9 
           ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— 
 
           
     1      -0.75    1.00    2.00    3.00    3.50    4.00    4.50    5.00    6.00    7.00    7.50    8.00    8.50    9.00 
           
     1      -0.75    1.00    2.00    3.00    3.51    4.00    4.50    5.00    6.01    7.00    7.50    8.00    8.50    9.00 
           
     2      -0.71    1.00    2.01    3.00    3.50    4.00    4.50    5.00    6.00    7.02    7.50    8.01    8.50    9.01 
           
     3      -0.75    1.01    2.01    3.01    3.50    4.01    4.51    5.00    6.00    7.00    7.50    8.01    8.50    9.00 
           
     3      -0.75    1.01    2.01    3.01    3.50    4.00    4.50    5.00    6.00    7.00    7.50    8.01    8.50    9.00 
           
     2      -0.75    1.04    2.00    3.00    3.50    4.00    4.50    5.03    6.00    7.00    7.50    8.00    8.50    9.00 
           
     1      -0.74    1.00    2.00    3.00    3.50    4.00    4.49    5.00    6.00    7.00    7.50    8.00    8.50    9.00 
           
     2      -0.74    1.01    2.00    3.01    3.52    4.00    4.50    5.00    6.00    7.02    7.50    8.00    8.51    9.01 
           
     2      -0.74    1.01    2.00    3.00    3.51    4.00    4.50    5.00    6.00    7.01    7.51    8.00    8.50    9.01 
           
     3      -0.75    1.01    2.15    3.01    3.50    4.17    4.49    5.00    6.00    7.01    7.57    8.19    8.51    9.00 
           
     3      -0.75    1.00    2.01    3.00    3.50    4.00    4.51    5.00    6.00    7.01    7.52    8.01    8.50    9.00 
           
     1      -0.74    1.00    2.00    3.00    3.52    4.01    4.55    5.00    6.00    7.00    7.50    8.02    8.51    9.02 
           
     1      -0.75    1.00    2.00    3.00    3.55    4.01    4.50    5.00    6.00    7.00    7.50    8.02    8.52    9.01 
           
     2      -0.72    1.01    2.01    3.01    3.50    4.00    4.51    5.00    6.00    7.01    7.51    8.00    8.51    9.01 
           
     2      -0.72    1.01    2.00    3.01    3.50    4.00    4.50    5.00    6.00    7.00    7.50    8.00    8.51    9.02 
           
     1      -0.75    1.00    2.00    3.00    3.51    4.00    4.50    5.00    6.00    7.00    7.50    8.01    8.51    9.00 
           
     3      -0.75    1.00    2.00    3.00    3.50    4.00    4.50    5.00    6.00    7.00    7.52    8.01    8.52    9.02 
           
     3      -0.75    1.00    2.00    3.00    3.50    4.00    4.50    5.00    6.00    7.00    7.51    8.01    8.52    9.02 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                       (. = no sample analyzed and/or reported) 
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                                                                     Appendix IV 
                                                       Individual Subject Blood Sampling Times 
                                                             Treatment B - EC Tablet Fed 
 
                            ————————————————————————————————————————————— Scheduled Time (h) ————————————————————————————————————————————— 
           Subject  Period   9.5      10      12      14      16      24      36      48      72      96     120     144     168     192 
           ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— 
 
           
     1       9.50   10.00   12.00   14.00   16.00   24.00   36.00   48.00   72.00   96.00  120.00  144.00  168.00  192.00 
           
     1       9.51   10.00   12.00   14.00   16.00   24.06   36.00   48.00   72.00   96.00  120.00  144.00  168.00  192.00 
           
     2       9.50   10.01   12.00   14.00   16.00   24.00   36.00   48.01   72.00   96.21  120.09  144.01  168.09  192.00 
           
     3       9.51   10.01   12.08   14.00   16.00   24.00   36.00   48.01   72.01   96.00  120.01  144.01  168.00  192.01 
           
     3       9.50   10.01   12.02   14.00   16.00   24.00   36.05   48.00   72.01   96.00  120.01  144.01  168.00  192.00 
           
     2       9.50   10.00   12.00   14.01   16.02   24.00   36.00   48.00   72.00   96.00  120.07  144.00  168.02  192.01 
           
     1       9.51   10.00   12.00   14.00   16.00   24.00   36.00   48.00   72.00   96.00  120.00  144.00  168.00  192.00 
           
     2       9.50   10.00   12.00   14.01   16.00   24.00   36.02   48.00   72.01   96.00  120.08  144.00  168.00  192.00 
           
     2       9.50   10.01   12.00   14.00   16.01   24.00   36.02   48.00   72.01   96.00  120.08  144.00  168.00  192.00 
           
     3       9.50   10.01   12.00   14.13   16.00   24.00   36.06   48.00   72.01   96.24  120.01  144.00  168.00  192.00 
           
     3       9.50   10.00   12.00   14.00   16.00   24.01   36.01   48.00   72.01   96.00  120.00  144.00  168.00  192.00 
           
     1       9.54   10.06   12.00   14.02   16.02   24.01   36.04   48.01   72.00   96.00  120.00  144.00  168.31  192.00 
           
     1       9.54   10.00   12.00   14.02   16.01   24.00   36.01   48.01   72.00   96.00  120.00  144.00  168.00  192.00 
           
     2       9.51   10.01   12.01   14.01   16.00   24.01   36.03   48.00   72.01   96.02  120.09  144.00  168.01  192.03 
           
     2       9.51   10.01   12.05   14.01   16.00   24.01   36.02   48.00   72.01   96.02  120.09  144.00  168.01  192.03 
           
     1       9.54   10.00   12.00   14.02   16.02   24.00   36.08   48.01   72.00   96.00  120.00  144.00  168.02  192.01 
           
     3       9.50   10.00   12.00   14.00   16.00   24.01   36.03   48.00   72.01   96.00  120.00  144.00  168.00  192.02 
           
     3       9.50   10.00   12.01   14.00   16.00   24.00   36.10   48.00   72.00   96.00  120.00  144.00  168.00  192.01 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                       (. = no sample analyzed and/or reported) 
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                                                                     Appendix IV 
                                                       Individual Subject Blood Sampling Times 
                                                     Treatment C - Uncoated Capsule + PPI Fasted 
 
                            ————————————————————————————————————————————— Scheduled Time (h) ————————————————————————————————————————————— 
           Subject  Period    0       1       2       3      3.5      4      4.5      5       6       7      7.5      8      8.5      9 
           ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— 
 
           
     2      -0.76    0.99    1.99    2.99    3.49    3.99    4.49    4.99    5.99    6.99    7.49    7.99    8.49    8.99 
           
     3      -0.75    1.00    2.00    3.00    3.50    4.00    4.50    5.00    6.00    7.00    7.50    8.00    8.50    9.00 
           
     3      -0.64    1.06    2.06    3.08    3.55    4.01    4.50    5.00    6.00    7.00    7.50    8.00    8.70    9.00 
           
     1      -0.74    1.00    2.00    3.00    3.50    4.01    4.50    5.00    6.00    7.00    7.50    8.00    8.50    9.00 
           
     2      -0.75    1.00    2.00    3.00    3.50    4.00    4.50    5.00    6.00    7.04    7.50    8.00    8.50    9.01 
           
     1      -0.77    1.00    2.02    3.00    3.50    4.00    4.50    5.00    6.00    7.00    7.50    8.00    8.50    9.00 
           
     2      -0.75    1.00    2.00    3.00    3.55    4.00    4.50    5.00    6.00    7.02    7.56    8.00    8.50    9.02 
           
     3      -0.75    1.00    2.00    3.00    3.50    4.00    4.50    5.00    6.00    7.00    7.50    8.00    8.50    9.00 
           
     1      -0.75    1.00    2.00    3.00    3.51    4.14    4.51    5.00    6.00    7.00    7.50    8.15    8.50    9.00 
           
     1      -0.66    1.04    2.05    3.11    3.57    4.09    4.52    5.15    6.00    7.04    7.50    8.01    8.51    9.01 
           
     2      -0.73    1.01    2.01    3.01    3.52    4.00    4.51    5.00    6.00    7.01    7.51    8.02    8.51    9.00 
           
     3      -0.75    1.00    2.01    3.00    3.50    4.01    4.51    5.00    6.00    7.01    7.51    8.19    8.53    9.03 
           
     3      -0.75    1.00    2.01    3.04    3.50    4.00    4.50    5.00    6.00    7.01    7.54    8.01    8.51    9.01 
           
     1      -0.75    1.01    2.00    3.00    3.52    4.00    4.50    5.00    6.00    7.00    7.50    8.02    8.51    9.01 
           
     3      -0.75    1.00    2.01    3.00    3.50    4.01    4.50    5.00    6.00    7.00    7.52    8.01    8.55    9.02 
           
     2      -0.72    1.01    2.00    3.01    3.50    4.00    4.50    5.00    6.00    7.00    7.50    8.00    8.50    9.02 
           
     1      -0.75    1.00    2.00    3.00    3.51    4.00    4.50    5.00    6.00    7.00    7.50    8.01    8.51    9.00 
           
     2      -0.72    1.03    2.00    3.00    3.50    4.00    4.50    5.00    6.00    7.00    7.50    8.00    8.50    9.01 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                       (. = no sample analyzed and/or reported) 
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                                                                     Appendix IV 
                                                       Individual Subject Blood Sampling Times 
                                                     Treatment C - Uncoated Capsule + PPI Fasted 
 
                            ————————————————————————————————————————————— Scheduled Time (h) ————————————————————————————————————————————— 
           Subject  Period   9.5      10      12      14      16      24      36      48      72      96     120     144     168     192 
           ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— 
 
           
     3       9.50   10.00   12.00   14.00   16.00   24.00   36.00   48.00   72.00   96.00  120.00  144.00  168.00  192.00 
           
     2       9.50   10.00   12.14   14.00   16.00   24.01   36.00   48.06   72.00   96.00  120.09  144.00  168.00  192.00 
           
     1       9.52   10.00   12.00   14.00   16.00   24.00   36.01   48.00   72.01   96.00  120.00  144.00  168.00  192.00 
           
     2       9.50   10.01   12.00   14.00   16.00   24.00   36.00   48.01   72.00   96.01  120.09  144.01  168.01  192.01 
           
     1       9.52   10.00   12.00   14.00   16.00   24.00   36.02   48.07   72.00   96.00  120.00  144.00  168.01  192.00 
           
     3       9.50   10.00   12.00   14.05   16.00   24.00   36.05   48.00   72.00   96.00  120.01  144.00  168.00  192.00 
           
     3       9.50   10.00   12.00   14.00   16.00   24.00   36.00   48.00   72.00   96.00  120.00  144.00  168.00  192.00 
           
     1       9.52   10.00   12.00   14.00   16.00   24.00   36.03   48.00   72.00   96.00  120.00  144.00  168.00  192.00 
           
     3       9.50   10.00   12.01   14.00   16.00   24.00   36.00   48.00   72.00   96.00  120.00  144.00  168.00  192.00 
           
     2       9.50   10.01   12.01   14.01   16.01   24.05   36.07   48.11   72.03   96.07  120.09  144.00  168.08  192.51 
           
     1       9.53   10.01   12.00   14.02   16.03   24.01   36.06   48.01   72.00   96.00  120.00  144.00  168.01  192.00 
           
     2       9.50   10.00   12.02   14.01   16.00   24.01   36.02   48.01   72.01   96.02  120.09  144.00  168.01  192.03 
           
     2       9.51   10.03   12.03   14.01   16.00   24.01   36.01   48.01   72.01   96.02  120.09  144.00  168.01  192.03 
           
     3       9.50   10.01   12.00   14.00   16.01   24.02   36.08   48.00   72.01   96.00  120.00  144.00  168.00  192.00 
           
     1       9.53   10.01   12.00   14.02   16.02   24.00   36.00   48.01   72.00   96.00  120.00  144.00  168.01  192.01 
           
     3       9.50   10.00   12.00   14.00   16.00   24.01   36.10   48.00   72.01   96.00  120.00  144.00  168.00  192.00 
           
     2       9.51   10.01   12.15   14.01   16.00   24.04   36.02   48.03   72.01   96.02  120.10  144.00  168.01  192.03 
           
     1       9.53   10.00   12.00   14.02   16.01   24.00   36.10   48.01   72.00   96.00  120.00  144.00  168.03  192.00 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                       (. = no sample analyzed and/or reported) 
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                                                                      Appendix V 
                                                   Descriptive Statistics for Plasma Concentrations 
 
                                            Scheduled    ———————— Arithmetic ———————— 
                                              Time                   Standard         ——— Geometric ——— 
                       Treatment               (h)    N     Mean      Error    CV (%)    Mean    CV (%)  Minimum     Median    Maximum 
             ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— 
 
                    EC Tablet Fasted            0.0   18     0.00       0.00      .        .        .       0.00       0.00       0.00 
                                                1.0   18    81.86      15.05    77.98    92.35    60.53     0.00      91.66     216.94 
                                                2.0   18   182.41      19.36    45.02   175.93    53.28     0.00     201.62     291.58 
                                                3.0   18   270.36      24.09    37.80   245.17    54.51    56.51     300.58     441.89 
                                                3.5   18   299.14      26.82    38.04   270.50    55.52    62.06     309.38     429.67 
                                                4.0   18   310.54      25.40    34.70   289.36    42.88   121.48     324.55     478.14 
                                                4.5   18   342.70      24.25    30.02   326.06    35.03   147.29     356.11     533.87 
                                                5.0   18   324.28      21.12    27.63   311.24    31.41   144.71     328.52     483.43 
                                                6.0   18   330.35      21.16    27.17   316.70    32.59   127.97     339.31     483.92 
                                                7.0   18   324.84      21.88    28.57   309.69    35.06   115.04     341.47     466.89 
                                                7.5   18   324.69      21.45    28.03   310.16    34.26   116.83     332.96     471.67 
                                                8.0   18   325.89      22.05    28.70   310.12    36.04   112.36     334.34     464.76 
                                                8.5   18   318.34      20.98    27.96   304.37    33.76   117.64     326.48     484.69 
                                                9.0   18   319.63      20.53    27.25   304.95    35.54   105.05     336.89     467.48 
                                                9.5   18   329.17      22.02    28.39   313.74    35.40   112.76     344.61     483.93 
                                               10.0   18   307.40      20.74    28.62   292.17    36.87    99.92     320.91     445.84 
                                               12.0   18   289.40      20.69    30.33   273.61    38.60    95.51     307.20     441.49 
                                               14.0   18   264.88      19.12    30.63   250.19    38.89    88.90     270.97     397.88 
                                               16.0   18   247.80      18.48    31.63   232.93    40.76    79.60     264.01     371.79 
                                               24.0   18   189.73      14.98    33.50   176.90    43.65    60.92     205.11     294.46 
                                               36.0   18   144.48      11.63    34.15   133.98    45.73    47.59     156.72     217.24 
                                               48.0   18   114.28      10.06    37.35   104.37    50.83    35.30     122.84     177.90 
                                               72.0   18    74.04       7.16    41.04    66.50    55.59    21.94      78.14     115.16 
                                               96.0   18    50.30       4.99    42.13    44.85    57.95    14.71      53.29      82.92 
                                              120.0   18    36.09       3.58    42.07    32.33    56.16    10.78      37.58      65.42 
                                              144.0   18    25.09       3.03    51.17    26.48    40.61     0.00      27.74      48.90 
                                              168.0   18    18.54       2.41    55.12    21.44    28.93     0.00      21.13      36.43 
                                              192.0   18    14.04       2.07    62.67    17.50    25.95     0.00      15.23      29.78 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                       
                Geometric mean and CV were not calculated if all values were <LOQ 
              Subject 
 Period 2, EC Tablet Fed, had a C(0) >= LOQ and >= 5% of Cmax and is excluded from the descriptive statistics. 
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                                                                      Appendix V 
                                                   Descriptive Statistics for Plasma Concentrations 
 
                                            Scheduled    ———————— Arithmetic ———————— 
                                              Time                   Standard         ——— Geometric ——— 
                       Treatment               (h)    N     Mean      Error    CV (%)    Mean    CV (%)  Minimum     Median    Maximum 
             ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— 
 
                     EC Tablet Fed              0.0   17     0.00       0.00      .        .        .       0.00       0.00       0.00 
                                                1.0   17    33.39       9.69   119.66    38.03   105.08     0.00      17.63     122.88 
                                                2.0   17    80.25      18.74    96.30    76.30   119.59     0.00      62.27     223.00 
                                                3.0   17   121.06      24.10    82.07   104.20   101.13     0.00      81.62     295.07 
                                                3.5   17   144.02      27.38    78.39   125.02   101.16     0.00     103.86     338.70 
                                                4.0   17   150.94      28.60    78.13   132.02    97.60     0.00     122.75     365.88 
                                                4.5   17   161.07      29.70    76.01   144.91    88.26     0.00     137.05     386.35 
                                                5.0   17   157.43      27.02    70.76   113.75   117.40    12.85     130.62     369.95 
                                                6.0   17   161.16      25.06    64.12   125.81    93.17    21.31     136.16     362.28 
                                                7.0   17   163.23      24.69    62.38   129.52    87.59    26.61     125.60     355.71 
                                                7.5   17   160.05      24.60    63.37   127.12    86.46    27.15     124.38     357.16 
                                                8.0   17   158.82      25.02    64.95   124.80    88.86    26.70     121.14     362.04 
                                                8.5   17   151.68      23.78    64.65   119.71    87.91    24.40     112.86     351.14 
                                                9.0   17   150.80      24.12    65.95   118.01    89.98    23.84     118.34     361.03 
                                                9.5   17   149.23      24.67    68.16   115.88    91.40    22.74     119.70     387.75 
                                               10.0   17   137.83      22.91    68.53   106.54    92.83    20.35     112.78     361.80 
                                               12.0   17   123.76      21.65    72.13    92.96   100.39    15.83     104.55     336.48 
                                               14.0   17   109.98      19.25    72.15    81.35   105.94    12.49      95.49     287.92 
                                               16.0   17    95.94      17.72    76.18    79.68    86.97     0.00      83.22     271.27 
                                               24.0   17    70.46      13.43    78.60    57.43    91.87     0.00      59.42     205.55 
                                               36.0   17    50.22      10.52    86.33    39.03   102.04     0.00      36.81     164.40 
                                               48.0   17    38.07       8.02    86.84    33.62    85.70     0.00      28.19     123.25 
                                               72.0   17    23.88       5.35    92.33    26.27    66.86     0.00      17.43      81.51 
                                               96.0   17    15.08       3.47    94.78    21.20    48.34     0.00      12.95      46.99 
                                              120.0   17    10.86       2.60    98.70    17.34    38.81     0.00      11.03      31.11 
                                              144.0   17     6.52       2.06   130.16    15.31    28.41     0.00       0.00      22.42 
                                              168.0   17     4.75       1.64   142.69    13.25    19.31     0.00       0.00      16.87 
                                              192.0   17     3.08       1.40   187.00    13.05    11.52     0.00       0.00      14.61 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                       
                Geometric mean and CV were not calculated if all values were <LOQ 
              Subject 
 Period 2, EC Tablet Fed, had a C(0) >= LOQ and >= 5% of Cmax and is excluded from the descriptive statistics. 
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                                                                      Appendix V 
                                                   Descriptive Statistics for Plasma Concentrations 
 
