Conditions: Healthy Volunteers
Keywords: Proton Pump Inhibitor Bioequivalence Drug-Drug Interaction Modified Release Nifedipine
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 64
Healthy volunteers: yes

Brief summary:
The purpose of this study is to measure the amount of study drug present in blood after being administered a generic version of nifedipine extended-release tablets, 60 mg (Valeant Pharmaceuticals, LLC) and brand-name version PROCARDIA XL extended-release tablets, 60 mg (Pfizer Inc.) individually and in presence of stomach acid reducing drug (antacid), omeprazole/sodium bicarbonate capsules, 40 mg/1100 mg (generic) on separate occasions, on an empty stomach. This study also involves administrations of an FDA-cleared capsule, SmartPill™, which will measure stomach acid, prior to each study arm.

Detailed description:
A question that arises with generic oral extended-release (ER) products is related to pH-dependent dissolution kinetics in comparison with that of their reference listed drug (RLD). For example, poorly water-soluble drugs with the presence of pKa in the gastrointestinal (GI) pH range have pH-dependent solubility and dissolution behaviors during in vivo drug release. In this case, the generic product which utilizes a different release mechanism could amplify or reduce such a pH dependence (e.g. osmotic pump RLD vs. matrix generic counterparts). This may render these generic ER products more or less dependent on gastric pH modification, commonly occurred in patients taking concomitant over-the-counter (OTC) proton pump inhibitors (PPIs) for the treatment of gastric acid-related disorders. It has been noted that PPIs (e.g. lansoprazole, omeprazole, esomeprazole) and PPIs with antacids (e.g. omeprazole/sodium bicarbonate) can drastically elevate the gastric pH, thus potentially changing the equilibrium solubility of co-administered drug substances or altering their release profiles.

For instance, nifedipine is a calcium channel blocker, indicated for the long-term treatment of hypertension and angina. The drug substance is a weak acid (pKa 3.9) and practically insoluble in water. Currently, there is one RLD of oral ER nifedipine tablets based on an osmotic pump design (Procardia XL) and a generic counterpart of ER nifedipine tablets employing a matrix formulation design which is different from this RLD product. Due to complicated release mechanisms, quality attribute profiles, and in vivo pharmacokinetics (PK) behaviors of ER products, FDA is assessing the need of a drug-drug interaction study between PPIs/antacids (e.g. omeprazole/sodium bicarbonate) and generic nifedipine ER products based on a formulation design which is different from that of its RLD.

To this end, the objective of this proposal is to investigate the dependence of in vivo PK on the formulation design of generic oral extended-release products in comparison with that of their RLD when co-administered with PPIs/antacids. The outcome of this study will help the Agency advance further understanding about product PK performance in potential patient population with abnormal gastric pH and improve review standards for equivalence of this category of oral ER products if necessary. The study results will help the Agency gain a better understanding of drug-drug interaction between oral modified-release products and PPIs/antacids and establish regulatory standards of bioequivalence approaches for this category of generic oral ER products.

Arms:
arm 1: 1 x 60 mg Nifedipine extended-release tablet arm 2: 1 x 60 mg PROCARDIA XL (nifedipine) extended-release tablet arm 3: 1 x 40 mg/1100 mg omeprazole/sodium bicarbonate capsule daily over a period of 7 days + 1 x 60 mg Nifedipine extended-release tablet on day 7 arm 4: 1 x 40 mg/1100 mg omeprazole/sodium bicarbonate capsule daily over a period of 7 days + 1 x 60 mg PROCARDIA XL (nifedipine) extended-release tablet on day 7

Interventions: intervention 1: Nifedipine 60 MG Extended Release Oral Tablet intervention 2: Nifedipine 60 MG Extended Release Oral Tablet intervention 3: omeprazole/sodium bicarbonate intervention 4: SmartPill (TM)
Intervention descriptions: intervention 1: Reference Drug (Brand) intervention 2: Test Drug (Generic) intervention 3: Proton Pump Inhibitor/Antacid for drug-drug interaction intervention 4: Gastric pH measurement using SmartPill (TM) Technology

Protocol document:
Prot_SAP_000.pdf: 
 
CONFIDENTIAL INFORMATION 
The information in this study protocol is confidential. Any disclosure, copying or distribution of the information contained within is 
strictly prohibited without written consent from BioPharma Services USA Inc. 
Page 1 of 74 
A Single-Dose, Open-label, Randomized, Crossover, Drug-Drug Interaction Study 
of Nifedipine Extended-release Tablets with or without Multiple-dose 
Administration of Proton-pump inhibitor Omeprazole/sodium bicarbonate in 
Healthy Volunteers 
 
 
PROTOCOL 
 
 
BPSUSA Protocol Number: 
2001 
Protocol Version Date: 
August 3, 2017 
Sponsor: 
Foods and Drug Administration, USA. 
 
 
PROTOCOL APPROVAL SIGNATORY PAGE:  
 
I am aware of, and agree to comply with, all of the procedures contained within this 
protocol and requirements of applicable regulatory agencies:  
 
 
 
____________________________________ 
________________________________ 
Kathleen Doisy, M.D. 
Principal Investigator 
BioPharma Services USA Inc. 
Date (Mmm dd, yyyy) 
 
 
 
 
 
 
 
 
 
 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 2 of 74 
 
A Single-Dose, Open-label, Randomized, Crossover, Drug-Drug Interaction Study 
of Nifedipine Extended-release Tablets with or without Multiple-dose 
Administration of Proton-pump inhibitor Omeprazole/sodium bicarbonate in 
Healthy Volunteers 
 
 
BPSUSA Protocol Number: 
2001 
Protocol Version Date: 
August 3, 2017 
Sponsor: 
Foods and Drug Administration, USA. 
 
 
PROTOCOL APPROVAL SIGNATORY PAGE: SPONSOR 
 
I am aware of, and agree to comply with, all of the procedures contained within this 
protocol and requirements of applicable regulatory agencies: 
 
 
 
 
 
 
 
 
 
____________________________________ ________________________________ 
Dajun Sun, Ph.D. 
Project 
Officer/Contract 
Office’s 
Representative  
  
Office of Generic Drugs, Food and Drug 
Administration  
 Date (Mmm dd, yyyy) 
 
 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 3 of 74 
REVISION HISTORY 
Amendment 1 
 
Description: 
1. Dajun Sun serves both the project officer and Contract Office’s Representative.  
2. Zegerid is switched to Cipla’s generic copy of omeprazole/sodium bicarbonate 
capsules at the same strength of 40 mg/1100 mg.  
3. Dr. Kathleen Doisy serves as the PI to replace Dr. David Moreton. 
 
Rationale: 
1. 
 
  
 
 
 
 
 
  
 
  
 
 
Version Date – April 18, 2017 
 
*(strikethrough represents deletion and underline represents addition) 
 
Description: 
1. Protocol version number was deleted and the Protocol version will now be 
considered from the date of the Protocol – “Protocol Version Date”. 
 
2. Section 6.0 – Study Population – The first sentence was changed as follows: 
A total of 64 required number of healthy volunteers, male and non-pregnant 
female, aged between 18 and 55 years of age will be screened according to the 
inclusion and exclusion criteria listed in Sections 7.3 and 7.4 to be sure that about 
62-64 are randomized. 
 
3. Section 7.2 - Inclusion Criteria – Bullet point 1 – following underlined words 
were added: 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 4 of 74 
Healthy, males and non-pregnant (excluding nursing and lactating) female 
volunteers, 18 to 55 years of age, inclusive. 
 
4. Section 7.6 – Study Restrictions - Bullet point 6 – the number of days of 
restriction was changed to 14 from previous 30 days. 
Any concomitant medication [prescription medications (e.g., prescription 
pills, topical systemic creams, inhalants, sprays [except for contraceptives]) 
or over-the-counter (e.g., acetaminophen, Ricola, oral multivitamins) (except 
for spermicidal/barrier contraceptive products)], any herbal and/or dietary 
supplements will not be permitted for 30 14 days prior to first study drug 
administration until the last blood draw in the final study period unless 
deemed otherwise by the PI/Sub-Investigator for treatment of any adverse 
events (AEs). 
 
5. Section 8.2 – Food and Fluid Intake – Study arm C and Study arm D – The 
underlined hours were added to the meal times: 
In this study, meals will be served at approximately 4.5, 9.5, 13.5, 24.5, 
28.5, 33.5, 37.5, 48.5, 52.5, 57.5, 61.5, 72.5, 76.5, 81.5, and 85.5 hours 
after capsules dosing on Day 3.  (Section 2.0 – Table of Study Procedures 
footnote i) was also updated with these timepoints). 
 
6. Section 14.5 – Compensation for Participation – The compensation was re-
structured in the table. However, the total compensation remains the same.  
 