                                            Scheduled    ———————— Arithmetic ———————— 
                                              Time                   Standard         ——— Geometric ——— 
                       Treatment               (h)    N     Mean      Error    CV (%)    Mean    CV (%)  Minimum     Median    Maximum 
             ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— 
 
             Uncoated Capsule + PPI Fasted      0.0   18     0.57       0.57   424.26    10.28      .       0.00       0.00      10.28 
                                                1.0   18   207.87      10.32    21.07   203.45    21.81   127.23     203.70     292.36 
                                                2.0   18   302.26      12.64    17.74   297.80    17.91   226.09     302.76     414.18 
                                                3.0   18   372.60      14.83    16.88   367.45    17.47   261.60     373.18     496.93 
                                                3.5   18   390.04      14.64    15.92   385.41    16.02   281.36     383.33     525.94 
                                                4.0   18   400.26      15.18    16.09   395.34    16.37   286.07     401.09     514.24 
                                                4.5   18   424.85      17.35    17.33   418.94    17.33   313.14     420.93     567.10 
                                                5.0   18   395.88      15.74    16.87   390.66    16.86   285.64     390.05     522.42 
                                                6.0   18   384.51      13.92    15.36   380.26    15.47   278.19     386.99     500.18 
                                                7.0   18   377.58      12.56    14.11   374.05    14.22   281.49     377.80     484.56 
                                                7.5   18   375.58      13.13    14.83   371.75    14.79   291.78     377.98     490.01 
                                                8.0   18   372.67      11.39    12.97   369.69    13.17   296.67     371.46     457.84 
                                                8.5   18   378.41      12.10    13.56   375.07    13.87   288.49     384.04     466.42 
                                                9.0   18   373.10      12.47    14.18   369.52    14.44   283.64     375.52     469.08 
                                                9.5   18   381.32      12.45    13.85   377.85    14.03   289.70     377.79     479.68 
                                               10.0   18   363.25      13.36    15.60   359.02    15.96   273.28     362.16     475.05 
                                               12.0   18   343.08      13.11    16.21   338.90    16.23   251.68     346.36     483.18 
                                               14.0   18   314.88      13.45    18.12   310.20    17.85   227.71     309.92     444.36 
                                               16.0   18   292.20      11.95    17.35   288.16    17.26   210.72     290.22     411.71 
                                               24.0   18   229.57      10.04    18.55   225.89    18.70   158.07     226.98     331.55 
                                               36.0   18   177.41       7.05    16.86   175.04    17.05   128.40     179.96     248.04 
                                               48.0   18   138.97       5.88    17.96   136.86    18.21    95.76     137.02     191.50 
                                               72.0   18    92.13       4.55    20.97    90.18    21.81    56.85      88.74     125.29 
                                               96.0   18    61.54       3.65    25.17    59.66    26.41    35.40      59.59      86.90 
                                              120.0   18    42.91       2.63    25.98    41.57    26.56    24.03      42.01      66.86 
                                              144.0   18    34.59       3.69    45.29    32.00    40.74    16.75      31.53      84.79 
                                              168.0   18    24.17       1.75    30.79    23.08    32.43    12.92      22.81      36.86 
                                              192.0   18    18.14       1.33    31.18    17.33    31.86    10.21      17.48      28.30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                       
                Geometric mean and CV were not calculated if all values were <LOQ 
              Subject 
 Period 2, EC Tablet Fed, had a C(0) >= LOQ and >= 5% of Cmax and is excluded from the descriptive statistics. 
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                                                                     Appendix VI 
                                                    Individual Subject Pharmacokinetic Parameters 
                                                            Treatment A - EC Tablet Fasted 
 
                       Lag                                              Regression    Final 
                      Time*  CMAX    TMAX  AUC(0-t)  AUC(inf)  % AUC    Start Time     Time  No. Points  Regr  Lambda_z   t½    CL/F    Vz/F 
       Subject Period  (h)  (ng/mL)  (h)   (hxng/mL) (hxng/mL) Extrap Nominal Actual  C>=LOQ  in Regr     r²     (/h)    (h)   (L/h)    (L) 
       ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— 
 
       
    3     .    147.29    4.50  4,857.67  5,511.14  11.9   47.00   48.00  120.00      4     0.9915 0.01649   42.03 2.415   146.42 
       
    2     .    269.11    8.50 11,565.25 12,455.79   7.1   71.00   72.00  168.00      5     0.9879 0.01444   48.01 1.068    74.02 
       
    1     .    278.51    4.50  7,607.44  8,260.34   7.9   47.00   48.00  120.00      4     0.9912 0.01954   35.47 1.611    82.45 
       
    2     .    441.89    3.00 16,120.60 17,169.64   6.1   47.00   48.01  192.01      7     0.9788 0.01418   48.88 0.775    54.66 
       
    1    3.00  397.87    7.50 18,547.33 19,815.71   6.4   48.00   48.07  192.00      7     0.9981 0.01406   49.30 0.672    47.77 
       
    3     .    450.27    4.50 22,675.96 25,209.09  10.0   36.00   36.05  192.00      8     0.9973 0.01175   58.97 0.528    44.91 
       
    3     .    483.93    9.50 22,738.24 24,182.85   6.0   36.00   36.00  192.00      8     0.9910 0.01476   46.96 0.550    37.29 
       
    1     .    411.20    3.52 19,268.61 20,226.41   4.7   23.00   24.00  192.00      9     0.9983 0.01587   43.69 0.658    41.47 
       
    3    2.00  450.94    6.00 18,755.35 19,781.67   5.2   72.00   72.00  192.00      6     0.9926 0.01456   47.62 0.673    46.22 
       
    2     .    424.72    4.55 16,498.83 18,491.08  10.8   96.00   96.07  192.51      5     0.9952 0.00974   71.13 0.720    73.86 
       
    1     .    382.79    9.53 19,676.87 21,468.36   8.3   36.00   36.06  192.00      8     0.9879 0.01315   52.69 0.620    47.13 
       
    2     .    445.60    4.53 18,779.74 19,761.83   5.0   36.00   36.02  192.03      8     0.9910 0.01573   44.07 0.673    42.82 
       
    2     .    370.37    9.51 19,630.94 20,973.13   6.4   36.00   36.01  192.03      8     0.9896 0.01441   48.09 0.635    44.02 
       
    3     .    392.60    4.00 14,002.34 15,276.58   8.3   95.00   96.00  192.00      5     0.9508 0.01078   64.31 0.871    80.83 
       
    1     .    355.54    6.00 11,500.16 12,493.18   7.9   95.00   96.00  192.01      5     0.9979 0.01105   62.72 1.065    96.40 
       
    3    2.00  219.93    7.52  6,732.08  7,574.44  11.1   72.00   72.01  144.00      4     0.9866 0.01201   57.70 1.757   146.27 
       
    2     .    312.57    4.50 15,414.33 16,514.39   6.7   36.00   36.02  192.03      8     0.9886 0.01387   49.98 0.806    58.11 
       
    1    2.00  533.87    4.50 24,102.97 25,484.26   5.4   36.00   36.10  192.00      8     0.9947 0.01522   45.54 0.522    34.31 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                        (. = parameter could not be estimated) 
                         *A lag time was not calculated if the first concentration >= LOQ occurred at the first sample time. 
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                                                                     Appendix VI 
                                                    Individual Subject Pharmacokinetic Parameters 
                                                             Treatment B - EC Tablet Fed 
 
                       Lag                                              Regression    Final 
                      Time*  CMAX    TMAX  AUC(0-t)  AUC(inf)  % AUC    Start Time     Time  No. Points  Regr  Lambda_z   t½    CL/F    Vz/F 
       Subject Period  (h)  (ng/mL)  (h)   (hxng/mL) (hxng/mL) Extrap Nominal Actual  C>=LOQ  in Regr     r²     (/h)    (h)   (L/h)    (L) 
       ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— 
 
       
    1    5.00   27.15    7.50    182.90    279.12  34.5    9.00    9.50   14.00      4     0.9938 0.12981    5.34 47.68   367.33 
       
    1    2.00  144.33    4.50  2,875.23  3,402.37  15.5   35.00   36.00   72.00      3     0.9942 0.02326   29.80 3.912   168.16 
       
    2    3.00   71.48    4.50  1,399.14  1,719.88  18.6   16.00   16.00   48.01      4     0.9594 0.03703   18.72 7.738   208.96 
       
    3     .    387.75    9.51 17,013.40 17,986.46   5.4   72.00   72.01  192.01      6     0.9690 0.01449   47.83 0.740    51.06 
       
    3     .     75.27    7.00  1,609.92       .      .      .       .     72.01      .      .      .          .    .         . 
       
    2     .     30.39    8.00  2,549.77  4,919.52  48.2   35.00   36.00  168.02      7     0.9893 0.00433  160.09 2.705   624.84 
       
    1     .     45.72    7.00    763.11  1,018.73  25.1   15.00   16.00   36.00      3     0.9875 0.03948   17.56 13.06   330.94 
       
    2     .    278.69    3.52  7,424.04  8,387.45  11.5   47.00   48.00  168.00      6     0.9627 0.01195   57.98 1.587   132.74 
       
    2    5.00  315.30    8.00 11,538.14 12,881.72  10.4   72.00   72.01  192.00      6     0.9511 0.01087   63.75 1.033    95.02 
       
    3    2.15  250.60    7.01  8,727.92  9,907.93  11.9   72.00   72.01  192.00      6     0.9625 0.00970   71.44 1.343   138.45 
       
    3     .     73.25    6.00  2,726.49       .      .      .       .    120.00      .      .      .          .    .         . 
       
    1    3.00  314.87    4.55  9,902.21 10,528.76   6.0   48.00   48.01  168.31      6     0.9841 0.01609   43.08 1.264    78.56 
       
    1     .    256.51    4.50  7,173.81  7,909.66   9.3   48.00   48.01  144.00      5     0.9857 0.01477   46.92 1.683   113.89 
       
    2     .    137.05    4.51  4,203.47  4,942.40  15.0   36.00   36.03   96.02      4     0.9850 0.01752   39.56 2.693   153.70 
       
    2     .     87.43    4.50  1,608.05  2,098.59  23.4   24.00   24.01   48.00      3     0.9518 0.02677   25.90 6.342   236.93 
       
    1     .    272.07    4.50  6,764.53  7,554.08  10.5   48.00   48.01  120.00      4     0.9760 0.01567   44.23 1.762   112.43 
       
    3     .    108.85    7.00  3,163.41  4,253.62  25.6   48.00   48.00  120.00      4     0.9562 0.00964   71.89 3.129   324.50 
       
    3     .    325.45    4.50 10,511.03 11,730.88  10.4   72.00   72.00  192.01      6     0.9850 0.01007   68.83 1.135   112.66 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                        (. = parameter could not be estimated) 
                         *A lag time was not calculated if the first concentration >= LOQ occurred at the first sample time. 
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                                                                     Appendix VI 
                                                    Individual Subject Pharmacokinetic Parameters 
                                                     Treatment C - Uncoated Capsule + PPI Fasted 
 
                       Lag                                              Regression    Final 
                      Time*  CMAX    TMAX  AUC(0-t)  AUC(inf)  % AUC    Start Time     Time  No. Points  Regr  Lambda_z   t½    CL/F    Vz/F 
       Subject Period  (h)  (ng/mL)  (h)   (hxng/mL) (hxng/mL) Extrap Nominal Actual  C>=LOQ  in Regr     r²     (/h)    (h)   (L/h)    (L) 
       ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— 
 
       
    2     .    445.77    2.99 20,896.85       .      .      .       .    191.99      .      .      .          .    .         . 
       
    3     .    353.87    3.50 13,764.48 14,481.24   4.9   72.00   72.00  192.00      6     0.9832 0.01425   48.65 0.919    64.50 
       
    3     .    447.08    4.50 16,092.90 16,804.88   4.2   48.00   48.00  192.10      7     0.9851 0.01599   43.36 0.792    49.54 
       
    1     .    460.34    4.50 17,746.68 18,479.64   4.0   35.00   36.00  192.00      8     0.9913 0.01683   41.18 0.720    42.78 
       
    2     .    420.63   10.01 24,901.94 27,095.86   8.1   36.00   36.03  192.01      8     0.9972 0.01290   53.74 0.491    38.08 
       
    1     .    402.97    4.50 22,358.35 24,570.85   9.0   36.00   36.00  192.01      8     0.9932 0.01236   56.07 0.542    43.81 
       
    2     .    459.34    4.50 19,914.87 21,093.09   5.6   35.00   36.00  192.00      8     0.9884 0.01490   46.51 0.631    42.34 
       
    3     .    367.72    4.50 15,920.08 16,873.34   5.6   36.00   36.04  192.00      8     0.9921 0.01484   46.71 0.789    53.16 
       
    1     .    477.57    3.51 21,464.59 22,684.16   5.4   23.00   24.00  192.00      9     0.9913 0.01519   45.64 0.587    38.63 
       
    1     .    566.16    4.52 27,087.62 29,032.66   6.7   36.00   36.15  192.08      8     0.9877 0.01402   49.43 0.458    32.69 
       
    2     .    375.17    5.00 19,190.70 20,783.64   7.7   36.00   36.02  192.01      8     0.9857 0.01316   52.69 0.640    48.68 
       
    3     .    496.93    3.00 18,655.05 19,475.16   4.2   24.00   24.00  192.00      9     0.9905 0.01656   41.85 0.683    41.26 
       
    3     .    405.34    4.00 20,677.13 22,327.76   7.4   24.00   24.00  192.00      9     0.9941 0.01382   50.15 0.596    43.13 
       
    1     .    567.10    4.50 19,428.23 20,907.70   7.1   95.00   96.00  192.01      5     0.9743 0.01177   58.91 0.637    54.10 
       
    3     .    406.89    9.02 18,674.17 19,730.51   5.4   24.00   24.01  192.00      9     0.9945 0.01514   45.78 0.675    44.55 
       
    2     .    525.94    3.50 23,040.95 24,447.55   5.8   36.00   36.04  192.03      8     0.9818 0.01495   46.37 0.544    36.42 
       
    1     .    313.14    4.50 14,392.65 15,267.89   5.7   23.00   24.00  192.00      9     0.9896 0.01531   45.28 0.872    56.94 
       
    2     .    460.65    4.50 22,362.06 23,751.30   5.8   24.00   24.00  192.03      9     0.9949 0.01490   46.51 0.560    37.60 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                        (. = parameter could not be estimated) 
                         *A lag time was not calculated if the first concentration >= LOQ occurred at the first sample time. 
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                                                                     Appendix VII 
                                                Descriptive Statistics for Pharmacokinetic Parameters 
 
                                                             ————————— Arithmetic ————————— 
                                                                          Standard          ——— Geometric ———— 
   Treatment                      Parameter       Units   N     Mean      Deviation  CV (%)    Mean     CV (%)   Minimum     Median      Maximum 
   ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— 
 
   EC Tablet Fasted               TLAG            h        4      2.2513      0.5012  22.26       .        .        1.9994      2.0014      3.0031 
                                  CMAX            ng/mL   18    376.0559     98.0308  26.07    360.8826  32.53    147.2910    395.2374    533.8655 
                                  TMAX            h       18      5.8976      2.2000  37.30       .        .        3.0036      4.5407      9.5333 
                                  AUC(0-t)        hxng/mL 18 16,026.3726  5,635.0075  35.16 14,790.8396  47.45  4,857.6726 17,523.0845 24,102.9710 
                                  AUC(inf)        hxng/mL 18 17,258.3266  5,955.0054  34.51 15,997.7562  45.74  5,511.1409 19,126.4525 25,484.2642 
                                  Lambda_z        /h      18      0.0140      0.0023  16.74      0.0138  17.10      0.0097      0.0143      0.0195 
                                  t½              h       18     50.9539      8.8704  17.41     50.2559  17.10     35.4694     48.4814     71.1336 
                                  CL/F            L/h     18      0.9233      0.5090  55.13      0.8319  45.74      0.5222      0.6966      2.4149 
                                  Vz/F            L       18     66.6092     33.9633  50.99     60.3180  45.88     34.3132     51.2159    146.4164 
 
   EC Tablet Fed                  TLAG            h        6      3.3586      1.3386  39.86       .        .        1.9994      3.0015      5.0017 
                                  CMAX            ng/mL   17    186.5738    117.6370  63.05    145.1312  94.12     27.1480    144.3250    387.7480 
                                  TMAX            h       17      5.8001      1.6925  29.18       .        .        3.5161      4.5542      9.5056 
                                  AUC(0-t)        hxng/mL 17  5,740.3997  4,680.9190  81.54  3,635.5289 170.21    182.9003  4,203.4749 17,013.3966 
                                  AUC(inf)        hxng/mL 15  6,973.4432  5,065.3161  72.64  4,654.6700 160.02    279.1198  7,554.0780 17,986.4628 
                                  Lambda_z        /h      15      0.0258      0.0303 117.32      0.0189  79.66      0.0096      0.0157      0.1298 
                                  t½              h       15     43.5216     20.9345  48.10     36.7348  79.66      5.3398     44.2336     71.8877 
                                  CL/F            L/h     15      6.3404     11.9177 187.96      2.8593 160.02      0.7399      1.7618     47.6820 
                                  Vz/F            L       15    175.0215     98.1477  56.08    151.5334  60.81     51.0613    138.4459    367.3285 
 