7. Similar changes were incorporated in the study ICF. 
 
 
Rationale: 
 
1. To be version consistent with the changes made after Research Involving 
Human Subjects Committee (RIHSC)-IRB (FDA) request. 
2. RIHSC-IRB (FDA) requested change. 
3. RIHSC-IRB (FDA) requested change. 
4. RIHSC-IRB (FDA) requested change. 
5. RIHSC-IRB (FDA) requested change. 
6. The compensation structure was re-aligned to be more subject friendly. 
7. For Protocol and ICF to be consistent. 
 
Version Date – May 16, 2017 
 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 5 of 74 
 
 
 
 
 
 
 
 
Version Date – August 3, 2017 
 
Description:   
1. In sections 2.0 – Table of Study Procedures – time point for procedure/activity 
ICF was changed from Period 1 to Screening. Superscript “a” explanation was 
updated from “at first period check in only” to “at screening and prior to any 
medical screening procedures”  
2. In Sections 1.0, 3.2, 6.0, and 7.1, sample size of 64 65-66 subjects will be enrolled 
(minimum of 52 subjects to complete the study). In Section 6.0, “No replacement 
will be made after randomization” was deleted. 
 
Rationale:   
1. To ensure there is no ambiguity in the protocol as it pertains to obtaining a study 
ICF. 
2. Increasing the number of enrolling subjects to 65-66 and allowing replacement of 
subjects prior to the first dosing can better ensure a minimum of 52 subjects to 
complete the clinical study.  
 
 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 6 of 74 
TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................... 1 
REVISION HISTORY ..................................................................................................... 3 
TABLE OF CONTENTS ................................................................................................. 6 
SPONSOR, INVESTIGATORS AND FACILITIES..................................................... 9 
INVESTIGATOR CREDENTIALS.............................................................................. 10 
1.0 
SYNOPSIS ............................................................................................................. 11 
2.0 
TABLE OF STUDY PROCEDURES .................................................................. 14 
3.0 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE ......................................................................................................... 16 
3.1 
Background Information ......................................................................................... 16 
3.2 
Rationale .................................................................................................................. 19 
3.3 
Product Information ................................................................................................ 20 
4.0 
STUDY OBJECTIVE ........................................................................................... 24 
4.1 
Study Objective ....................................................................................................... 24 
5.0 
STUDY DESIGN ................................................................................................... 27 
5.1 
Discussion of Study Design .................................................................................... 27 
5.2 
Study Duration and Confinement ............................................................................ 28 
5.3 
Randomization and Blinding ................................................................................... 28 
6.0 
STUDY POPULATION ........................................................................................ 30 
7.0 
SUBJECT SELECTION AND WITHDRAWAL/TERMINATION ................ 31 
7.1 
Sample Size ............................................................................................................. 31 
7.2 
Inclusion Criteria ..................................................................................................... 31 
7.3 
Exclusion Criteria .................................................................................................... 32 
7.4 
Informed Consent Procedure ................................................................................... 34 
7.5 
Screening Procedures .............................................................................................. 35 
7.6 
Study Restrictions ................................................................................................... 35 
7.7 
Withdrawal/Termination ......................................................................................... 37 
8.0 
STUDY PROCEDURES ....................................................................................... 39 
8.1 
Study Period Check-in Procedures .......................................................................... 39 
8.2 
Food and Fluid Intake ............................................................................................. 39 
8.3 
Dosing ..................................................................................................................... 40 
8.4 
Gastric pH ............................................................................................................... 41 
8.5 
Safety Monitoring ................................................................................................... 42 
8.5.1 Vital Signs ............................................................................................................... 42 
8.5.2 ECG ......................................................................................................................... 42 
8.5.3 Health Monitoring ................................................................................................... 42 
8.6 
Post-Study Tests ...................................................................................................... 43 
8.7 
Sample Collection and Processing .......................................................................... 43 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 7 of 74 
8.8 
Sample Shipment ..................................................................................................... 44 
9.0 
DRUG PRODUCTS .............................................................................................. 45 
9.1 
Drug Information ..................................................................................................... 45 
9.2 
Labeling, 
Maintenance, 
and 
Retention 
of 
Study 
Drugs 
(Nifedipine, 
omeprazole/sodium bicarbonate, SmartPillTM) ....................................................... 45 
9.3 
Drug Inventory ........................................................................................................ 45 
9.4 
Disposition of Unused Study Drug (Nifedipine, omeprazole/sodium bicarbonate, 
SmartPillTM) ............................................................................................................ 46 
10.0 Potential Risks and Benefits ................................................................................. 47 
10.1 Potential Risks ......................................................................................................... 47 
10.2 Potential Benefits .................................................................................................... 48 
11.0 SAFETY ASSESSMENT ...................................................................................... 49 
11.1 Definitions ............................................................................................................... 49 
11.2 Characteristics of an Adverse Event ....................................................................... 50 
11.2.1 Relationship to Study Drug .................................................................................... 50 
11.2.2 Expectedness of SAE ............................................................................................. 51 
11.2.3 Severity Assessment ............................................................................................... 51 
11.3 Adverse Events Reporting ....................................................................................... 52 
11.4 Procedures for Reporting Pregnancy ....................................................................... 54 
12.0 BIOANALYTICAL ANALYSIS ......................................................................... 56 
12.1 Analytical Procedures ............................................................................................. 56 
12.1.1 Samples to be assayed ............................................................................................ 56 
12.1.2 Analyte(s) in Biological Matrix ............................................................................. 56 
13.0 PHARMACOKINETIC AND STATISTICAL ANALYSIS ............................. 57 
13.1 Pharmacokinetic Analysis Data Set ........................................................................ 57 
13.2 Pharmacodynamic (PD) Analysis Data Set ............................................................. 57 
13.3 Analysis of Data ...................................................................................................... 57 
13.3.1 Pharmacokinetic Analysis ...................................................................................... 58 
13.3.2 Pharmacodynamic Analysis ................................................................................... 59 
13.3.3 Statistical Analysis ................................................................................................. 59 
14.0 ETHICAL CONSIDERATIONS / PROTECTION OF HUMAN SUBJECTS61 
14.1 Basic Principles ....................................................................................................... 61 
14.2 Institutional Review Board ...................................................................................... 61 
14.3 Informed Consent Form .......................................................................................... 61 
14.4 Confidentiality ......................................................................................................... 61 
14.5 Compensation for Participation ............................................................................... 62 
14.6 In Case of an Injury Related to this Research ......................................................... 63 
15.0 ADMINISTRATIVE CONSIDERATIONS ....................................................... 64 
15.1 Revisions and/or Amendments to the Protocol ....................................................... 64 
15.2 Investigator Responsibilities ................................................................................... 64 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 8 of 74 
15.3 Study Completion/Termination ............................................................................... 64 
15.4 Sponsor Visits ......................................................................................................... 64 
16.0 DATA MANAGEMENT/RECORD KEEPING ................................................ 65 
16.1 Source Data ............................................................................................................. 65 
16.2 Quality of Data ........................................................................................................ 65 
16.3 Retention of Documents .......................................................................................... 65 
17.0 REFERENCES ...................................................................................................... 66 
APPENDIX A – SCHEDULE OF EVENTS ................................................................ 68 
APPENDIX B – CLINICAL LABORATORY ASSESSMENT ................................. 71 
APPENDIX C – LIST OF COMMON ABBREVIATIONS ....................................... 72 
APPENDIX D – RESTRICTED LIST OF DIURETICS ............................................ 73 
APPENDIX E – NIFEDIPINE LABEL ........................................................................ 74 
APPENDIX F – PROCARDIA XL LABEL ................................................................. 74 
APPENDIX G –OMEPRAZOLE/SODIUM BICARBONATE LABEL ................... 74 
APPENDIX H – SMARTPILL™ 510(k) SUMMARY ................................................ 74 
  