   Uncoated Capsule + PPI Fasted  TLAG            h        0       .           .        .         .        .         .           .           . 
                                  CMAX            ng/mL   18    441.8128     69.5915  15.75    436.6144  16.01    313.1404    446.4265    567.1021 
                                  TMAX            h       18      4.7257      1.8443  39.03       .        .        2.9919      4.4997     10.0092 
                                  AUC(0-t)        hxng/mL 18 19,809.4048  3,508.5981  17.71 19,511.1356  18.23 13,764.4776 19,671.5530 27,087.6171 
                                  AUC(inf)        hxng/mL 17 21,047.4835  4,021.6837  19.11 20,682.9228  19.58 14,481.2370 20,907.7004 29,032.6560 
                                  Lambda_z        /h      17      0.0145      0.0014   9.62      0.0145   9.88      0.0118      0.0149      0.0168 
                                  t½              h       17     48.1660      4.8635  10.10     47.9431   9.88     41.1780     46.5084     58.9137 
                                  CL/F            L/h     17      0.6551      0.1293  19.74      0.6435  19.58      0.4584      0.6366      0.9190 
                                  Vz/F            L       17     45.1889      8.3112  18.39     44.5075  17.94     32.6936     43.1304     64.4999 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                       
                   Geometric mean and CV were not calculated for Tmax or Tlag. 
              Subject 
 Period 2, EC Tablet Fed, had a C(0) >= LOQ and >= 5% of Cmax and is excluded from the descriptive statistics. 
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                                                                    Appendix VIII 
                                                  Statistical Analysis of Pharmacokinetic Parameters 
 
--------------------------------------------------------------- ASSAY=Total Molybdenum --------------------------------------------------------------- 
 
                                                                  The GLM Procedure 
 
                                                               Class Level Information 
 
                                        Class          Levels    Values 
 
                                        SUBJECT            18  
 
                                        PERIOD              3    1 2 3 
 
                                        TREATMENT           3    A B C 
 
                                        SEQUENCE            6    ABC ACB BAC BCA CAB CBA 
 
 
                                                         Data for Analysis of LNCMAX LNAUCT 
 
                                                       Number of Observations Read          53 
                                                       Number of Observations Used          53 
 
 
                                                             Data for Analysis of LNAUC 
 
                                                       Number of Observations Read          53 
                                                       Number of Observations Used          50 
 
 
NOTE: Variables in each group are consistent with respect to the presence or absence of missing values. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                           LNCMAX = ln(Cmax); LNAUCT = ln[AUC(0-t)]; LNAUC = ln[AUC(inf)]. 
                       
tment A - EC Tablet Fasted; Treatment B - EC Tablet Fed; Treatment C - Uncoated Capsule + PPI Fasted 
               Subject 
 Period 2, EC Tablet Fed, had a C(0) >= LOQ and >= 5% of Cmax and is excluded from the statistical analyses. 
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                                                                    Appendix VIII 
                                                  Statistical Analysis of Pharmacokinetic Parameters 
 
--------------------------------------------------------------- ASSAY=Total Molybdenum --------------------------------------------------------------- 
 
                                                                  The GLM Procedure 
 
Dependent Variable: LNCMAX 
 
                                                                         Sum of 
                                 Source                      DF         Squares     Mean Square    F Value    Pr > F 
 
                                 Model                       21     17.88490026      0.85166192       4.11    0.0002 
 
                                 Error                       31      6.42240550      0.20717437 
 
                                 Corrected Total             52     24.30730576 
 
 
                                                 R-Square     Coeff Var      Root MSE    LNCMAX Mean 
 
                                                 0.735783      8.040249      0.455164       5.661070 
 
 
                                 Source                      DF     Type III SS     Mean Square    F Value    Pr > F 
 
                                 SEQUENCE                     5      1.74914402      0.34982880       1.69    0.1668 
                                 SUBJECT(SEQUENCE)           12      4.05190490      0.33765874       1.63    0.1341 
                                 PERIOD                       2      0.02154484      0.01077242       0.05    0.9494 
                                 TREATMENT                    2     11.60818873      5.80409436      28.02    <.0001 
 
 
                                  Tests of Hypotheses Using the Type III MS for SUBJECT(SEQUENCE) as an Error Term 
 
                                 Source                      DF     Type III SS     Mean Square    F Value    Pr > F 
 
                                 SEQUENCE                     5      1.74914402      0.34982880       1.04    0.4401 
 
 
                                                                                 Standard 
                                     Parameter                   Estimate           Error    t Value    Pr > |t| 
 
                                     B-A                      -0.90419611      0.15523662      -5.82      <.0001 
                                     A-C                      -0.19049775      0.15172137      -1.26      0.2187 
 
 
 
 
 
 
 
                                           LNCMAX = ln(Cmax); LNAUCT = ln[AUC(0-t)]; LNAUC = ln[AUC(inf)]. 
                       
tment A - EC Tablet Fasted; Treatment B - EC Tablet Fed; Treatment C - Uncoated Capsule + PPI Fasted 
               Subject 
 Period 2, EC Tablet Fed, had a C(0) >= LOQ and >= 5% of Cmax and is excluded from the statistical analyses. 
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                                                                    Appendix VIII 
                                                  Statistical Analysis of Pharmacokinetic Parameters 
 
--------------------------------------------------------------- ASSAY=Total Molybdenum --------------------------------------------------------------- 
 
                                                                  The GLM Procedure 
 
Dependent Variable: LNAUCT 
 
                                                                         Sum of 
                                 Source                      DF         Squares     Mean Square    F Value    Pr > F 
 
                                 Model                       21     40.44238385      1.92582780       4.43    <.0001 
 
                                 Error                       31     13.46679128      0.43441262 
 
                                 Corrected Total             52     53.90917513 
 
 
                                                 R-Square     Coeff Var      Root MSE    LNAUCT Mean 
 
                                                 0.750195      7.128694      0.659100       9.245731 
 
 
                                 Source                      DF     Type III SS     Mean Square    F Value    Pr > F 
 
                                 SEQUENCE                     5      5.15134533      1.03026907       2.37    0.0621 
                                 SUBJECT(SEQUENCE)           12      6.80651709      0.56720976       1.31    0.2646 
                                 PERIOD                       2      0.40445189      0.20222595       0.47    0.6321 
                                 TREATMENT                    2     26.68046366     13.34023183      30.71    <.0001 
 
 
                                  Tests of Hypotheses Using the Type III MS for SUBJECT(SEQUENCE) as an Error Term 
 
                                 Source                      DF     Type III SS     Mean Square    F Value    Pr > F 
 
                                 SEQUENCE                     5      5.15134533      1.03026907       1.82    0.1840 
 
 
                                                                                 Standard 
                                     Parameter                   Estimate           Error    t Value    Pr > |t| 
 
                                     B-A                      -1.37848178      0.22479020      -6.13      <.0001 
                                     A-C                      -0.27697732      0.21969995      -1.26      0.2168 
 
 
 
 
 
 
 
                                           LNCMAX = ln(Cmax); LNAUCT = ln[AUC(0-t)]; LNAUC = ln[AUC(inf)]. 
                       
tment A - EC Tablet Fasted; Treatment B - EC Tablet Fed; Treatment C - Uncoated Capsule + PPI Fasted 
               Subject 
 Period 2, EC Tablet Fed, had a C(0) >= LOQ and >= 5% of Cmax and is excluded from the statistical analyses. 
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                                                                    Appendix VIII 
                                                  Statistical Analysis of Pharmacokinetic Parameters 
 
--------------------------------------------------------------- ASSAY=Total Molybdenum --------------------------------------------------------------- 
 
                                                                  The GLM Procedure 
                                                                 Least Squares Means 
 
                                                                                 LNCMAX 
                                                              TREATMENT          LSMEAN 
 
                                                              A              5.88855268 
                                                              B              4.98435657 
                                                              C              6.07905043 
 
 
                                                                                 LNAUCT 
                                                              TREATMENT          LSMEAN 
 
                                                              A              9.60176332 
                                                              B              8.22328154 
                                                              C              9.87874064 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                           LNCMAX = ln(Cmax); LNAUCT = ln[AUC(0-t)]; LNAUC = ln[AUC(inf)]. 
                       
tment A - EC Tablet Fasted; Treatment B - EC Tablet Fed; Treatment C - Uncoated Capsule + PPI Fasted 
               Subject 
 Period 2, EC Tablet Fed, had a C(0) >= LOQ and >= 5% of Cmax and is excluded from the statistical analyses. 
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                                                                    Appendix VIII 
                                                  Statistical Analysis of Pharmacokinetic Parameters 
 
--------------------------------------------------------------- ASSAY=Total Molybdenum --------------------------------------------------------------- 
 
                                                                  The GLM Procedure 
 
Dependent Variable: LNAUC 
 
                                                                         Sum of 
                                 Source                      DF         Squares     Mean Square    F Value    Pr > F 
 
                                 Model                       21     34.11877540      1.62470359       6.09    <.0001 
 
                                 Error                       28      7.47080100      0.26681432 
 
                                 Corrected Total             49     41.58957641 
 
 
                                                  R-Square     Coeff Var      Root MSE    LNAUC Mean 
 
                                                  0.820368      5.496773      0.516541      9.397163 
 
 
                                 Source                      DF     Type III SS     Mean Square    F Value    Pr > F 
 
                                 SEQUENCE                     5      7.44208565      1.48841713       5.58    0.0011 
                                 SUBJECT(SEQUENCE)           12      7.76118463      0.64676539       2.42    0.0263 
                                 PERIOD                       2      0.59316463      0.29658231       1.11    0.3431 
                                 TREATMENT                    2     14.44787685      7.22393843      27.07    <.0001 
 
 
                                  Tests of Hypotheses Using the Type III MS for SUBJECT(SEQUENCE) as an Error Term 
 
                                 Source                      DF     Type III SS     Mean Square    F Value    Pr > F 
 
                                 SEQUENCE                     5      7.44208565      1.48841713       2.30    0.1100 
 
 
                                                                                 Standard 
                                     Parameter                   Estimate           Error    t Value    Pr > |t| 
 
                                     B-A                      -1.14888271      0.18557883      -6.19      <.0001 
                                     A-C                      -0.13736930      0.17620792      -0.78      0.4422 
 
 
 
 
 
 
 
                                           LNCMAX = ln(Cmax); LNAUCT = ln[AUC(0-t)]; LNAUC = ln[AUC(inf)]. 
                       
tment A - EC Tablet Fasted; Treatment B - EC Tablet Fed; Treatment C - Uncoated Capsule + PPI Fasted 
               Subject 
 Period 2, EC Tablet Fed, had a C(0) >= LOQ and >= 5% of Cmax and is excluded from the statistical analyses. 
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July 14, 2014 
 
                                                                    Appendix VIII 
                                                  Statistical Analysis of Pharmacokinetic Parameters 
 
--------------------------------------------------------------- ASSAY=Total Molybdenum --------------------------------------------------------------- 
 
                                                                  The GLM Procedure 
                                                                 Least Squares Means 
 
                                                              TREATMENT    LNAUC LSMEAN 
 
                                                              A              9.68020375 
                                                              B              8.53132104 
                                                              C              9.81757305 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                           LNCMAX = ln(Cmax); LNAUCT = ln[AUC(0-t)]; LNAUC = ln[AUC(inf)]. 
                       
tment A - EC Tablet Fasted; Treatment B - EC Tablet Fed; Treatment C - Uncoated Capsule + PPI Fasted 
               Subject 
 Period 2, EC Tablet Fed, had a C(0) >= LOQ and >= 5% of Cmax and is excluded from the statistical analyses. 
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                                                                     Appendix VII 
                                                  Statistical Analysis of Pharmacokinetic Parameters 
 
                                                                                                                     Within 
                                            ——————— Geometric Means ——————— Geometric  —— 90% Confidence Interval —— Subject Power* 
                  Comparison      Parameter      Test          Reference    Mean Ratio  Lower Limit    Upper Limit   CV (%)   (%) 
                  ————————————————————————————————————————————————————————————————————————————————————————————————————————————————— 
 
                  B-A             CMAX            146.11          360.88       40.49        31.12          52.68      47.98   67.14 
                                  AUC(0-t)      3,726.71       14,790.84       25.20        17.21          36.89      73.76   77.30 
                                  AUC(inf)      5,071.14       15,997.76       31.70        23.12          43.47      55.30   72.58 
 
                  A-C             CMAX            360.88          436.61       82.65        63.91         106.90      47.98   66.48 
                                  AUC(0-t)     14,790.84       19,511.14       75.81        52.23         110.02      73.76   76.76 
                                  AUC(inf)     15,997.76       18,353.45       87.16        64.59         117.63      55.30   71.10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                  Data were natural log-transformed before analysis. 
                                                  *Power to detect a 20% difference at alpha = 0.05. 
                       
tment A - EC Tablet Fasted; Treatment B - EC Tablet Fed; Treatment C - Uncoated Capsule + PPI Fasted 
               Subject 
 Period 2, EC Tablet Fed, had a C(0) >= LOQ and >= 5% of Cmax and is excluded from the statistical analyses. 
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Appendix IX — Individual Subject Total Mo Concentration vs. Time Graphs — Linear Axes 
 
Conc (ng/mL)
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Subject
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EC Tablet Fed
Uncoated Capsule + PPI Fasted
Subject
Treatment
EC Tablet Fasted
EC Tablet Fed
Uncoated Capsule + PPI Fasted
Subject
Treatment
EC Tablet Fasted
EC Tablet Fed
Uncoated Capsule + PPI Fasted
Subject
Treatment
EC Tablet Fasted
EC Tablet Fed
Uncoated Capsule + PPI Fasted
 
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Wilson Therapeutics USA, Inc. 
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Appendix IX — Individual Subject Total Mo Concentration vs. Time Graphs — Linear Axes 
 
Conc (ng/mL)
0
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Time (hr)
0
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Subject
Treatment
EC Tablet Fasted
EC Tablet Fed
Uncoated Capsule + PPI Fasted
Subject
Treatment
EC Tablet Fasted
EC Tablet Fed
Uncoated Capsule + PPI Fasted
Subject
Treatment
EC Tablet Fasted
EC Tablet Fed
Uncoated Capsule + PPI Fasted
Subject
Treatment
EC Tablet Fasted
EC Tablet Fed
Uncoated Capsule + PPI Fasted
 
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Wilson Therapeutics USA, Inc. 
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Appendix IX — Individual Subject Total Mo Concentration vs. Time Graphs — Linear Axes 
 
Conc (ng/mL)
0
100
200
300
400
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600
Time (hr)
0
24
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Subject
Treatment
EC Tablet Fasted
EC Tablet Fed
Uncoated Capsule + PPI Fasted
Subject
Treatment
EC Tablet Fasted
EC Tablet Fed
Uncoated Capsule + PPI Fasted
Subject
Treatment
EC Tablet Fasted
EC Tablet Fed
Uncoated Capsule + PPI Fasted
Subject
Treatment
EC Tablet Fasted
EC Tablet Fed
Uncoated Capsule + PPI Fasted
 
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Wilson Therapeutics USA, Inc. 
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Appendix IX — Individual Subject Total Mo Concentration vs. Time Graphs — Linear Axes 
 
Conc (ng/mL)
0
100
200
300
400
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600
Time (hr)
0
24
48
72
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Conc (ng/mL)
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Subject
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EC Tablet Fasted
EC Tablet Fed
Uncoated Capsule + PPI Fasted
Subject
Treatment
EC Tablet Fasted
EC Tablet Fed
Uncoated Capsule + PPI Fasted
Subject
Treatment
EC Tablet Fasted
EC Tablet Fed
Uncoated Capsule + PPI Fasted
Subject
Treatment
EC Tablet Fasted
EC Tablet Fed
Uncoated Capsule + PPI Fasted
 
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Appendix IX — Individual Subject Total Mo Concentration vs. Time Graphs — Linear Axes 
 
Conc (ng/mL)
0
100
200
300
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500
600
Time (hr)
0
24
48
72
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216
Conc (ng/mL)
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Time (hr)
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Subject
Treatment
EC Tablet Fasted
EC Tablet Fed
Uncoated Capsule + PPI Fasted
Subject
Treatment
EC Tablet Fasted
EC Tablet Fed
Uncoated Capsule + PPI Fasted
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Appendix X — Individual Subject Total Mo Concentration vs. Time Graphs — Semi-Logarithmic Axes 
 
Conc (ng/mL)
1
10
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1000
Time (hr)
0
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Conc (ng/mL)
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Conc (ng/mL)
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Subject
 Treatment=EC Tablet Fasted
Subject
Treatment=EC Tablet Fed
Subject
Treatment=Uncoated Capsule + PPI Fasted
 
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Appendix X — Individual Subject Total Mo Concentration vs. Time Graphs — Semi-Logarithmic Axes 
 
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
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144
168
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Conc (ng/mL)
1
10
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Time (hr)
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Conc (ng/mL)
1
10
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1000
Time (hr)
0
24
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72
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216
Subject
 Treatment=EC Tablet Fasted
Subject
Treatment=EC Tablet Fed
Subject
Treatment=Uncoated Capsule + PPI Fasted
 
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July 14, 2014 
Appendix X — Individual Subject Total Mo Concentration vs. Time Graphs — Semi-Logarithmic Axes 
 
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Conc (ng/mL)
1
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Time (hr)
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216
Conc (ng/mL)
1
10
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1000
Time (hr)
0
24
48
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216
Subject
 Treatment=EC Tablet Fasted
Subject
Treatment=EC Tablet Fed
Subject
Treatment=Uncoated Capsule + PPI Fasted
 
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Appendix X — Individual Subject Total Mo Concentration vs. Time Graphs — Semi-Logarithmic Axes 
 
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
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216
Conc (ng/mL)
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Time (hr)
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Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Subject
 Treatment=EC Tablet Fasted
Subject
Treatment=EC Tablet Fed
Subject
Treatment=Uncoated Capsule + PPI Fasted
 
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July 14, 2014 
Appendix X — Individual Subject Total Mo Concentration vs. Time Graphs — Semi-Logarithmic Axes 
 
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
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Conc (ng/mL)
1
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1000
Time (hr)
0
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Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
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Subject
 Treatment=EC Tablet Fasted
Subject
Treatment=EC Tablet Fed
Subject
Treatment=Uncoated Capsule + PPI Fasted
 
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July 14, 2014 
Appendix X — Individual Subject Total Mo Concentration vs. Time Graphs — Semi-Logarithmic Axes 
 
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
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Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Subject
 Treatment=EC Tablet Fasted
Subject
Treatment=EC Tablet Fed
Subject
Treatment=Uncoated Capsule + PPI Fasted
 
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July 14, 2014 
Appendix X — Individual Subject Total Mo Concentration vs. Time Graphs — Semi-Logarithmic Axes 
 
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
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Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Subject
 Treatment=EC Tablet Fasted
Subject
Treatment=EC Tablet Fed
Subject
Treatment=Uncoated Capsule + PPI Fasted
 
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July 14, 2014 
Appendix X — Individual Subject Total Mo Concentration vs. Time Graphs — Semi-Logarithmic Axes 
 
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
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96
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144
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Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Subject
 Treatment=EC Tablet Fasted
Subject
Treatment=EC Tablet Fed
Subject
Treatment=Uncoated Capsule + PPI Fasted
 
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July 14, 2014 
Appendix X — Individual Subject Total Mo Concentration vs. Time Graphs — Semi-Logarithmic Axes 
 
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Subject
 Treatment=EC Tablet Fasted
Subject
Treatment=EC Tablet Fed
Subject
Treatment=Uncoated Capsule + PPI Fasted
 
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Page 60 
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July 14, 2014 
Appendix X — Individual Subject Total Mo Concentration vs. Time Graphs — Semi-Logarithmic Axes 
 
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Subject
 Treatment=EC Tablet Fasted
Subject
Treatment=EC Tablet Fed
Subject
Treatment=Uncoated Capsule + PPI Fasted
 
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July 14, 2014 
Appendix X — Individual Subject Total Mo Concentration vs. Time Graphs — Semi-Logarithmic Axes 
 
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
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96
120
144
168
192
216
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Subject
 Treatment=EC Tablet Fasted
Subject
Treatment=EC Tablet Fed
Subject
Treatment=Uncoated Capsule + PPI Fasted
 
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July 14, 2014 
Appendix X — Individual Subject Total Mo Concentration vs. Time Graphs — Semi-Logarithmic Axes 
 
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Subject
 Treatment=EC Tablet Fasted
Subject
Treatment=EC Tablet Fed
Subject
Treatment=Uncoated Capsule + PPI Fasted
 
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Page 63 
Study WTX101-102 
July 14, 2014 
Appendix X — Individual Subject Total Mo Concentration vs. Time Graphs — Semi-Logarithmic Axes 
 
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Subject
 Treatment=EC Tablet Fasted
Subject
Treatment=EC Tablet Fed
Subject
Treatment=Uncoated Capsule + PPI Fasted
 
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July 14, 2014 
Appendix X — Individual Subject Total Mo Concentration vs. Time Graphs — Semi-Logarithmic Axes 
 
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Subject
 Treatment=EC Tablet Fasted
Subject
Treatment=EC Tablet Fed
Subject
Treatment=Uncoated Capsule + PPI Fasted
 
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Study WTX101-102 
July 14, 2014 
Appendix X — Individual Subject Total Mo Concentration vs. Time Graphs — Semi-Logarithmic Axes 
 
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Subject
 Treatment=EC Tablet Fasted
Subject
Treatment=EC Tablet Fed
Subject
Treatment=Uncoated Capsule + PPI Fasted
 
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July 14, 2014 
Appendix X — Individual Subject Total Mo Concentration vs. Time Graphs — Semi-Logarithmic Axes 
 
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
120
144
168
192
216
Conc (ng/mL)
1
10
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1000
Time (hr)
0
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Conc (ng/mL)
1
10
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1000
Time (hr)
0
24
48
72
96
120
144
168
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216
Subject
 Treatment=EC Tablet Fasted
Subject
Treatment=EC Tablet Fed
Subject
Treatment=Uncoated Capsule + PPI Fasted
 
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July 14, 2014 
Appendix X — Individual Subject Total Mo Concentration vs. Time Graphs — Semi-Logarithmic Axes 
 
Conc (ng/mL)
1
10
100
1000
Time (hr)
0
24
48
72
96
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Conc (ng/mL)
1
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Time (hr)
0
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Conc (ng/mL)
1
10
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1000
Time (hr)
0
24
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Subject
 Treatment=EC Tablet Fasted
Subject
Treatment=EC Tablet Fed
Subject
Treatment=Uncoated Capsule + PPI Fasted
 
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Appendix X — Individual Subject Total Mo Concentration vs. Time Graphs — Semi-Logarithmic Axes 
 
Conc (ng/mL)
1
10
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1000
Time (hr)
0
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96
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Time (hr)
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Subject
 Treatment=EC Tablet Fasted
Subject
Treatment=EC Tablet Fed
Subject
Treatment=Uncoated Capsule + PPI Fasted
 
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16.1.9.2 
Statistical Methods 
16.1.9.2.1 Statistical Analysis Plan 
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Statistical Analysis Plan 
A Phase 1, Single-Center, Randomized, 3-Period Crossover Study in Healthy 
Volunteers to Evaluate the Absorption of WTX101 After Single Dose 
Administration of an Enteric Coated Formulation with and without food and a Non-
Coated Formulation Coadministered with a Proton Pump Inhibitor without Food 
 
 
 
Protocol No. WTX101-102 
Celerion Project CA13895 
 
Final Version 1.0 
Date: 12 May 2014 
Compound Name: WTX101 
Final Protocol Date: 25 February 2014  
 
 
 
Sponsor:  
Wilson Therapeutics USA, Inc. 
P.O. Box 17757 
Urbana, Illinois 61803 - USA  
 
Wilson Therapeutics, AB 
Västra Trädgårdsgatan 15  
11453 Stockholm, Sweden  
 
 
Sponsor Representative:   
 
11 Ridgefield Road 
Winchester, Massachusetts, 01890, USA 
Celerion 
621 Rose Street 
Lincoln, NE 68502 
 
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Wilson Therapeutics USA, lnc. 
wrx101: WTx101-102 
Celerion, Clinical Study Report No. CA 13895 
Statistical Analysis Plan Signature Page 
Sponsor: Wilson Ther.apeutics USA, Inc. 
Compound Name: WTX101 
Protocol: WfX101-102 
-
P.O. Box 17757 
Urbana. Illinois 61803 - USA 
Wilson Therapeutics, AB 
Vastra Tradgardsgatan 15 
11453 Stockholm, Sweden 
Study Title: A.Phase 1, Single-Center, Randomized, 3-Period Crossover Study in 
Healthy Volunteers to Evaluate the Absorption of WTX 101 After Single Dose 
Administration of an Enteric Coated Formulation with and without food and a Non-
Coated Formulation Coadministered with a Proton Pump Inhibitor without Food 
'· 
Issue Date: 
L14 
Signature:
Celerion 
621 Rose Street 
NE 68502 
11 Ridgefield Road 
Winchester 
Massachusetts, 01890 
Statistical Analysis Plan 12 May 2014 
Date: /3 lvf/Jj 2o II./.. 
Date: 
I<_. 
Page 2of66 
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Wilson Therapeutics USA, Inc. 
WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 3 of 66 
Table of Contents 
 
1. 
INTRODUCTION ................................................................................................. 4 
2. 
OBJECTIVES AND ENDPOINTS ........................................................................ 4 
2.1 
Objectives ................................................................................................ 4 
2.2 
Endpoints ................................................................................................. 4 
3. 
STUDY DESIGN .................................................................................................. 4 
4. 
ANALYSIS POPULATIONS ................................................................................. 6 
4.1 
Analysis Populations ................................................................................ 6 
5. 
TREATMENT DESCRIPTIONS ........................................................................... 6 
5.1 
Test Treatment ......................................................................................... 6 
5.2 
Reference Treatment................................................................................ 6 
6. 
PHARMACOKINETIC ANALYSIS ........................................................................ 6 
7. 
EFFICACY/PHARMACODYNAMICS ................................................................... 6 
8. 
SAFETY ............................................................................................................... 7 
8.1 
Subject Discontinuation ............................................................................ 7 
8.2 
Demographics .......................................................................................... 7 
8.3 
Adverse Events ........................................................................................ 7 
8.4 
Labs (Serum Chemistry, Hematology, Coagulation, and 
Urinalysis) ................................................................................................ 8 
8.5 
Vital Signs ................................................................................................ 9 
8.6 
ECG ......................................................................................................... 9 
8.7 
Concomitant Medications ....................................................................... 10 
8.8 
Physical Examination ............................................................................. 10 
9. 
SUMMARY TABLES AND FIGURES ................................................................. 10 
10. 
DATA LISTING TITLES AND NUMBERS .......................................................... 12 
11. 
TABLE SHELLS ................................................................................................. 14 
12. 
LISTING SHELLS .............................................................................................. 37 
 
 
 
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WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 4 of 66 
1. INTRODUCTION 
The following analysis plan provides the framework for the summarization of the data 
from this study. The analysis plan may change due to unforeseen circumstances. 
Any changes made after the locking of the database will be documented in the 
clinical study report. Please note that the header for this page will be the one used 
for the main body of the report.  
2. OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
The primary objectives are: 
• The effect of dosing with an Enteric coated (EC) tablet versus dosing with the 
current non-coated capsule administered with a proton pump inhibitor (PPI; 
omeprazole) under fasting conditions on the absorption of WTX101. 
•  The effect of dosing an EC tablet with and without food on the absorption of 
WTX101 
• The safety and tolerability of WTX101. 
2.2 
Endpoints 
The primary endpoints are: 
 
• Plasma concentrations and PK parameters (e.g., AUC0-inf, AUC0-t, Cmax, tmax, λz, 
and t½, CL/F, and Vz/F) for total Molybdenum (Mo) following WTX101 EC tablet 
administration under fasting and fed conditions and WTX101 non coated 
capsule coadministered with a PPI under fasting conditions 
•  Safety and tolerability will be evaluated based on physical examinations, vital 
sign measurements, Electrocardiogram (ECGs), adverse events (AEs), and 
clinical laboratory tests. 
3. STUDY DESIGN 
This will be a single-center, open-label, randomized, 3-period, 3-treatment, 6-sequence 
crossover study evaluating the PK of single doses of WTX101 in healthy subjects based 
on the measurement of plasma total Mo.  
Eighteen (18) healthy, non-tobacco using adult male and female subjects who complete 
the study screening assessments and meet all eligibility criteria will be enrolled. These 
subjects will receive the corresponding product, according to a randomization scheme 
generated at Celerion. 
Screening of subjects will occur within 28 days prior to the first WTX101 dose.  
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WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 5 of 66 
Subjects randomized to receive PPI in Period 1 (Treatment C) will report to the Clinical 
Research Unit (CRU) on Day -5, i.e. 5 days prior to first dosing with WTX101, to receive 
a morning dose of omeprazole under fasting conditions. These subjects will be given a 
container with omeprazole doses and will continue once daily (QD) administration of 
omeprazole under fasting conditions on an outpatient basis, until their return to the CRU 
for check-in on Day -1. To ensure that the planned number of subjects are dosed with 
WTX101 on Day 1 of Period 1, stand-by subjects will also receive QD doses of 
omeprazole, as described above. Should any subject withdraw from the study after 
omeprazole administration, but before receiving WTX101 in Period 1, they will be 
replaced with a stand-by subject.  
Subjects randomized to receive PPI in Periods 2 or 3 will receive the container with 
omeprazole doses prior to discharge from the CRU after the 192-hour post-dose 
procedures in Period 1 or Period 2, as appropriate. These subjects will initiate QD 
administration of omeprazole under fasting conditions at home the following day and 
continue until their return to the CRU for their next admission. 
In each of the 3 periods, all subjects (Treatments A, B, and C) will be admitted to the 
CRU on Day -1, and will receive WTX101 EC tablets alone under fasting conditions 
(Treatment A); WTX101 EC tablets alone under fed conditions (Treatment B); or, 
omeprazole under fasting conditions followed by WTX101 non-coated capsules under 
fasting conditions (Treatment C). Pharmacokinetic (PK) sampling (for the measurement 
of plasma concentrations of total elemental Molybdenum (Mo)) will be obtained at the 
following timepoints while subjects remain in the CRU: Time 0 (within 1 hour predose), 
and then 1, 2, 3, 3.5, 4, 4.5, 5, 6, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12, 14, 16, 24, 36, and 48 
hours postdose. Subjects will be discharged on Day 3 following the 48 hours postdose 
procedures, unless medically necessary to extend confinement to 72 hours. 
Subjects will be required to return to the CRU for outpatient visits on 6 consecutive days 
(Days 4, 5, 6, 7, 8 and 9) in each period, for subsequent PK sampling and procedures at: 
72, 96, 120, 144, 168, and 192 hours postdose.  
The washout between WTX101 doses in each period will be at least 14 days.  
Subjects will return to the CRU 14 days (+/-2 days) after the final study medication 
administration for an end of study (EOS) visit with follow-up procedures, and to 
determine if any AE has occurred since the last study visit. Subjects who terminate the 
study early should be seen and assessed by an Investigator, whenever possible, to 
undergo the procedures associated with the EOS visit. 
Safety will be monitored throughout the study.  
Subjects who complete the study may be involved in the study for up to 48 days 
excluding screening (Day -5 of period one to the EOS visit). 
Subjects may be replaced at the discretion of the Sponsor. 
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WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 6 of 66 
4. ANALYSIS POPULATIONS 
4.1 
Analysis Populations 
Safety Population:  All subjects who received at least one dose of the WTX101. 
5. TREATMENT DESCRIPTIONS 
5.1 
Test Treatment 
Treatment B: 60 mg WTX101 (2 x WTX101 EC tablets, 30mg) at Hour 0 on Day 1, 30 
minutes after the start of a high-fat breakfast, preceded by an overnight 
fast. 
Treatment C: 20 mg omeprazole (1 x 20 mg delayed-release capsule) QD on the 
mornings of Days -5 to -1 following an overnight fast, 20 mg omeprazole 
capsule at Hour -1 on Day 1 following an overnight fast, and 60 mg 
WTX101 (2 x WTX101 non-coated capsules, 30mg) at Hour 0 on Day 1 
A brief treatment description will be used in tables and listings as: 
Treatment B: 60 mg WTX101 on Day 1 (Fed). 
Treatment C: 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg 
omeprazole capsule at Hour -1 and 60 mg WTX101 at Hour 0 on Day 1 
(Fasted) 
5.2 
Reference Treatment 
Treatment A: 60 mg WTX101 (2 x WTX101 EC tablets, 30mg) at Hour 0 on Day 1 
following an overnight fast 
 
A brief treatment description will be used in tables and listings as: 
 
Treatment A: 60 mg WTX101 on Day 1 (Fasted). 
 
Treatments will be referred to in the text of the report as: 
 
Treatment A (WTX101 alone, fasted), Treatment B (WTX101 alone, fed), and Treatment 
C (WTX101 with omeprazole, fasted). 
6. PHARMACOKINETIC ANALYSIS 
A separate pharmacokinetic analysis plan (PKAP) will be prepared by Kramer 
Consulting LLC and agreed upon with the Sponsor. 
7. EFFICACY/PHARMACODYNAMICS 
Not applicable 
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WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 7 of 66 
8. SAFETY  
All clinical safety and tolerability data will be listed by subject and assessment 
timpoints, including rechecks, unscheduled assessments, and early termination, 
chronologically. 
Continuous variables will be summarized using N, mean, standard deviation 
(SD), coefficient of variance (CV), median, minimum, and maximum. Frequency 
counts will be reported for all categorical data.  
Decimal point will be presented as follows: N will be presented without decimal, 
minimum/maximum in same precision as in the database, mean/median in one 
more decimal than minimum/maximum, and SD in one more decimal than 
mean/median. 
Where individual data points are missing because of dropouts or other reasons, 
the data will be summarized based on reduced denominators.  
No inferential statistics will be performed. 
8.1 
Subject Discontinuation 
Individual subject’s dosing status (treatment dosed) will be provided along with 
their completion status and date.  Frequency counts of all subjects dosed in the 
study, completing the study, and discontinuing early from the study along with the 
reason for discontinuation will be tabulated by treatment sequence and overall for 
this presentation. 
8.2 
Demographics 
Descriptive statistics will be calculated for continuous demographic variables 
(age, weight, height, and body mass index) and frequency counts will be 
tabulated for categorical demographic variables (gender, race, and ethnicity) by 
treatment sequence and overall. 
8.3 
Adverse Events 
Adverse events (AEs) will be coded with Medical Dictionary for Regulatory 
Activities (MedDRA®) Version 16.1. 
A treatment-emergent adverse event (TEAE) is defined as an AE that is starting 
or worsening at the time of or after study drug administration. An AE that occurs 
during the washout period between drugs is considered treatment emergent to 
the last drug given. If an AE that was reported during the study increases in 
severity that AE is given a resolution date and time and a new record initiated 
with the new severity.  If the severity of an AE remains the same or decreases, 
the AE will be kept open through to resolution. All AEs captured in the database 
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WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 8 of 66 
will be listed in by-subject data listings. However, only TEAEs will be 
summarized. For treatment C, the TEAEs will be summarized by time interval 
(prior to WTX101 dosing and post WTX101 dosing) and overall.  
 
Summary tables will include the number of subjects reporting the TEAE and 
percent of subjects who received study drug, number of TEAEs and percent of 
total TEAEs. These results will be summarized by treatment and overall. Number 
of subjects reporting at least one TEAE and number of TEAEs will also be 
summarized by treatment, severity (NCI CTCAE toxicity grading scale 5-point 
severity scale), and relationship to treatment. In addition, all AEs (preferred term) 
for all periods but exclude those who took Omeprazole in Period 1 (i.e. following 
first WTX101-101 dosing) will be summarized  by the number and percentage of 
subjects with the same AE and also by severity and the relationship to drug. All 
AEs will be listed by subject, including verbatim term, onset date and time, 
resolved date and time, seriousness, severity, frequency, and relationship to 
treatment. 
 
Should any serious adverse events (SAEs), AEs leading to discontinuation, and 
AEs resulting in death occur during this study, the AEs will be displayed in the 
data listings and discussed in the text of the study report. 
8.4 
Labs (Serum Chemistry, Hematology, Coagulation, and Urinalysis) 
Serum chemistry, hematology, coagulation, and urinalysis will be performed at 
screening following a fast of at least 8 hours, the check-in for each period 
following a fast of at least 6 hours, 36 hour pose WTX101 dose in each period, 
and end of study (or upon early termination).  
 
Descriptive statistics at specified time points (Check-in and 36 hour post 
WTX101 dose) will be provided for serum chemistry, hematology, coagulation, 
and urinalysis results by treatment. Change from Baseline [Check-in (Day -1) 
prior to WTX101 dosing] to the postdose time point (Hour 36) will also be 
provided for serum chemistry, hematology, coagulation, and urinalysis results for 
each treatment. Shift from baseline value tables, which provide the frequency of 
each shift in out of range results, will be provided by treatment for serum 
chemistry, hematology, coagulation, and urinalysis results. In addition, 
descriptive statistics at screening and end of study will be provided for serum 
chemistry, hematology, coagulation, and urinalysis results for all subjects as well. 
 
All out-of-range values for serum chemistry, hematology, coagulation, and 
urinalysis will be listed by subject.  Out-of-range values are considered to be 
values that are out-of normal range as defined by the clinical laboratory. The 
normal range values will be displayed in the data listings. 
 