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 9 of 74 
SPONSOR, INVESTIGATORS AND FACILITIES 
Principal 
Investigator: 
Kathleen Doisy, M.D. 
BioPharma Services USA Inc. 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Sponsor: 
Dajun Sun, Ph.D.  
Staff fellow 
Office of Research and 
Standards, Office of Generic 
Drugs, Center for Drug 
Evaluation and Research, U.S. 
Food and Drug Administration, 
 
 
  
 
 
  
 
 
 
B
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 10 of 74 
INVESTIGATOR CREDENTIALS 
Dr. Kathleen Doisy, Principal Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________ 
________________________________ 
Kathleen Doisy, M.D. 
Principal Investigator 
 
 
 
Date (Mmm dd, yyyy) 
 
 
 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 11 of 74 
1.0 
SYNOPSIS 
Title: 
A Single-Dose, Open-label, Randomized, Crossover, Drug-Drug Interaction  Study 
of Nifedipine Extended-release Tablets with or without Multiple-dose 
Administration of Proton-pump inhibitor Omeprazole/sodium bicarbonate in 
Healthy Volunteers. 
Objective: 
The objective of this study is to compare pharmacokinetics of nifedipine from both 
generic Nifedipine oral extended-release tablets, 60 mg and reference listed drug 
PROCARDIA XL (nifedipine; RLD) extended-release tablets, 60 mg when co-
administered 
with 
or 
without 
proton 
pump 
inhibitor 
(PPI)/antacid, 
omeprazole/sodium bicarbonate 40 mg/1100 mg capsules in healthy males and 
non-pregnant females under fasting conditions, whose gastric pH will be measured 
by SmartPill™ technology.  
Experimental Design: 
A single-dose, randomized, open-label, drug-drug interaction (DDI), 4-way 
crossover, four-treatment, four-sequence, bioequivalence study. 
Study Rationale: 
This is an in vivo study to evaluate the test and RLD formulation pharmacokinetics 
of nifedipine when co-administered with or without PPI/antacid. The outcome of 
this study will help the Agency advance further understanding about product PK 
performance of nifedipine in potential patient population co-administered with PPI 
or with abnormal gastric pH and improve review standards for equivalence of this 
category of oral ER products if necessary. 
Study Population: 
65-66 subjects will be enrolled (minimum of 52 subjects to complete the study). 
The subjects will be dosed in two or more groups. 
 
Healthy, non-smoking male and non-pregnant female volunteers, 18-55 years of 
age, with a body mass index (BMI) within 18.5-35.0 kg/m2, inclusive.  
Test Drug: 
Nifedipine extended-release tablets, 60 mg 
 
Reference Drug: 
PROCARDIA XL extended-release tablets, 60 mg 
 
PPI/antacid: 
omeprazole/sodium bicarbonate 40 mg/1100 mg capsule  
Study arm A (Test Drug): 
1 x 60 mg Nifedipine extended-release tablet 
Study arm B  
(Reference Drug): 
1 x 60 mg PROCARDIA XL (nifedipine) extended-release tablet 
Study arm C (PPI/ antacid 
+ Test Drug)  
1 x 40 mg/1100 mg omeprazole/sodium bicarbonate capsule daily over a period of 
7 days + 1 x 60 mg Nifedipine extended-release tablet on day 7 
Study arm D (PPI/ antacid 
+ Reference Drug)  
1 x 40 mg/1100 mg omeprazole/sodium bicarbonate capsule daily over a period of 
7 days + 1 x 60 mg PROCARDIA XL (nifedipine) extended-release tablet on day 7 
Duration of Confinement: 
Study arm A and B:  
• 
Day 1: From at least 10 hours prior to dosing  


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 12 of 74 
• 
Day 2-3: All day confinement.  
• 
Day 4:  After 48 hours blood draw, subjects will be discharged. 
 
A total confinement of at least 58 hours in each study arm. 
Study arm C and D:  
• 
Day 1-2 (walk-in): From at least 1 hour prior to omeprazole/sodium 
bicarbonate capsules dosing until at least 1 hour post-dose.  
• 
Day 3: From at least 1 hour prior to omeprazole/sodium bicarbonate 
capsules dosing followed by check-in procedure or subjects can check-in 
the evening. 
• 
Day 4-8:  All day confinement. 
• 
Day 9:  After 48 hours blood draw, subjects will be discharged. 
Total confinement from Day 1 to Day 9 will be of at least 148 hours 
(approximately 6 days) in each study arm. 
The total anticipated duration of the clinical part of the study will be approximately 
13 to 19 weeks (since signing the ICF by the first subject up to the last planned 
study procedure of the last subject). 
Washout: 
At least 14 days after Nifedipine only dosing (Study arms A or B) and for Study 
arms C and D (e.g., omeprazole/sodium bicarbonate followed with Nifedipine), at 
least 14 days after the last dose with omeprazole/sodium bicarbonate until the next 
treatment dose. 
Safety Monitoring: 
• Vital signs (blood pressure [BP], heart rate [HR], respiratory rate [RR], and 
temperature) will be obtained throughout the study. 
• Laboratory testing (hematology, serum biochemistry and urinalysis) will be 
conducted at check-in for all study arms. 
• The PI/Sub-Investigator will be present from approximately 30 minutes prior to 
SmartPillTM administration until at least 6 hours after the last subject is dosed 
with nifedipine ER tablets in each study arm.  
• The PI/Sub-Investigator will remain on-call throughout the duration of the 
study. 
Type of Vacutainer 
Pre-chilled K2EDTA Vacutainer®, 4 mL 
Blood Sampling Time 
points: 
Pre-dose (0 hour) and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 20, 24, 36 and 48 hours 
after nifedipine dosing in each study arm. 
Total Blood Volume: 
Approximately 345 mL of blood, including ~29 mL for pre- and post- study 
procedures and ~ 44 mL for laboratory testing at each period check-in. 
Gastric pH 
Gastric pH using SmartPillTM Technology 
SmartPillTM capsules will be administered on Day 2 approximately 30 minutes 
before nifedipine dosing (Study arm A and B), and on Day 7 prior to dosing of 
nifedipine and omeprazole/sodium bicarbonate capsules (Study arm C and D). 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 13 of 74 
Gastric pH Time-points 
The pH will be measured at 0, 1, 2, 3, 4, 5, 6, 7, and 8 hours after SmartPillTM 
administration in each study arm. The pH will be monitored continuously for 24 
hours post-dose. 
Analyte(s) to be measured: 
Plasma samples will be assayed for nifedipine using a validated analytical method 
according to the principles of Good Laboratory Practice. 
Pharmacokinetics and 
Gastric pH: 
Descriptive statistics of pharmacokinetic parameters AUCt, AUCinf and Cmax, as 
well as Tmax, λ and T1/2 will be calculated for each study arm group. The 
descriptive statistics of the gastric pH and change of gastric pH will be calculated 
for both test and reference products.  
Statistical Analysis: 
 