When change from baseline is calculated, baseline is the last schedule 
assessment before dosing of WTX101 in each period, also including rechecks 
and unscheduled assessments, whichever is later. Rechecks, unscheduled 
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assessments and early termination measurements taken after WTX101 dosing 
will not be used in the summarization. 
 
Clinical laboratory values will also be displayed in a data listing by subject. 
8.5 
Vital Signs 
Vital signs (blood pressure, heart rate, respiration rate, and body temperature) 
will be performed at screening, Check-in, predose, Hour 1, Hour 4, Hour 8, Hour 
12, and Hour 24 post WTX101 dose for each period, and at the end of study (or 
upon early termination). 
Descriptive statistics for vital sign measurements (blood pressure, heart rate, 
respiration rate, and body temperature) at specified time points (Check-in, 
predose, Hour 1, Hour 4, Hour 8, Hour 12, and Hour 24 post WTX101 dose) and 
change from Baseline to postdose observations will be provided for vital sign 
measurements by treatment. In addition, descriptive statistics at screening and 
end of study will be provided for vital sign measurements for all subjects as well. 
 
When change from baseline is calculated, baseline is the last schedule 
assessment before dosing of WTX101 in each period, also including rechecks 
and unscheduled assessments, whichever is later. Rechecks, unscheduled 
assessments and early termination measurements taken after WTX101 dosing 
will not be used in the summarization. 
 
Vital signs will also be displayed in a data listing by subject. 
8.6 
ECG  
Single 12-lead ECG will be performed at screening, Check-in, predose, Hour 1, 
Hour 4, Hour 8, Hour 12, and Hour 24 post WTX101 dose for each period, and at 
the end of study (or upon early termination). 
 
ECGs will be performed on subjects after at least 2 minutes in supine position. All 
ECG tracings will be reviewed by the Study Physician or his/her designee. 
 
Descriptive statistics will be calculated for heart rate, PR, QRS, QT, QTcB and 
QTcF (Bazett’s and Fridericia’s correction) intervals by treatment at the specified 
time points (Check-in, predose, Hour 1, Hour 4, Hour 8, Hour 12, and Hour 24 
post WTX101 dose ) as well as change from baseline to the postdose time 
points. In addition, descriptive statistics at screening and end of study will be 
provided for vital sign measurements for all subjects as well. 
 
When change from baseline is calculated, baseline is the last schedule 
assessment before dosing of WTX101 in each period, also including rechecks 
and unscheduled assessments, whichever is later. Rechecks, unscheduled 
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Statistical Analysis Plan 12 May 2014 
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assessments and early termination measurements taken after WTX101 dosing 
will not be used in the summarization. 
 
ECG results will be classified as normal, abnormal not clinically significant, or 
abnormal clinically significant by the Principal Investigator (PI). Frequency of 
ECG results shift from baseline will be provided at specified time points by 
treatment.  
 
ECGs will also be displayed in a data listing by subject.  
 
8.7 
Concomitant Medications 
All concomitant medications recorded during the study will be coded with the 
WHO Dictionary Version 01Sep2013.  
8.8 
Physical Examination 
A full physical examination will be performed at screening, check-in, and at the 
end of the study or upon early termination. A symptom-driven physical 
examination may be performed at other times, at the PI’s discretion. Physical 
examination will be presented in a data listing. A normal-abnormal shift table will 
also be presented for physical exam results. Abnormal findings will be discussed 
in the clinical study report. 
 
9. SUMMARY TABLES AND FIGURES 
Summary tables and figures are numbered following the ICH structure. Please 
note that all summary tables and figures will be generated using SAS® Version 
9.3 or higher.  
The following is a list of table numbers and titles that will be included as summary 
tables: 
14.1 
Demographic Data Summary Tables 
Table 14.1.1 
Summary of Disposition 
Table 14.1.2 
Disposition of Subjects 
Table 14.1.3 
Demographic Summary 
14.2 
Pharmacokinetic Data Summary Tables and Figures  
Please note: This part will be covered by the separated PKAP. 
14.3 
Safety Data Summary Tables 
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14.3.1 
Displays of Adverse Events 
Table 14.3.1.1 
Adverse Event Frequency by Treatment – Number of 
Subjects Reporting the Event (% of Subject Dosed) 
Table 14.3.1.2 
Adverse Event Frequency by Treatment – Number of 
Adverse Events (% of Total Adverse Events) 
Table 14.3.1.3 
Adverse Event Frequency by Treatment, Severity, and 
Relationship to Drug – Number of Subjects Reporting 
Events 
Table 14.3.1.4 
Adverse Event Frequency by Treatment, Severity, and 
Relationship to Drug – Number of Adverse Events 
Table 14.3.1.5 
Adverse Event Frequency by Severity and Relationship to 
Drug Following First WTX101-101 Dosing – Number of 
Subjects Reporting Events 
Table 14.3.1.6 
Adverse Event Frequency by Severity, and Relationship to 
Drug Following First WTX101-101 Dosing – Number of 
Adverse Events 
14.3.2 
Listings of Deaths, other Serious and Significant Adverse 
Events 
Table 14.3.2.1 
Serious Adverse Events (if no serious adverse event 
occurred, a statement ‘No serious adverse event is 
reported’ will be in the table. 
14.3.3. 
Narratives of Deaths, other Serious and Certain other 
Significant Adverse Events 
14.3.4. 
Abnormal Laboratory Value Listing (each patient) 
Table 14.3.4.1 
Out-of-Range Values and Recheck Results – Serum 
Chemistry 
Table 14.3.4.2 
Out-of-Range Values and Recheck Results – Hematology 
Table 14.3.4.3 
Out-of-Range Values and Recheck Results – Coagulation 
Table 14.3.4.4 
Out-of-Range Values and Recheck Results – Urinalysis 
Table 14.3.4.5 
Out-of-Range Values and Recheck Results – Other 
14.3.5. 
Displays of Other Laboratory, Vital Signs, Electrocardiogram, 
Physical Examination, and Other Safety Data 
Table 14.3.5.1 
Clinical Laboratory Summary and Change from Baseline – 
Serum Chemistry 
Table 14.3.5.2 
Clinical Laboratory Shift from Baseline – Serum Chemistry 
Table 14.3.5.3 
Clinical Laboratory Summary and Change from Baseline – 
Hematology 
Table 14.3.5.4 
Clinical Laboratory Shift from Baseline – Hematology 
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Statistical Analysis Plan 12 May 2014 
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Table 14.3.5.5 
Clinical Laboratory Summary and Change from Baseline – 
Coagulation 
Table 14.3.5.6 
Clinical Laboratory Shift from Baseline – Coagulation 
Table 14.3.5.7 
Clinical Laboratory Summary and Change from Baseline – 
Urinalysis 
Table 14.3.5.8 
Clinical Laboratory Shift from Baseline – Urinalysis 
Table 14.3.5.9 
Vital Sign Summary and Change from Baseline 
Table 14.3.5.10 12-Lead Electrocardiogram Summary and Change from 
Baseline  
Table 14.3.5.11 12-Lead Electrocardiogram Shift from Baseline 
Table 14.3.5.12 Physical Examination Shift from Screening 
 
10. DATA LISTING TITLES AND NUMBERS 
Note: Hepatitis and HIV results that are provided by the clinical laboratory will not be 
presented in subject data listings and will not be included in any database transfer. 
Data listings are numbered following the ICH structure. The following is a list of 
appendix numbers and titles that will be included as data listings: 
16.1. Study Information 
Appendix 16.1.10.1 
Clinical Laboratory Reference Ranges 
16.2. Subject Data Listings 
16.2.1. 
Subject Discontinuation 
Appendix 16.2.1 Subject Discontinuation 
16.2.2. 
Protocol Deviations 
Appendix 16.2.2 Protocol Deviations 
16.2.3. 
Subjects Excluded from Pharmacokinetic Analysis 
Appendix 16.2.3 Subjects Excluded from Pharmacokinetic Analysis 
 
Note: Appendices 16.2.2 and 16.2.3 are generated in MS Word for inclusion in 
the study report 
16.2.4. 
Demographic Data 
Appendix 16.2.4.1  
Demographics 
Appendix 16.2.4.2.1 Physical Examination (I of II) 
Appendix 16.2.4.2.2 Physical Examination (II of II) 
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Appendix 16.2.4.2.3 Physical Examination Descriptions 
Appendix 16.2.4.3  
Medical History 
Appendix 16.2.4.4  
Substance Use 
16.2.5. 
Compliance and Drug Concentration Data 
Appendix 16.2.5.1.1 Inclusion Criteria 
Appendix 16.2.5.1.2 Exclusion Criteria 
Appendix 16.2.5.2  
Subject Eligibility 
Appendix 16.2.5.3.1 Check-in and Return Criteria 
Appendix 16.2.5.3.2 Check-in and Return Responses 
Appendix 16.2.5.3.3 Check-out Date and Time 
Appendix 16.2.5.4.1 Test Compound Description 
Appendix 16.2.5.4.2 Test Compound Administration Times 
Appendix 16.2.5.4.3 Drug and Diary Accountability 
Appendix 16.2.5.5  
Blood Draw Times 
Appendix 16.2.5.6  
Meal Times 
Appendix 16.2.5.7  
Concomitant Medications 
16.2.6. 
Individual Pharmacokinetic Data 
Please note: This part will be covered by the separated PKAP. 
16.2.7. 
Individual Adverse Event Listings 
Appendix 16.2.7.1  
Adverse Events (I of II) 
Appendix 16.2.7.2  
Adverse Events (II of II) 
Appendix 16.2.7.3  
Adverse Event Non-Medication Procedures 
Appendix 16.2.7.4  
Adverse Event Preferred Term Classification 
16.2.8. 
Individual Laboratory Measurements 
Appendix 16.2.8.1  
Clinical Laboratory Report - Serum Chemistry 
Appendix 16.2.8.2  
Clinical Laboratory Report - Hematology  
Appendix 16.2.8.3  
Clinical Laboratory Report - Coagulation 
Appendix 16.2.8.4  
Clinical Laboratory Report - Urinalysis  
Appendix 16.2.8.5  
Clinical Laboratory Report - Urine Drug Screening 
Appendix 16.2.8.6  
Clinical Laboratory Report - Other  
Appendix 16.2.8.7  
Clinical Laboratory Report - Comments 
16.2.9. 
Other Safety Observations 
Appendix 16.2.9.1  
Vital Signs 
Appendix 16.2.9.2  
12-Lead Electrocardiogram 
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Appendix 16.2.9.3  
Phone Participant 
 
11. TABLE SHELLS  
The following table shells provide a framework for the display of data from this study. 
The shells may change due to unforeseen circumstances. These shells may not be 
reflective of every aspect of this study, but are intended to show the general layout of 
the tables that will be included in the final report. 
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Page 1 of 1 
                                                  Table 14.1.1  Summary of Disposition  
  
 
                                                           Treatment Sequence 
                                              --------------------------------------------------------------- 
          Disposition                         ABC        ACB        BAC        BCA        CAB        CBA         Overall 
          --------------------------------------------------------------------------------------------------------------------- 
          Dosed                                XX         XX         XX         XX         XX         XX           XX 
 
          Completed                            XX         XX         XX         XX         XX         XX           XX 
 
          Discontinued Early                    X          X          X          X          X          X            X 
 
             <Discontinuation Reason>           X          X          X          X          X          X            X 
  
  
 
  
  
Note:  Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted) 
  
 
  
  
 
  
  
 
  
  
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
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                                                 Page 1 of 1 
                                                   Table 14.1.2  Disposition of Subjects 
  
           Randomized       Treatment Dosed         Treatment Completed                Study Completion 
   Subject   Dosing     ----------------------  -----------------------------    ---------------------------------------- 
   Number   Sequence       A     B      C            A      B       C               Status                           Date 
   ------------------------------------------------------------------------------------------------------------------------- 
       X     XXX          Yes    Yes    Yes          Yes    Yes     Yes              Completed Study                DDMMMYYYY 
       X     XXX           No    Yes    Yes           No    Yes     Yes              Terminated Study Prematurely   DDMMMYYYY 
       X     XXX          Yes    Yes    Yes          Yes    Yes     Yes              Completed Study                DDMMMYYYY 
       X     XXX          Yes    Yes    Yes          Yes    Yes     Yes              Completed Study                DDMMMYYYY 
       X     XXX          Yes    Yes    Yes          Yes    Yes     Yes              Completed Study                DDMMMYYYY 
       X     XXX          Yes    Yes    Yes          Yes    Yes     Yes              Completed Study                DDMMMYYYY 
       X     XXX          Yes    Yes    Yes          Yes    Yes     Yes              Completed Study                DDMMMYYYY 
       X     XXX          Yes    Yes    Yes          Yes    Yes     Yes              Completed Study                DDMMMYYYY 
       X     XXX          Yes    Yes    Yes          Yes    Yes     Yes              Completed Study                DDMMMYYYY 
      XX     XXX          Yes    Yes    Yes          Yes    Yes     Yes              Terminated Study Prematurely   DDMMMYYYY 
      XX     XXX          Yes    Yes    Yes          Yes    Yes     Yes              Completed Study                DDMMMYYYY 
      XX     XXX          Yes    Yes    Yes          Yes    Yes     Yes              Completed Study                DDMMMYYYY 
      XX     XXX          Yes    Yes    Yes          Yes    Yes     Yes              Completed Study                DDMMMYYYY 
      XX     XXX          Yes    Yes    Yes          Yes    Yes     Yes              Completed Study                DDMMMYYYY 
      XX     XXX          Yes    Yes    Yes          Yes    Yes     Yes              Completed Study                DDMMMYYYY 
                        ----   ----   ----         ----   ----    ----         
                          XX     XX     XX           XX     XX      XX            
  
 
 
Note:  Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted)  
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
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                                                                                                                       Page 1 of 2 
                                                    Table 14.1.3  Demographic Summary 
  
                                                             
                                                                                   
                                                         Treatment Sequence  
                                          -------------------------------------------------  
  Trait        
                         ABC     ACB      BAC     BCA     CAB     CBA           Overall 
  -------------------------------------------------------------------------------------------------------------------- 
   Gender     Female                       XX       XX      XX       XX      XX       XX              XX 
              Male                         XX       XX      XX       XX      XX       XX              XX 
 
   Race         White                        XX       XX      XX       XX      XX       XX              XX 
                Black or African American    XX       XX      XX       XX      XX       XX              XX 
                Asia                         XX       XX      XX       XX      XX       XX              XX                            
 
   Ethnicity   Hispanic or Latino            XX       XX      XX       XX      XX       XX              XX 
               Not Hispanic or Latino        XX       XX      XX       XX      XX       XX              XX 
 
   Age          N                             X         X      X         X      X         X                X  
                Mean                       XX.X      XX.X   XX.X      XX.X   XX.X      XX.X             XX.X  
                SD                          X.X       X.X    X.X       X.X    X.X       X.X              X.X  
                CV                          X.X       X.X    X.X       X.X    X.X       X.X              X.X  
                Median                     XX.X      XX.X   XX.X      XX.X   XX.X      XX.X             XX.X  
                Minimum                    XX.X      XX.X   XX.X      XX.X   XX.X      XX.X             XX.X  
                Maximum                    XX.X      XX.X   XX.X      XX.X   XX.X      XX.X             XX.X  
   ---------------------------------------------------------------------------------------------------------------------- 
 
  
  
 
Note:  Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted)  
  
  
  
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
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                                                                                                                       Page 2 of 2 
                                                    Table 14.1.3  Demographic Summary 
  
                                                             
                                                                              
                                                         Treatment Sequence  
                                          -------------------------------------------------  
  Trait        
                         ABC     ACB      BAC     BCA     CAB     CBA           Overall 
  -------------------------------------------------------------------------------------------------------------------- 
   Weight (kg)             N                  X         X      X         X      X         X                X  
                           Mean            XX.X      XX.X   XX.X      XX.X   XX.X      XX.X             XX.X  
                           SD               X.X       X.X    X.X       X.X    X.X       X.X              X.X  
                           CV               X.X       X.X    X.X       X.X    X.X       X.X              X.X  
                           Median          XX.X      XX.X   XX.X      XX.X   XX.X      XX.X             XX.X  
                           Minimum         XX.X      XX.X   XX.X      XX.X   XX.X      XX.X             XX.X  
                           Maximum         XX.X      XX.X   XX.X      XX.X   XX.X      XX.X             XX.X  
 
   Height (cm)             N                  X         X      X         X      X         X                X  
                           Mean            XX.X      XX.X   XX.X      XX.X   XX.X      XX.X             XX.X  
                           SD               X.X       X.X    X.X       X.X    X.X       X.X              X.X  
                           CV               X.X       X.X    X.X       X.X    X.X       X.X              X.X  
                           Median          XX.X      XX.X   XX.X      XX.X   XX.X      XX.X             XX.X  
                           Minimum         XX.X      XX.X   XX.X      XX.X   XX.X      XX.X             XX.X  
                           Maximum         XX.X      XX.X   XX.X      XX.X   XX.X      XX.X             XX.X  
 
   Body Mass Index (kg/m2) N                  X         X      X         X      X         X                X  
                           Mean            XX.X      XX.X   XX.X      XX.X   XX.X      XX.X             XX.X  
                           SD               X.X       X.X    X.X       X.X    X.X       X.X              X.X  
                           CV               X.X       X.X    X.X       X.X    X.X       X.X              X.X  
                           Median          XX.X      XX.X   XX.X      XX.X   XX.X      XX.X             XX.X  
                           Minimum         XX.X      XX.X   XX.X      XX.X   XX.X      XX.X             XX.X  
                           Maximum         XX.X      XX.X   XX.X      XX.X   XX.X      XX.X             XX.X  
   ---------------------------------------------------------------------------------------------------------------------- 
 
Note:  Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted)  
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
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                                                                                                                       Page 1 of X 
 
        Table 14.3.1.1  Adverse Event Frequency by Treatment - Number of Subjects Reporting Events (% of Subjects Dosed) 
  
                                                                        Treatment 
                                             --------------------------------------------------- 
                                                                                 C                   Overall    
                                                                  ------------------------------    Following 
                                                                    Prior to   Post                 the First 
                                                                    WTX101     WTX101                 WTX101  
  Adverse Event* 
 
 
 
 
 