 
 
For Pharmacokinetic Data: Analysis of Variance (ANOVA) for ln-transformed 
AUCt, AUCinf and Cmax, and untransformed Tmax, λ and T1/2. Tmax will also be 
analyzed using an additional non-parametric test (Wilcoxon test). The 90% 
confidence intervals (CI) for the ratios of geometric means for AUCt, AUCinf and 
Cmax will be calculated based on the least square means (LSMEANS) and 
ESTIMATE of the ANOVA. 
For Pharmacodynamic Data: Analysis of Variance (ANOVA) for gastric pH and 
change of gastric pH from baseline will be carried out. 
 
 
 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 14 of 74 
2.0 
TABLE OF STUDY PROCEDURES 
Procedure/Activity 
Time points 
Screening 
Each 
Period 
Check-in 
Period 
1 
Period 
2 
Period 
3 
Period 
4 
Post-
Study 
ICF 
Xa 
 
 
 
 
 
 
Drugs of Abuse 
X 
X 
 
 
 
 
 
Alcohol Test 
X 
X 
 
 
 
 
 
Cotinine 
X 
X 
 
 
 
 
 
Pregnancy (hCG) Test* 
X 
X 
 
 
 
 
 
Vital Signs (BP, HR, RR 
and Temperature) 
X 
 
Xb 
Xb 
Xb 
Xb 
X 
Laboratory Testing 
X  
X# 
 
 
 
 
X  
Medical History 
X 
 
 
 
 
 
 
BMI 
X 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Assessment 
X 
 
 
 
 
 
 
Restrictions Compliance 
Check 
 
X 
X 
X 
X 
X 
 
Physical Exam 
X 
 
 
 
 
 
X 
SmartPillTM Administration 
 
 
Xc 
Xc 
Xc 
Xc 
 
Nifedipine ER tablets 
Dosing (Test) 
 
 
Xd 
 
Xd 
 
 
PROCARDIA XL (Ref) 
 
 
 
Xd 
 
Xd 
 
omeprazole/sodium 
bicarbonate capsules Dosing 
 
 
 
 
Xe 
Xe 
 
pH Measurement 
 
 
Xf 
Xf 
Xf 
Xf 
 
PK Sampling 
 
 
Xg 
Xg 
Xg 
Xg 
 
Adverse Event Reporting 
 
Xh 
X 
X 
X 
X 
X 
Meals 
 
X 
Xi 
Xi 
Xi 
Xi 
 


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BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 16 of 74 
3.0 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
3.1 
Background Information 
Among the top 200 prescription oral drugs in the US, approximately one-third are 
modified-release (MR) oral drug products (e.g. extended-release, delayed-release) 
which provide unique clinical benefits compared to their immediate-release (IR) 
counterparts. The complicated formulation designs and manufacturing processes of 
MR oral dosage forms have posed regulatory challenges for the evaluation of 
Abbreviated New Drug Applications (ANDAs). Oral ER dosage forms have been 
used extensively for long-term therapeutic efficacy, reduced adverse events, and 
improved patient compliance. Common formulation designs which help achieve an 
extended release for oral dosage forms can be briefly classified into three types: 
matrices, coated beads, and osmotic pumps. The mechanisms employed to achieve a 
controlled release in oral drug delivery systems are based on diverse and complex 
principles (e.g. dissolution, diffusion, osmosis, swelling, and erosion) among which 
the development of push-pull osmotic pump systems and diffusion- or dissolution-
controlled monolithic devices or reservoir systems has been widely applied to many 
ER oral dosage forms [1]. In some cases, a generic ER product may employ a 
completely different release mechanism and/or critical excipients from those of the 
reference listed drug (RLD) products. 
One of the most noted advantages of osmotic drug delivery systems is the ability to 
maintain a zero-order (i.e. constant) drug release rate, independent of the physical 
properties of the drug substances and a number of external parameters such as 
dissolution medium pH and hydrodynamics of mixing [2]. For this reason, a number 
of oral ER dosage forms have been formulated using osmotic release oral system 
(OROS) technology (e.g. Invega, Concerta, Procardia XL, Ditropan XL, and 
Tegretol-XR) (also known as “osmotic pump”) to achieve desired pharmacokinetic 
(PK) profiles and clinical performance [3]. The generic applicants of oral ER drug 
products may employ a different controlled-release design from that of the osmotic 
pump RLD, considering that the manufacturing processes or formulation designs of 
RLD product may not always be available to the generic applicants (e.g. patent 
protection).  
A question that arises with generic oral ER products is related to pH-dependent 
dissolution kinetics in comparison with that of their RLD. Depending on the 
formulation design, poorly water-soluble nifedipine with a pKa in the 
gastrointestinal (GI) pH range may have pH-dependent solubility. In this case, the 
in vitro dissolution of matrix-based ER tablets may also be pH-dependent as the 
drug release is controlled by diffusion driven by a concentration gradient between 
surface drug concentration and solubility. Bioequivalence (BE) between these 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 17 of 74 
generic products based on a matrix design and their RLDs based on an osmotic 
pump design is often demonstrated via an in vivo bioequivalence pharmacokinetic 
study using healthy volunteers whose gastric pH is within the physiological norm 
(e.g. pH 1.2). In this case, ANDA applicants are not required to employ the same 
release mechanism and formulation design as the osmotic pump RLD. Whether or 
not the two products are still bioequivalent in subjects with an elevated gastric pH 
environment as commonly occurred in patients with achlorhydria or population who 
take concomitant proton pump inhibitors (PPIs) would require additional 
evaluation.   
Food and Drug Administration performed a comprehensive and systematic analysis 
on generic MR oral drug products in different therapeutic classes based on in-house 
data on formulations, clinical studies, and post-market surveillance work. The 
formulations of 15 osmotic pump MR oral drug products and all their approved and 
pending generic counterparts were identified and analyzed for potential failure 
modes related to bioequivalence in a risk analysis. Additional modeling work was 
used to predict the impact of dissolution variations of carbamazepine, metoprolol 
succinate, venlafaxine HCl (lag time of drug release) [4], and nifedipine (pH-
dependent dissolution behavior) MR oral drugs on the resulting PK profiles. These 
simulation studies helped identify the range of release curve alterations within 
which the BE of generic products can be maintained and also help suggest potential 
in vivo predictive dissolution conditions. Based on in-house formulation analysis 
and dissolution testing, a generic version of nifedipine extended-release (ER) tablets 
using a matrix design has been identified as having pH-dependent dissolution 
behaviors compared to its reference product (i.e. Procardia XL) in which the drug 
release is pH-independent.  
Nifedipine is a calcium channel blocker, indicated for the long-term treatment of 
hypertension and angina. The drug substance is a practically water-insoluble weak 
acid (pKa 3.9), which has a pH-dependent solubility across physiological pHs in the 
GI tract [5]. Currently, there is one RLD of oral ER nifedipine tablets based on an 
osmotic pump design (i.e. Procardia XL) [6] Nifedipine release from Procardia XL 
is independent of the pH environment of the dissolution medium or gastrointestinal 
motility according to the drug label [6], whereas the drug label of the generic copy 
of nifedipine ER tablets based on a matrix design does not mention any drug-drug 