 
       A        B        Dosing     Dosing    Overall      Dosing     Overall 
  ---------------------------------------------------------------------------------------------------------------------------- 
  Number of Subjects Dosed                   XX (100%)  XX (100%)  XX (100%) XX (100%)  XX (100%)  XX (100%)   XX (100%)      
  Number of Subjects With Adverse Events      X ( XX%)   X ( XX%)   X ( XX%)  X ( XX%)   X ( XX%)   X ( XX%)   X ( XX%)   
  Number of Subjects Without Adverse Events   X ( XX%)   X ( XX%)   X ( XX%)  X ( XX%)   X ( XX%)   X ( XX%)   X ( XX%)   
  --------------------------------------------------------------------------------------------------------------------------- 
  System Organ Class             
       Preferred Term                         X (  X%)   X (  X%)   X (  X%)    X (  X%)   X (  X%)   X (  X%)   X (  X%)       
       Preferred Term                         X (  X%)   X (  X%)   X (  X%)    X (  X%)   X (  X%)   X (  X%)   X (  X%)       
       Preferred Term                         X (  X%)   X (  X%)   X (  X%)    X (  X%)   X (  X%)   X (  X%)   X (  X%)       
       Preferred Term                         X (  X%)   X (  X%)   X (  X%)    X (  X%)   X (  X%)   X (  X%)   X (  X%)       
       Preferred Term                         X (  X%)   X (  X%)   X (  X%)    X (  X%)   X (  X%)   X (  X%)   X (  X%)       
     
Note:  * Adverse events are classified according to MedDRA Version 16.1. Each Subject was only counted once per preferred term.   
       Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted)  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
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                                                                                                                       Page 1 of X 
 
            Table 14.3.1.2  Adverse Event Frequency by Treatment - Number of Adverse Events (% of Total Adverse Events) 
  
 
                                                                        Treatment 
                                             -----------------------------------------------------  
                                                                             C                           Overall     
                                                                    ------------------------------      Following 
                                                                     Prior to   Post                    the First 
                                                                     WTX101     WTX101                   WTX101  
  Adverse Event* 
 
 
 
 
 
 
       A         B        Dosing     Dosing    Overall        Dosing      Overall 
  ------------------------------------------------------------------------------------------------------------------------------ 
  Number of Adverse Events                   XX (100%)    XX (100%)  XX (100%) XX (100%)   XX (100%)      XX (100%) 
XX(100%) 
     
  ------------------------------------------------------------------------------------------------------------------------------ 
  System Organ Class                  
       Preferred Term                         X (  X%)    X (  X%)   X (  X%)    X (  X%)   X (  X%)     X (  X%)    X (  X%)  
       Preferred Term                         X (  X%)    X (  X%)   X (  X%)    X (  X%)   X (  X%)     X (  X%)    X (  X%)  
       Preferred Term                         X (  X%)    X (  X%)   X (  X%)    X (  X%)   X (  X%)     X (  X%)    X (  X%)    
       Preferred Term                         X (  X%)    X (  X%)   X (  X%)    X (  X%)   X (  X%)     X (  X%)    X (  X%)    
       Preferred Term                         X (  X%)    X (  X%)   X (  X%)    X (  X%)   X (  X%)     X (  X%)    X (  X%)    
 
Note:  * Adverse events are classified according to MedDRA Version 16.1.       
       Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted)  
 
 
 
 
 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
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                                                                                                                       Page 1 of X 
                                                                                                                                               
Table 14.3.1.3  Adverse Event Frequency by Treatment, Severity, and Relationship to Drug 
- Number of Subjects Reporting Events 
                                                                                                                                                      
                                                                                
                             Number of          Severity Grade                 Relationship to Drug                                   
                             Subjects with  ------------------------  -------------------------------------------                     
 Adverse Event*   Treatment  Adverse Events    1    2    3    4    5  Likely Probably Possibly Unlikely Unrelated                     
 ----------------------------------------------------------------------------------------------------------------                     
 Abdominal pain       A             X          X    X    X    X    X      X         X        X        X       X                       
 Constipation         A             X          X    X    X    X    X      X         X        X        X       X                       
 Headache             A             X          X    X    X    X    X      X         X        X        X       X                       
                      B             X          X    X    X    X    X      X         X        X        X       X                       
 Myalgia              A             X          X    X    X    X    X      X         X        X        X       X                       
 Nasal congestion    C1             X          X    X    X    X    X      X         X        X        X       X                       
 Skin laceration     C2             X          X    X    X    X    X      X         X        X        X       X                       
 -------------------------------------------------------------------------------------------------------- -------                     
 Treatment A                        X          X    X    X    X    X      X         X        X        X       X                       
 Treatment B                        X          X    X    X    X    X      X         X        X        X       X                       
 Treatment C1                       X          X    X    X    X    X      X         X        X        X       X                       
 Treatment C2                       X          X    X    X    X    X      X         X        X        X       X                       
 Treatment C                        X          X    X    X    X    X      X         X        X        X       X                       
 Overall                            X          X    X    X    X    X      X         X        X        X       X                       
 ----------------------------------------------------------------------------------------------------------------  
Note: * Adverse events are classified according to MedDRA Version 16.1.                                                               
      When a subject experienced the same AE at more than one level of severity during a treatment period, only the  
      most severe one was counted. When a subject experienced the same AE at more than one level of drug relationship 
      during a treatment period, only the most related one was counted.  
      Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Death due to AE.                    
       Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted)  
       Treatment C1 = Treatment C prior to WTX101 dosing, Treatment C2 = Treatment C post WTX101 dosing 
                                                                                                                                      
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab tblae3a_auto.sas  DDMMMYYYY HH:MM                                                            
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Wilson Therapeutics USA, Inc. 
WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 22 of 66 
                                                                                                                       Page 1 of X 
Table 14.3.1.4  Adverse Event Frequency by Treatment, Severity, and Relationship to Drug 
- Number of Adverse Events 
                                                                                                                                                      
                                                                                
                                                   Severity Grade                 Relationship to Drug                                
                                Number of    ------------------------  -------------------------------------------                    
 Adverse Event*   Treatment  Adverse Events    1    2    3    4    5   Likely Probably Possibly Unlikely Unrelated                    
 ----------------------------------------------------------------------------------------------------------------                     
 Abdominal pain       A             X          X    X    X    X    X      X         X        X        X       X                       
 Constipation         A             X          X    X    X    X    X      X         X        X        X       X                       
 Headache             A             X          X    X    X    X    X      X         X        X        X       X                       
                      B             X          X    X    X    X    X      X         X        X        X       X                       
 Myalgia              A             X          X    X    X    X    X      X         X        X        X       X                       
 Nasal congestion    C1             X          X    X    X    X    X      X         X        X        X       X                       
 Skin laceration     C2             X          X    X    X    X    X      X         X        X        X       X                       
 -------------------------------------------------------------------------------------------------------- -------                     
 Treatment A                        X          X    X    X    X    X      X         X        X        X       X                       
 Treatment B                        X          X    X    X    X    X      X         X        X        X       X                       
 Treatment C1                       X          X    X    X    X    X      X         X        X        X       X                       
 Treatment C2                       X          X    X    X    X    X      X         X        X        X       X                       
 Treatment C                        X          X    X    X    X    X      X         X        X        X       X                       
 Overall                            X          X    X    X    X    X      X         X        X        X       X                       
 ----------------------------------------------------------------------------------------------------------------  
Note: * Adverse events are classified according to MedDRA Version 16.1.                                                               
      Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Death due to AE.                    
       Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted)  
       Treatment C1 = Treatment C prior to WTX101 dosing, Treatment C2 = Treatment C post WTX101 dosing 
                                                                                                                                      
                                                                                                                             
                                                                                                                                      
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab tblae4a_auto.sas  DDMMMYYYY HH:MM                                                            
       
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Wilson Therapeutics USA, Inc. 
WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 23 of 66 
                                                                                                                         Page 1 of X 
                                                                                                                                               
Table 14.3.1.5  Adverse Event Frequency by Severity and Relationship to Drug Following First WTX101-101 Dosing 
- Number of Subjects Reporting Events 
                                                                                                                                                      
                                                                                
                   Number of          Severity Grade                 Relationship to Drug                                   
                   Subjects with  ------------------------  -------------------------------------------                            
 Adverse Event*    Adverse Events    1    2    3    4    5  Likely Probably Possibly Unlikely Unrelated                            
 ------------------------------------------------------------------------------------------------------                             
 Abdominal pain           X          X    X    X    X    X      X         X        X        X       X                                 
 Constipation             X          X    X    X    X    X      X         X        X        X       X                                 
 Headache                 X          X    X    X    X    X      X         X        X        X       X                                 
                          X          X    X    X    X    X      X         X        X        X       X                                 
 Myalgia                  X          X    X    X    X    X      X         X        X        X       X                                 
 Nasal congestion         X          X    X    X    X    X      X         X        X        X       X                                 
 Skin laceration          X          X    X    X    X    X      X         X        X        X       X                                 
 ---------------------------------------------------------------------------------------------- -------                             
 Overall                  X          X    X    X    X    X      X         X        X        X       X                                 
 ------------------------------------------------------------------------------------------------------  
Note: * Adverse events are classified according to MedDRA Version 16.1.                                                               
      When a subject experienced the same AE at more than one level of severity during a treatment period, only the  
      most severe one was counted. When a subject experienced the same AE at more than one level of drug relationship 
      during a treatment period, only the most related one was counted.  
      Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Death due to AE.                    
                                                                                                                                      
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab tblae3a_auto.sas  DDMMMYYYY HH:MM                                                            
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Wilson Therapeutics USA, Inc. 
WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 24 of 66 
                                                                                                                       Page 1 of X 
Table 14.3.1.6  Adverse Event Frequency by Severity and Relationship to Drug Following First WTX101-101 Dosing 
- Number of Adverse Events 
                                                                                                                                                      
                                                                                
                                         Severity Grade                 Relationship to Drug                                   
                      Number of    ------------------------  -------------------------------------------                            
 Adverse Event*    Adverse Events    1    2    3    4    5   Likely Probably Possibly Unlikely Unrelated                            
 ------------------------------------------------------------------------------------------------------                             
 Abdominal pain           X          X    X    X    X    X      X         X        X        X       X                                 
 Constipation             X          X    X    X    X    X      X         X        X        X       X                                 
 Headache                 X          X    X    X    X    X      X         X        X        X       X                                 
                          X          X    X    X    X    X      X         X        X        X       X                                 
 Myalgia                  X          X    X    X    X    X      X         X        X        X       X                                 
 Nasal congestion         X          X    X    X    X    X      X         X        X        X       X                                 
 Skin laceration          X          X    X    X    X    X      X         X        X        X       X                                 
 ---------------------------------------------------------------------------------------------- -------                             
 Overall                  X          X    X    X    X    X      X         X        X        X       X                                 
 ------------------------------------------------------------------------------------------------------  
Note: * Adverse events are classified according to MedDRA Version 16.1.                                                               
      Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Death due to AE.                    
                                                                                                                                      
                                                                                                                             
                                                                                                                                      
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab tblae4a_auto.sas  DDMMMYYYY HH:MM                                                            
       
 
 
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Wilson Therapeutics USA, Inc. 
WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 25 of 66 
                                                                                                          Page 1 of X 
                               Table 14.3.2.1  Serious Adverse Events 
                                                                                                                                        
----------------------------------------------------------------------------------------------------------------------- 
No serious adverse event is reported during the study.                                                                                                       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab cdash_tblae_ser.sas  DDMMMYYYY HH:MM    
 
 
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Wilson Therapeutics USA, Inc. 
WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 26 of 66 
                                                                                                                       Page 1 of X 
                          Table 14.3.4.1  Out-of-Range Values and Recheck Results - Serum Chemistry 
  
                                        
 
 
     
 
                                               Test Name 
                                 
 
 
         
   Test Name    Test Name    Test Name   Test Name     F: X-XX   
Subject Age/   Study                
      
 
       X.X-XX.X      X.X-X.X      XXX-XXX      X.X-X      M: X-XX   
Number  Gender Period  Treatment   Day  Hour   Date       (mg/dL)       (mEq/L)      (mEq/L)     (g/dL)      (mg/dL)   
  
----------------------------------------------------------------------------------------------------------------------- 
      X  XX/M   Screen          
  
 
 
DDMMMYYYY      X.X           X.X LN      XXX         X.X           XX    
                1      A         
-X   -X.X 
DDMMMYYYY      X.X           X.X LN      XXX         X.X           XX    
                         
 
 
 X    X.X 
DDMMMYYYY      X.X           X.X LN      XXX         X.X           XX    
                2      B         
-X   -X.X 
DDMMMYYYY      X.X           X.X LN      XXX         X.X           XX    
                         
 
 
 X    X.X 
DDMMMYYYY      X.X           X.X LN      XXX         X.X           XX    
 
 
Note:  H = Above Normal Range, L = Below Normal Range 
       Computer: N = Not Clinically Significant, Y = Clinically Significant 
       PI interpretation: - = Not Clinically Significant 
       Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted)  
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
  
 
 
 
Please note that Table 14.3.4.2-5 will resemble 14.3.4.1.  
 
 
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WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 27 of 66 
                                                                                                                       Page 1 of X 
                              Table 14.3.5.1  Clinical Laboratory Summary and Change From Baseline - Serum Chemistry 
  
                                                                                           
                                                                                Treatment                   Change From Baseline 
                                                                          -----------------------------  -----------------------------           
  Laboratory Test (unit)   Normal Range Time point  Statistic    Overall        A          B          C        A          B        C 
  ------------------------------------------------------------------------------------------------------------------------------------- 
  Test Name (unit)         XX.X – XX.X   Screen     N                XX        
                                                    Mean           X.XX        
                                                    SD            X.XXX        
                                                    CV            X.XXX        
                                                    Median         X.XX        
                                                    Minimum         X.X        
                                                    Maximum        XX.X        
 
                                        Baseline    N                           XX        XX         XX         
                                                    Mean                      X.XX      X.XX       X.XX         
                                                    SD                       X.XXX     X.XXX      X.XXX         
                                                    CV                       X.XXX     X.XXX      X.XXX         
                                                    Median                    X.XX      X.XX       X.XX         
                                                    Minimum                    X.X       X.X        X.X         
                                                    Maximum                   XX.X      XX.X       XX.X         
 
                                        Hour 36     N                           XX        XX         XX        XX        XX        XX     
                                                    Mean                      X.XX      X.XX       X.XX      X.XX      X.XX      X.XX     
                                                    SD                       X.XXX     X.XXX      X.XXX     X.XXX     X.XXX     X.XXX     
                                                    CV                       X.XXX     X.XXX      X.XXX     X.XXX     X.XXX     X.XXX     
                                                    Median                    X.XX      X.XX       X.XX      X.XX      X.XX      X.XX     
                                                    Minimum                    X.X       X.X        X.X       X.X       X.X       X.X     
                                                    Maximum                   XX.X      XX.X       XX.X      XX.X      XX.X      XX.X     
 
                                       End of Study N                XX        
                                                    Mean           X.XX        
                                                    SD            X.XXX        
                                                    CV            X.XXX        
                                                    Median         X.XX        
                                                    Minimum         X.X        
                                                    Maximum        XX.X        
 
<Similar for remaining tests.> 
 
Note:  Baseline is the last observation, including rechecks, obtained prior to dosing of WTX101 in the treatment period. 
       Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
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Wilson Therapeutics USA, Inc. 
WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 28 of 66 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted)  
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                         
 
 
 
 
 
Please note that Tables 14.3.5.3, 14.3.5.5, and 14.3.5.7 will resemble 14.3.5.1. 
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Wilson Therapeutics USA, Inc. 
WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 29 of 66 
                                                                                                                       Page 1 of X 
 
                              Table 14.3.5.2  Clinical Laboratory Shift From Baseline - Serum Chemistry 
 
                                                Baseline* L                     Baseline* N                     Baseline* H 
                                              -----------------------------  -------------------------------   ----------------------------- 
                                                        Postdose                        Postdose                         Postdose 
                    Normal             Treat- -----------------------------    -----------------------------    ----------------------------  
Laboratory Test     Range   Time Point ment    L          N          H          L          N         H           L          N          H         
---------------------------------------------------------------------------   ------------------------------   ----------------------------- 
Test Name (units)   XX-XXX  Hour 36    A       X (  X%)  XX ( XX%)  X (  X%)   X (  X%)  XX ( XX%)  X (  X%)   X (  X%)   XX ( XX%)  X ( X%)  
                                       B       X (  X%)  XX ( XX%)  X (  X%)   X (  X%)  XX ( XX%)  X (  X%)   X (  X%)   XX ( XX%)  X ( X%)                 
                                       C       X (  X%)  XX ( XX%)  X (  X%)   X (  X%)  XX ( XX%)  X (  X%)   X (  X%)   XX ( XX%)  X ( X%)  
 
 
 
<Similar for remaining laboratory tests and time points> 
 
 
 
 
 
 
Note:  L = Below Normal Range, N = Within Normal Range, H = Above Normal Range. 
       * Baseline is the last observation, including rechecks, obtained prior to dosing of WTX101 in the treatment period. 
                  The percentage are based on the number of subjects within the test*treatment*timepoint.            
       Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted)  
 
 
 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                         
 
 
 
 
Please note that Tables 14.3.5.4 and 14.3.5.6 will resemble 14.3.5.2. 
 
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Wilson Therapeutics USA, Inc. 
WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 30 of 66 
                                                                                                                       Page 1 of X 
 
                              Table 14.3.5.8  Clinical Laboratory Shift From Baseline - Urinalysis 
 
                                                                 Baseline* N          Baseline* O      
                                                              -------------------  ----------------- 
                                                                   Postdose            Postdose        
                    Normal                                    ------------------  ------------------ 
Laboratory Test     Range      Time Point       Treatment        N       O           N       O         
---------------------------------------------------------------------------------------------------- 
Test Name (units)   XX-XXX     Hour 36          A             X (  X%)  X (  X%)   X (  X%)  X (  X%)     
                                                B             X (  X%)  X (  X%)   X (  X%)  X (  X%)     
                                                C             X (  X%)  X (  X%)   X (  X%)  X (  X%)     
 
 
 
<Similar for remaining laboratory tests and time points> 
 
 
 
 
 
 
Note:  N = Within Normal Range, O = Outside Normal Range. 
       * Baseline is the last observation, including rechecks, obtained prior to dosing of WTX101 in the treatment period. 
       The percentage are based on the number of subjects within the test*treatment*timepoint.            
       Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted)  
 
 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                         
 
 
 
 
 
 
 
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WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 31 of 66 
                                                                                                                       Page 1 of X 
                              Table 14.3.5.9  Vital Sign Summary and Change From Baseline  
  
                                                                                                   
                                                                            Treatment                    Change From Baseline 
                                                                   --------------------------------    -----------------------------           
  Measurement (unit)        Time point     Statistic     Overall          A          B         C            A          B         C 
  ----------------------------------------------------------------------------------------------------------------------------------- 
  Test Name (unit)             Screen        N                XX          
                                             Mean           X.XX          
                                             SD            X.XXX          
                                             CV            X.XXX          
                                             Median         X.XX          
                                             Minimum         X.X          
                                             Maximum        XX.X       
     
                               Check-in      N                           XX        XX        XX       
                                             Mean                      X.XX      X.XX      X.XX       
                                             SD                       X.XXX     X.XXX     X.XXX       
                                             CV                       X.XXX     X.XXX     X.XXX       
                                             Median                    X.XX      X.XX      X.XX       
                                             Minimum                    X.X       X.X       X.X       
                                             Maximum                   XX.X      XX.X      XX.X       
 
                               Baseline      N                           XX        XX        XX       
                                             Mean                      X.XX      X.XX      X.XX       
                                             SD                       X.XXX     X.XXX     X.XXX       
                                             CV                       X.XXX     X.XXX     X.XXX       
                                             Median                    X.XX      X.XX      X.XX       
                                             Minimum                    X.X       X.X       X.X       
                                             Maximum                   XX.X      XX.X      XX.X       
 
                                Hour 1       N                           XX        XX        XX              XX        XX        XX     
                                             Mean                      X.XX      X.XX      X.XX            X.XX      X.XX      X.XX     
                                             SD                       X.XXX     X.XXX     X.XXX           X.XXX     X.XXX     X.XXX     
                                             CV                       X.XXX     X.XXX     X.XXX           X.XXX     X.XXX     X.XXX     
                                             Median                    X.XX      X.XX      X.XX            X.XX      X.XX      X.XX     
                                             Minimum                    X.X       X.X       X.X             X.X       X.X       X.X     
                                             Maximum                   XX.X      XX.X      XX.X            XX.X      XX.X      XX.X     
 
 
<Similar for remaining time points and measurements. For the end of study time point, all subjects will be pooled together as overall as for 
screen time point.> 
 
Note:  Baseline is the last observation, including rechecks, obtained prior to dosing of WTX101 in the treatment period. 
       Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
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Wilson Therapeutics USA, Inc. 
WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 32 of 66 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted)  
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM    
 
 
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Wilson Therapeutics USA, Inc. 
WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 33 of 66 
Page 1 of X 
                                   Table 14.3.5.10  12-Lead Electrocardiogram Summary and Change From Baseline 
 
                                                                            Treatment                    Change From Baseline  
                                                                   --------------------------------    -----------------------------   -           
  Parameter (unit)        Time point     Statistic     Overall          A          B         C            A          B         C  
  ------------------------------------------------------------------------------------------------------------------------------------- 
  Heart Rate (bpm)             Screen        N                XX           
                                             Mean           X.XX           
                                             SD            X.XXX           
                                             CV            X.XXX           
                                             Median         X.XX           
                                             Minimum         X.X           
                                             Maximum        XX.X        
 
                               Check-in      N                           XX        XX        XX           
                                             Mean                      X.XX      X.XX      X.XX           
                                             SD                       X.XXX     X.XXX     X.XXX           
                                             CV                       X.XXX     X.XXX     X.XXX           
                                             Median                    X.XX      X.XX      X.XX           
                                             Minimum                    X.X       X.X       X.X           
                                             Maximum                   XX.X      XX.X      XX.X           
 
                               Baseline      N                           XX        XX        XX           
                                             Mean                      X.XX      X.XX      X.XX           
                                             SD                       X.XXX     X.XXX     X.XXX           
                                             CV                       X.XXX     X.XXX     X.XXX           
                                             Median                    X.XX      X.XX      X.XX           
                                             Minimum                    X.X       X.X       X.X           
                       
 
 
 
 
  Maximum                   XX.X      XX.X      XX.X       
 
        
 
 
 
 
 
 Hour 1       N                           XX        XX        XX              XX        XX        XX    
                   
 
 
 
 
 
  Mean                      X.XX      X.XX      X.XX            X.XX      X.XX      X.XX    
                 
 
 
 
 
 
      SD                       X.XXX     X.XXX     X.XXX           X.XXX     X.XXX     X.XXX    
                     
 
 
 
 
 
  CV                       X.XXX     X.XXX     X.XXX           X.XXX     X.XXX     X.XXX    
                     
 
 
 
 
 
  Median                    X.XX      X.XX      X.XX            X.XX      X.XX      X.XX    
                    
 
 
 
 
 
  Minimum                    X.X       X.X       X.X             X.X       X.X       X.X    
                     
 
 
 
 
 
  Maximum                   XX.X      XX.X      XX.X            XX.X      XX.X      XX.X    
 
 
<Similar for remaining time points and parameters. For the end of study time point, all subjects will be pooled together as overall as for 
screen time point.> 
 
Note:  Baseline is the last non-missing measurement, including rechecks, obtained prior to dosing of WTX101 in the treatment period. 
       Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
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Wilson Therapeutics USA, Inc. 
WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 34 of 66 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted)  
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab_PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 
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Wilson Therapeutics USA, Inc. 
WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 35 of 66 
                                                                 Page 1 of X  
                              Table 14.3.5.11  12-Lead Electrocardiogram Shift From Baseline                                     
                                                                                           
                               Baseline = N                   Baseline = ANCS                    Baseline = ACS 
                       -----------------------------     -----------------------------    -----------------------------        
                                  Postdose                          Postdose                          Postdose                   
                       -----------------------------     -----------------------------    -----------------------------        
 Treatment  Time Point   N         ANCS       ACS          N       ANCS       ACS           N         ANCS     ACS             
-----------------------------------------------------------------------------------------------------------------------        
     A       Hour 1     X (  X%)   XX ( XX%)  X (  X%)         X (  X%)  XX ( XX%)  X (  X%)          X (  X%)   XX ( XX%)  X (  X%)             
             Hour 4     X (  X%)   XX ( XX%)  X (  X%)         X (  X%)  XX ( XX%)  X (  X%)          X (  X%)   XX ( XX%)  X (  X%)             
             Hour 8     X (  X%)   XX ( XX%)  X (  X%)         X (  X%)  XX ( XX%)  X (  X%)          X (  X%)   XX ( XX%)  X (  X%)             
             Hour 12    X (  X%)   XX ( XX%)  X (  X%)         X (  X%)  XX ( XX%)  X (  X%)          X (  X%)   XX ( XX%)  X (  X%)             
             Hour 24    X (  X%)   XX ( XX%)  X (  X%)         X (  X%)  XX ( XX%)  X (  X%)          X (  X%)   XX ( XX%)  X (  X%)             
 
     B       Hour 1     X (  X%)   XX ( XX%)  X (  X%)         X (  X%)  XX ( XX%)  X (  X%)          X (  X%)   XX ( XX%)  X (  X%)             
             Hour 4     X (  X%)   XX ( XX%)  X (  X%)         X (  X%)  XX ( XX%)  X (  X%)          X (  X%)   XX ( XX%)  X (  X%)             
             Hour 8     X (  X%)   XX ( XX%)  X (  X%)         X (  X%)  XX ( XX%)  X (  X%)          X (  X%)   XX ( XX%)  X (  X%)             
             Hour 12    X (  X%)   XX ( XX%)  X (  X%)         X (  X%)  XX ( XX%)  X (  X%)          X (  X%)   XX ( XX%)  X (  X%)             
             Hour 24    X (  X%)   XX ( XX%)  X (  X%)         X (  X%)  XX ( XX%)  X (  X%)          X (  X%)   XX ( XX%)  X (  X%)             
 
     C       Hour 1     X (  X%)   XX ( XX%)  X (  X%)         X (  X%)  XX ( XX%)  X (  X%)          X (  X%)   XX ( XX%)  X (  X%)             
             Hour 4     X (  X%)   XX ( XX%)  X (  X%)         X (  X%)  XX ( XX%)  X (  X%)          X (  X%)   XX ( XX%)  X (  X%)             
             Hour 8     X (  X%)   XX ( XX%)  X (  X%)         X (  X%)  XX ( XX%)  X (  X%)          X (  X%)   XX ( XX%)  X (  X%)             
             Hour 12    X (  X%)   XX ( XX%)  X (  X%)         X (  X%)  XX ( XX%)  X (  X%)          X (  X%)   XX ( XX%)  X (  X%)             
             Hour 24    X (  X%)   XX ( XX%)  X (  X%)         X (  X%)  XX ( XX%)  X (  X%)          X (  X%)   XX ( XX%)  X (  X%)             
               
Note:  N = Normal, ANCS = Abnormal, Not Clinically Significant, ACS = Abnormal, Clinically Significant  
       Baseline is last non-missing measurements, including rechecks, obtained prior to dosing of WTX101 in the treatment period. 
       Percentages are based on total number of observations for each treatment at each time point.   
       Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted)  
                                                                               
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab ecgshift.sas  DDMMMYYYY  HH:MM   
 
 
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                                                                 Page 1 of X  
                              Table 14.3.5.12  Physical Examination Shift From Screening                                     
                                                                                           
                                    Screen = Normal                   Screen = Abnormal          
                                -----------------------------     -----------------------------          
                                       During Study                       During Study 
                                -----------------------------     -----------------------------          
 System     Time Point             Normal      Abnormal               Normal         Abnormal               
--------------------------------------------------------------------------------------------        
 XXXXXXX    Period 1 Check-in        X            X                     X                X                 
            Period 2 Check-in        X            X                     X                X                 
            Period 3 Check-in        X            X                     X                X                 
            End of Study             X            X                     X                X                 
 
 XXXXXXX    Period 1 Check-in        X            X                     X                X                 
            Period 2 Check-in        X            X                     X                X                 
            Period 3 Check-in        X            X                     X                X                 
            End of Study             X            X                     X                X                 
 
 XXXXXXX    Period 1 Check-in        X            X                     X                X                 
            Period 2 Check-in        X            X                     X                X                 
            Period 3 Check-in        X            X                     X                X                 
            End of Study             X            X                     X                X                 
 
               
                                                                               
Program:  /AAXXXXX/ECR/sas_prg/stsas/tab ecgshift.sas  DDMMMYYYY  HH:MM        
                          
 
 
 
 
 
 
 
 
 
 
 
 
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12. LISTING SHELLS 
The following listing shells provide a framework for the display of data from this study. The shells may change due to unforeseen 
circumstances. These shells may not be reflective of every aspect of this study, but are intended to show the general layout of the 
listings that will be included in the final report. 
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Page 1 of X 
                                   Appendix 16.1.10.1  Clinical Laboratory Reference Ranges 
 
        Laboratory Group           Test Name                     Gender      Age Category  Normal Range    Unit      
        ------------------------------------------------------------------------------------------------------------ 
        Serum Chemistry            Test Name                     <>          <>            XX – XX         units 
                                   Test Name                     <>          <>            XX – XX         units 
                                   Test Name                     <>          <>            XX – XX         units 
                                   Test Name                     <>          <>            XX – XX         units 
                                   Test Name                     <>          <>            XX – XX         units 
                                   Test Name                     <>          <>            XX – XX         units 
                                                                                                                     
        Hematology                 Test Name                     <>          <>            XX – XX         units 
                                   Test Name                     <>          <>            XX – XX         units 
                                   Test Name                     <>          <>            XX – XX         units 
                                   Test Name                     <>          <>            XX – XX         units 
                                   Test Name                     <>          <>            XX – XX         units 
 
<similar for remaining Laboratory Groups and Test Names> 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
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                                                                                                                   Page 1 of X 
                                                 Appendix 16.2.1  Subject Discontinuation 
  
                                         Subject  Study              Completed  
                                          Number   Period    Date      Study?   Reason for Discontinuation  Comment 
                                       ----------------------------------------------------------------------------- 
                                              X    Post   DDMMMYYYY     Yes    
                                              X    Post   DDMMMYYYY     Yes    
                                              X    Post   DDMMMYYYY     Yes    
                                              X    Post   DDMMMYYYY     Yes    
                                              X    Post   DDMMMYYYY     No      Personal Reason           
                                              X    Post   DDMMMYYYY     Yes    
                                              X    Post   DDMMMYYYY     Yes    
                                              X    Post   DDMMMYYYY     Yes    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 
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                                                                                                                   Page 1 of X 
                                                      Appendix 16.2.4.1  Demographics 
                                                                                                                                
                                                                                                                      Informed             
               Subject      Date Of       Age                                          Height    Weight      BMI      Consent       
               Number        Birth       (yrs)    Gender    Race        Ethnicity      (cm)      (kg)      (kg/m^2)    Date        
              ------------------------------------------------------------------------------------------------------------------ 
                    X      DDMMMYYYY       XX     XXXX      XXXXXXXXX   XXXXXXXXXXX     XX.X     XXX.X       XX.XX   DDMMMYYYY      
                    X      DDMMMYYYY       XX     XXXX      XXXXXXXXX   XXXXXXXXXXX     XX.X     XXX.X       XX.XX   DDMMMYYYY      
                    X      DDMMMYYYY       XX     XXXX      XXXXXXXXX   XXXXXXXXXXX     XX.X     XXX.X       XX.XX   DDMMMYYYY      
                    X      DDMMMYYYY       XX     XXXX      XXXXXXXXX   XXXXXXXXXXX     XX.X     XXX.X       XX.XX   DDMMMYYYY      
                    X      DDMMMYYYY       XX     XXXX      XXXXXXXXX   XXXXXXXXXXX     XX.X     XXX.X       XX.XX   DDMMMYYYY      
                    X      DDMMMYYYY       XX     XXXX      XXXXXXXXX   XXXXXXXXXXX     XX.X     XXX.X       XX.XX   DDMMMYYYY      
                    X      DDMMMYYYY       XX     XXXX      XXXXXXXXX   XXXXXXXXXXX     XX.X     XXX.X       XX.XX   DDMMMYYYY      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
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                                                                                                                   Page 1 of X 
                                        
 
Appendix 16.2.4.2.1  Physical Examination (I of II) 
  
                                                                                                                    
          Subject  Study                           Was PE                                                          
          Number   Period    Day  Hour   Date    Performed?     System1    System2    System3    System4    System5      
          ------------------------------------------------------------------------------------------------------------- 
            X      Screen      .    .  DDMMMYYYY      YES        NORMAL     NORMAL     NORMAL     NORMAL     NORMAL       
                      X        X    X  DDMMMYYYY      YES        NORMAL     NORMAL     NORMAL     NORMAL     NORMAL       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: * = See Appendix 16.2.4.2.3 Physical Examination Description.                                                                
      HEENT = Head, Eyes, Ears, Nose, Throat.                                                                                                
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
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                                                                                                                    Page 1 of X 
                                        Appendix 16.2.4.2.2  Physical Examination (II of II) 
  
                                                                                                               
                   Subject Study                                                                  
                   Number  Period      Day  Hour   Date       System6   System7    System8    System9     Etc.        
                  ---------------------------------------------------------------------------------------------- 
                      X    Screen       .    .  DDMMMYYYY    NORMAL     NORMAL     NORMAL     NORMAL      NORMAL     
                            X           X    X  DDMMMYYYY    NORMAL     NORMAL     NORMAL     NORMAL      NORMAL     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: * = See Appendix 16.2.4.2.3 Physical Examination Descriptions.                                                               
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 
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Page 1 of X 
                                   Appendix 16.2.4.2.3  Physical Examination Descriptions 
 
 Subject  Study                                                                                                             
 Number   Period  Day   Hour   Date       Result    System                Description or Comment                                       
 -------------------------------------------------------------------------------------------------------------------------- 
      X   Screen    .    .    DDMMMYYYY   ABNORMAL   Skin                  RIGHT CHEST SCAR-NCS                                         
                                                                                                                            
      X   Screen    .    .    DDMMMYYYY   ABNORMAL   Skin                  ABDOMINAL SCAR-NCS                                           
                                                                                                                            
      X   Screen    .    .    DDMMMYYYY   ABNORMAL   Skin                  ABDOMINAL SCAR-NCS                                           
                                                                                                                            
     XX    X        X    X    DDMMMYYYY   ABNORMAL   Skin                  ABDOMINAL SCAR-NCS                                           
                                                                                                                            
     XX   Screen    .    .    DDMMMYYYY   ABNORMAL   Back                  MILD SCOLIOSIS-NCS                                           
                                                                                                                            
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Note:  HEENT = Head, Eyes, Ears, Nose, Throat, NCS = Not Clinically Significant.                                                                             
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 
 
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                                                                                                                   Page 1 of X 
                                                  Appendix 16.2.4.3  Medical History 
  
Date 
Subject    Any     Study                                    ------------------------                                         
Number   History?  Period  System Reviewed    Category         Start         End        Ongoing?   Condition or Event                            
-------------------------------------------------------------------------------------------------------------------------- 
    X      XXX     Screen  XXXXXX  XXXXX      Medical         DDMMMYYYY                 YES        XXXXXXX XXXXXX XXXXXXXX                                   
                                              Surgical        DDMMMYYYY    DDMMMYYYY    NO 
    
    X      XXX     Screen  XXXXXXXX XXXXX     Medical         DDMMMYYYY    DDMMMYYYY    NO                 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 
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                                                                                                                   Page 1 of X 
                                                    Appendix 16.2.4.4  Substance Use 
  
 
 Subject  Study                                                                 Start       End              
 Number   Period  Substance                  Description of Use                 Date        Date             Description 
 ------------------------------------------------------------------------------------------------------------------------------------- 
      X   Screen  XXXXXXXX XXX               XXXXX XXXXXXX XXXXXX               MMYYYY     <added if         XXXXXXXXXX XXXXXX XXXX  
   end date is  
   different from  
   start date > 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 
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                                                                                                                   Page 1 of X 
                                                  Appendix 16.2.5.1.1  Inclusion Criteria 
  
  
   X.  < >?  
   X.  < >?                                  
   X.  < >?                                                                                         
   X.  < >?             
   X.  < >?             
   X.  < >?             
   X.  < >?             
   X.  < >?             
   X.  < >?             
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 
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Statistical Analysis Plan 12 May 2014 
Page 47 of 66 
                                                                                                                   Page 1 of X 
                                                  Appendix 16.2.5.1.2  Exclusion Criteria 
  
  
   X.  < >?                                                                         
   X.  
   X.  
   X.  
   X.  
   X.  
   X.  
   X.  
   X.  
  XX.  
  XX.  
  XX.  
  XX.  
  XX. 
  XX. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 
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                                                                                                                   Page 1 of X 
                                                 Appendix 16.2.5.2  Subject Eligibility 
  
                                 
     Subject  Study             Did subject meet 
     Number   Period       all eligibility criteria?     Criterion Not Met*     Specify 
     ------------------------------------------------------------------------------------------------------ 
          X   Screen                 No                   EXCLUSION X             XXXXXXXXXXXXXXX XXXX 
  
          X   Screen                 Yes         
   
          X   Screen                 Yes  
  
          X   Screen                  No                 INCLUSION X             XXXXXXXXXX XXXXXXXXX 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: * = Please refer to Appendices 16.2.5.1.1 and 16.2.5.1.2 for specific inclusion and exclusion criteria.                              
                                                                      
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
                                                               
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                                                                                                                   Page 1 of X 
Appendix 16.2.5.3.1  Check-in and Return Criteria 
  
  
   X.  < >?                                             
   X.  IF (Y)ES TO ANY QUESTION, WAS SUBJECT APPROVED FOR STUDY?                                                                             
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 
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                                                                                                                   Page 1 of X 
Appendix 16.2.5.3.2  Check-in and Return Responses 
  
                                     Check-in Criteria                                                                
Subject  Study                       -------------------                                                          
Number   Period     Date                 X          X     Comment                                                 
---------------------------------------------------------------------------------------------------------------- 
    X     X      DDMMMYYYY              No        N/A     Will only be present and populated if there is a comment                                           
          X      DDMMMYYYY              No        N/A     present in the study database.                                                        
          X      DDMMMYYYY              No        N/A                                                            
 
    X     X      DDMMMYYYY              No        N/A                                                            
          X      DDMMMYYYY              No        N/A                                                            
          X      DDMMMYYYY              No        N/A                                                            
 
    X     X      DDMMMYYYY              No        N/A                                                            
          X      DDMMMYYYY              No        N/A                                                            
          X      DDMMMYYYY              No        N/A                                                            
 
 
 
 
 
 
 
 
 
 
 
 
 
 
           
                                             
 
Note: N/A = Not Applicable.                                                                                                                  
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
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                                                                                                                   Page 1 of X 
Appendix 16.2.5.3.3  Check-out Date and Time 
  
                         Check-out 
Subject  Study  -------------------                                                          
Number   Period     Date     Time                 Comment                                                 
------------------------------------------------------------------------------------------------- 
    X     X      DDMMMYYYY   HH:MM               
          X      DDMMMYYYY   HH:MM               
          X      DDMMMYYYY   HH:MM                                                                     
 
    X     X      DDMMMYYYY   HH:MM                                                                     
          X      DDMMMYYYY   HH:MM                                                                     
          X      DDMMMYYYY   HH:MM                                                                     
 
    X     X      DDMMMYYYY   HH:MM                                                                     
          X      DDMMMYYYY   HH:MM                                                                     
          X      DDMMMYYYY   HH:MM                                                                     
 
 
 
 
 
 
 
 
 
 
 
 
 
           
                                             
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 
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                                                                                                                   Page 1 of X 
                                              Appendix 16.2.5.4.1  Test Compound Description 
  
                         Compound                                                      Form            Route    
                         -------------------------------------------------------------------------------------- 
                         XXXXXXXXXXXXXX                                                < >             XXXX     
 
                         XXXXXXXXXXXXXX                                                < >             XXXX     
                                                                                                                                                 
  
  
 
  
  
 
  
  
 
  
  
 
  
  
 
  
  
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 
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                                                                                                                   Page 1 of X 
                                          Appendix 16.2.5.4.2  Test Compound Administration Times 
  
Subject   Study                                    Actual                              Did You                                          
Number    Period Treatment  Day  Hour   Date       Time   Compound            Dosage    Fast?        Comments                
-------------------------------------------------------------------------------------------------------------------- 
   X        X       X         X   X.X DDMMMYYYY   X:XX:XX  XXXXXXXXX          < >       XXX                    
            X       X         X   X.X DDMMMYYYY   X:XX:XX  XXXXXXXXX          < >       XXX                    
            X       X         X   X.X DDMMMYYYY   X:XX:XX  XXXXXXXXX          < >       XXX                    
                    X         X   X.X DDMMMYYYY   X:XX:XX  XXXXXXXXX          < >       XXX                    
                    X         X   X.X DDMMMYYYY   X:XX:XX  XXXXXXXXX          < >       XXX                    
                                                                                                                                           
  
                                                                                                      
 
  
 
 
 
 
 
 
 
 
 
 
 
Note:  Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted) 
  
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
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                                                                                                                   Page 1 of X 
                                          Appendix 16.2.5.4.3  Drug and Diary Accountability 
  
Subject   Study                         (1)     If no,  (2) Dispense Test  (3) Condition of Test Compound/                                                   
Number    Period    Date       Time    Diary?   Comment   Compounds?           Turn in Diary?               Treatment    Comments  
----------------------------------------------------------------------------------------------------------------------------- 
   X      ALL     DDMMMYYYY   X:XX:XX   XXX                  XXX                 XXX                            X 
 
   X      ALL     DDMMMYYYY   X:XX:XX   XXX                  XXX                 XXX                            X 
    
   X      ALL     DDMMMYYYY   X:XX:XX   XXX                  XXX                 XXX                            X 
                                                                                                                                             
  
                                                                                                      
 
  
 
 
 
 
 
 
 
 
 
 
 
Note:  (1) Was the subject given the test compound, dosing diary and instructions? 
       (2) Was the subject instructed to take the doses as directed on the drug packaging at their scheduled time with 240 mL of water? 
       (3) Did the subject return their diary and test compound container (empty or not)? 
       Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted) 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                                   
 
 
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Page 1 of X 
                                                   Appendix 16.2.5.5  Blood Draw Times 
  
Subject  Study                                          Actual                                                                     
Number   Period  Treatment   Day    Hour     Date       Time    Bioassay  Comments                                           
--------------------------------------------------------------------------------------------------------------------------------- 
 X         X       X           X    -X.XX  DDMMMYYYY   X:XX:XX  XXXXXXXXXXX                                                       
                                     X.XX  DDMMMYYYY   X:XX:XX  XXXXXXXXXXX                                                       
                                     X.XX  DDMMMYYYY   X:XX:XX  XXXXXXXXXXX                                                       
                                     X.XX  DDMMMYYYY  XX:XX:XX  XXXXXXXXXXX                                                       
                                     X.XX  DDMMMYYYY  XX:XX:XX  XXXXXXXXXXX                                                       
                                     X.XX  DDMMMYYYY  XX:XX:XX  XXXXXXXXXXX                                                       
                                     X.XX  DDMMMYYYY  XX:XX:XX  XXXXXXXXXXX                                                       
                                    XX.XX  DDMMMYYYY  XX:XX:XX  XXXXXXXXXXX                                                       
                                    XX.XX  DDMMMYYYY  XX:XX:XX  XXXXXXXXXXX                                                       
                               X    XX.XX  DDMMMYYYY   X:XX:XX  XXXXXXXXXXX                                                       
                                    XX.XX  DDMMMYYYY   X:XX:XX  XXXXXXXXXXX                                                       
                                    XX.XX  DDMMMYYYY  XX:XX:XX  XXXXXXXXXXX                                                       
                               X    XX.XX  DDMMMYYYY   X:XX:XX  XXXXXXXXXXX                                                       
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted) 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
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                                                                                                                   Page 1 of X 
                                                       Appendix 16.2.5.6  Meal Times 
  
 Subject  Study                                                    Start     Stop         Time Interval                                            
 Number   Period Treatment   Day   Hour  Event         Date        Time      Time      (Start HR to Stop HR)        Comments                                 
 -------------------------------------------------------------------------------------------------------------------------------- 
    X       X      X          -X  -XX.X  SNACK      DDMMMYYYY   XX:XX:XX  XX:XX:XX                                                
                               X    X.X  BREAKFAST  DDMMMYYYY   XX:XX:XX  XX:XX:XX       X.X to X.X                                         
                                    X.X  LUNCH      DDMMMYYYY   XX:XX:XX  XX:XX:XX                                                
                                    X.X  DINNER     DDMMMYYYY   XX:XX:XX  XX:XX:XX                                                
                                   XX.X  SNACK      DDMMMYYYY   XX:XX:XX  XX:XX:XX                                                
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted) 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
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                                                                                                                   Page 1 of X 
                                                Appendix 16.2.5.7  Concomitant Medications 
  
                                                                                                                                    
     Subject Study            Medication                                Start   Start   Stop    Stop                                
     Number  Period Treatment (WHO* Term)           Dosage   Route      Date    Time    Date    Time  Frequency Indication Continuing? 
     ------------------------------------------------------------------------------------------------------------------------------ 
       X     Screen           None                                                                                                  
                  1    X      ACETAMINOPHEN          620 mg  ORAL      DDMMMYYYY HH:MM  HH:MM  DDMMMYYYY  Once   Toothache  No      
                               (ACETAMINOPHEN) 
           
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Concomitant medications are coded with WHO Dictionary Version 01SEP2013. 
       Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted) 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
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WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 58 of 66 
  
                                                                                                                   Page 1 of X 
 
                                        Appendix 16.2.7.1  Adverse Events (I of II) 
 
                                                                          Time from                                             
                                                                          Last Dose       Onset         Resolved      Duration  
Subject Study  Treat-                                                     ---------- --------------- --------------- ------------ 
Number  Period ment   TE?^   Adverse Event*       Preferred Term           (DD:HH:MM)   Date    Time    Date    Time  (DD:HH:MM) 
---
-------------------------------------------------------------------------------------------------------------------------- 
  
Screen               None                                                                                                
          1     X     Yes    XXXXXXXXXXXXX        XXXXXXXXXX XXXXXXX        XX:XX:XX  DDMMMYYYY  X:XX DDMMMYYYY  X:XX  XX:XX:XX  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  ^ = Abbreviation for treatment-emergent, * = Adverse events are classified according to the MedDRA Version 16.1.                                      
       Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted) 
       Treatment C1 = Treatment C prior to WTX101 dosing, Treatment C2 = Treatment C post WTX101 dosing 
                                                                                                                                      
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
<Programmer Note: For treatment C, the AEs will be classified based on the onset date/time as prior to or post WTX101 dosing, notes as C1 
and C2).
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Wilson Therapeutics USA, Inc. 
WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 59 of 66 
                                                                                                                   Page 1 of X 
                                       Appendix 16.2.7.2  Adverse Events (II of II) 
 
                                                                                                  Relation-             
                                                       Onset                                      ship to               
    Subject Study            Adverse              ---------------                                 Study                 
    Number  Period Treatment Event                  Date    Time  Freq   Severity Ser* Outcome    Drug       Action     
    --
------------------------------------------------------------------------------------------------------------ 
     
Screen           None                                                                                       
              1        X     XXXXXXXXXXXXXXXXXX   DDMMMYYYY  X:XX Inter. Grade 1   NS   Resolved   XXXXXXXX   None       
 
  
  
  
 
 
 
 
 
 
 
 
 
                                                               
Note:  Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted)  
       Treatment C1 = Treatment C prior to WTX101 dosing, Treatment C2 = Treatment C post WTX101 dosing  
      Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Death due to AE.                    
       Ser* represents Serious:  NS = Not Serious                                                                            
       Freq represents Frequency:  SI = Single Episode, Inter. = Intermittent, Cont. = Continuous                            
                                                                                                                                       
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
<Programmer Note: For treatment C, the AEs will be classified based on the onset date/time as prior to or post WTX101 dosing, notes as C1 
and C2). 
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WTX101: WTX101-102  
Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 60 of 66 
                                                                                                                   Page 1 of X 
 
                                         Appendix 16.2.7.3  Adverse Event Non-Medication Procedures 
 
                                                            Onset            Procedure Given                
                 Subject Study            Adverse      --------------- ------------------------------------ 
                 Number  Period Treatment Event          Date    Time  Date      Time  Description          
                 ------------------------------------------------------------------------------------------ 
                      X    X       X      DRY LIPS     DDMMMYYYY XX:XX DDMMMYYYY XX:XX PETROLEUM JELLY      
 
                      X    X       X      CONSTIPATION DDMMMYYYY XX:XX DDMMMYYYY XX:XX PRUNE JUICE          
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted)  
       Treatment C1 = Treatment C prior to WTX101 dosing, Treatment C2 = Treatment C post WTX101 dosing  
                                                                                                                                      
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
<Programmer Note: For treatment C, the AEs will be classified based on the onset date/time as prior to or post WTX101 dosing, notes as C1 
and C2).
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Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
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                                                                                                                   Page 1 of X 
                                                               
                              Appendix 16.2.7.4  Adverse Event Preferred Term Classification 
 
                                                                                                                Onset      
 Subject Study            Adverse                                                                          --------------- 
 Number  Period Treatment Event                      Preferred Term             Body System                  Date    Time  
 
------------------------------------------------------------------------------------------------------------------ 
 
   1        X     XXXXXXX XXXXX XXXX XXXXXX  XXXXXXXXXX XXXXXXX         XXXXXXXXXXXXXXXXXXXXX      DDMMMYYYY  X:XX 
 
  
 
 
 
 
 
 
 
  
Note:  * Adverse events are classified according to the MedDRA Version 16.1.                                                  
       Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted)  
       Treatment C1 = Treatment C prior to WTX101 dosing, Treatment C2 = Treatment C post WTX101 dosing  
                                                                                                                                      
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
<Programmer Note: For treatment C, the AEs will be classified based on the onset date/time as prior to or post WTX101 dosing, notes as C1 
and C2).   
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Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 62 of 66 
Appendices 16.2.8.2 to 16.2.8.6 will have the following format. 
                                                                                                                   Page 1 of X 
                             Appendix 16.2.8.1  Clinical Laboratory Report - Serum Chemistry  
  
                                                                                                                                                
                                                            Parameter1  Parameter2   Parameter3    Parameter4  Parameter5 Parameter6  
     Subject   Age/   Study                                 < Range>    < Range>     < Range>      < Range>    < Range>   < Range>                           
     Number    Gender Period  Treatment   Hour    Date       (Unit)      (Unit)       (Unit)        (Unit)      (Unit)     (Unit)      
     --------------------------------------------------------------------------------------------------------------------------------- 
        X       XX    Screen                 .  DDMMMYYYY      XX HN       XX           XX            XX          XX HN      XX        
                XX    X           X             DDMMMYYYY      XX LY       XX LN        XX            XX LY       XX         XX        
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programmer Note: Replace Parameter1, 2 etc. with actual lab tests in the study. 
 
 
 
 
Note: H = Above Reference Range, L = Below Reference Range                                                                                         
Computer: N = Not Clinically Significant, Y = Clinically Significant                                                                         
PI Interpretation: - = Not Clinically Significant, R = To be Rechecked, ^ = Will be Retested at a Later Event                                
Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
Treatment B = 60 mg WTX101 on Day 1 (Fed) 
Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  Hour 0 
on Day 1 (Fasted)  
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
                                                          
 
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Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 63 of 66 
 
                                                                                                                   Page 1 of X 
                                         Appendix 16.2.8.7  Clinical Laboratory Report - Comments 
  
 Subject Study                                                                                                                              
 Number  Period  Treatment  Hour    Date    Department         Test                      Result       Unit      Comment                     
 ------------------------------------------------------------------------------------------------------------------------------------------ 
   X       X       X         -X.X DDMMMYYYY Other Tests        Fibrinogen                XXX          mg/dL     Not significant in the      
                                                                                                                context of this study.      
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted)  
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
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Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
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                                                                                                                   Page 1 of X 
                                                      Appendix 16.2.9.1  Vital Signs 
  
                                                            Blood Pressure (mmHg)           Respir- Temper-                       
 Subject Study                                          ----------------------------- Pulse  ation   ature   Weight           
 Number  Period Treatment Day  Hour    Date      Time   Test  Arm  Systolic/Diastolic (bpm)  (rpm)    (C)     (kg)       Comments     
 --------------------------------------------------------------------------------------------------------------------------------------- 
   X     Screen             .    .   DDMMMYYYY  X:XX:XX                                                       XXX.X                         
                            .    .   DDMMMYYYY  X:XX:XX SITX Right      XXX/ XX         XX     XX     XX.X    
            X        X     -X -XX.X  DDMMMYYYY XX:XX:XX SITX Right      XXX/ XX         XX     XX     XX.X 
                            X  -X.X  DDMMMYYYY  X:XX:XX SITX Right      XXX/ XX         XX     XX     XX.X                                   
                                X.X  DDMMMYYYY  X:XX:XX SITX Right      XXX/ XX         XX     XX     XX.X                                     
                               XX.X  DDMMMYYYY XX:XX:XX SITX Right      XXX/ XX         XX     XX     XX.X 
                           
 
 
 
 
 
 
 
 
 
 
 
Note:  SITX = X-minute sitting, R = Recheck Value.                                                                                           
       Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted)  
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 
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Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
Page 65 of 66 
                                                                                                                  Page 1 of X 
                                               Appendix 16.2.9.2  12-Lead Electrocardiogram 
  
                                                                          Heart                                                                      
Subject Study                                                             Rate       PR    QRS     QT    QTCB*   QTCF*                                       
Number  Period   Treatment    Day  Hour   Date      Time    Result        (bpm)    (msec) (msec) (msec) (msec)  (msec) Comments                             
--------------------------------------------------------------------------------------------------------------------------------------------  
X     Screen                   .    .   DDMMMYYYY  X:XX:XX  Normal          XX     XXX.X   XX.X  XXX.X  XXX.X   XXX.X                                       
           X         X         X   X.X  DDMMMYYYY  X:XX:XX  Abnormal,NCS    XX     XXX.X   XX.X  XXX.X  XXX.X   XXX.X                                       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  QTcB* = QTc corrected using Bazzet’s correction, QTcF* = QTc corrected using Fridericia’s correction. 
       NCS = Not clinically significant 
       Treatment A = 60 mg WTX101 on Day 1 (Fasted) 
       Treatment B = 60 mg WTX101 on Day 1 (Fed) 
       Treatment C = 20 mg omeprazole QD on the morning of Days -5 to -1 (Fasted), 20 mg omeprazole capsule at Hour -1 and 60 mg WTX101 at  
Hour 0 on Day 1 (Fasted)  
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 
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Celerion, Clinical Study Report No. CA13895 
 
Statistical Analysis Plan 12 May 2014 
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                                                                                                                  Page 1 of X 
                                               Appendix 16.2.9.3  Phone Participant 
  
                                                                                                             
Subject Study                                                  
Number  Period   Time Point      Date     Time     Result            Comments 
------------------------------------------------------------------------------------------------------------------------------- 
  X       All   First attempt   DDMMMYYYY HH:MM     XXXXX            XXXXXXXXXXXX                               
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
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