interaction with PPIs as per required consistent labeling between generic and 
reference products (See the package insert of generic nifedipine ER tablets). 
Nevertheless, the generic counterpart of nifedipine ER tablets employing a matrix 
formulation design may have pH-dependent dissolution profiles in comparison to 
the RLD, considering that such a pH-dependent dissolution behaviors of similar 
nifedipine ER products formulated in a matrix design have been reported in 
literature [5, 7, 8] marketed in Europe. Additional in vivo studies have confirmed 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 18 of 74 
the different PK behaviors of two European nifedipine ER oral drug products using 
an osmotic pump or matrix design [7-9]. These clinical studies clearly showed that 
the pharmacokinetic properties and behaviors of two nifedipine ER dosage forms 
(osmotic pump vs. matrix) have a different sensitivity to concomitant food intake 
which is known to alter the gastric pH. Nevertheless, the current labeling on generic 
nifedipine ER tablets referencing Procardia XL does not mention any drug-drug 
interaction with proton pump inhibitors as the RLD and generic labeling should be 
consistent. 
The generic nifedipine ER product which utilizes a different release mechanism 
could amplify or reduce such a pH dependence (e.g. osmotic pump RLD vs. matrix 
generic counterparts). Under the existing regulatory practice, ANDA applicants of 
oral ER drug products are not required to conduct BE studies comparing the generic 
products with the RLD in patients chronically taking PPIs or with an abnormal 
gastric pH. This may render these generic ER products more or less dependent on 
gastric pH modification, commonly occurred in patients taking concomitant PPIs 
for the treatment of gastric acid-related disorders. It has been noted that PPIs (e.g. 
lansoprazole, 
omeprazole, 
esomeprazole) 
and 
PPIs 
with 
antacids 
(e.g. 
omeprazole/sodium bicarbonate) can drastically elevate the gastric pH, thus 
potentially changing the equilibrium solubility of co-administered drug substances 
or altering their release profiles. In the case of nifedipine, clinical studies have 
shown that in healthy volunteers receiving a single dose of 10 mg nifedipine IR 
tablets, AUC and Cmax of nifedipine after pretreatment with omeprazole 20 mg 
once daily for 8 days were 1.26 and 0.87 times those after pre-treatment with 
placebo [10-12]. This shows a potential drug-drug interaction between PPIs and 
nifedipine that is formulated in an immediate-release dosage form.  
Whether such a pH-dependent in vitro dissolution behavior can translate into any 
difference in in vivo pharmacokinetics for generic nifedipine ER tablets based on a 
matrix design can only be evaluated in subjects with an elevated gastric pH. 
Additional regulatory requirements in this category of oral drug products may be 
warranted if such changes in PK profiles as a result of pH-dependent dissolution 
behaviors for matrix-based nifedipine ER tablets could affect the efficacy and safety 
profiles. Due to complicated release mechanisms, quality attribute profiles, and in 
vivo pharmacokinetic behaviors of ER products, FDA is assessing the need of a 
drug-drug interaction study between PPIs/antacids (e.g. omeprazole/sodium 
bicarbonate) and generic nifedipine ER products based on a formulation design 
which is different from that of its RLD. In so doing, FDA aims to evaluate 
formulation dependence of interaction with PPIs/antacids which are known to 
elevate gastric pH and potentially affect in vivo drug release. The study results will 
help the Agency gain a better understanding of drug-drug interaction between oral 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 19 of 74 
MR products and PPIs/antacids and establish regulatory standards of 
bioequivalence approaches for this category of generic oral ER products. 
3.2 
Rationale 
The current research proposal is funded by the FDA via a contract agreement 
(HHSF 22320161004I) with the purpose of investigating the in vivo performance 
consistency of oral MR drug products under the effect of an elevated gastric pH 
environment (e.g. co-administration of PPIs). We have chosen to focus on 
nifedipine ER tablets (brand name and generic products) because the RLD is an 
osmotic pump and there is a generic version commercially available as matrix-
based formulations. We will evaluate the bioequivalence in an open label, clinical 
study with and without multiple-dose PPI co-adminsitered with the brand name 
drug and a generic version. In the current study, clearance, volume of distribution, 
and absorption, as determined by physiological variables (e.g. gastric emptying, 
motility, pH), are assumed to have less inter-occasion variability compared to the 
variability arising from formulation performance within the same subject [6, 12-14]. 
Therefore, differences between two products because of formulation factors can be 
determined [15].  
This clinical study will be open-label because blood concentration levels cannot be 
influenced by knowledge of the identity of treatment, however, the laboratory 
analysts will be unaware of the study product sequences. The period of 48 hours, 
over which blood samples will be collected, is considered to be sufficiently long to 
adequately characterize the concentration-time profile of extended-release 
nifedipine (the mean half-life of nifedipine is less than 10 hours). It has been shown 
that administering multiple-dose (e.g. 7 days) PPIs (i.e. omeprazole) in healthy 
volunteers can effectively increase their gastric pH [16, 17]. In the current clinical 
study, subjects will be dosed with PPIs in the first two days without confinement 
(i.e. outpatient visits) to reduce their burden. Dosing the subjects with PPIs in 
confinement for the last 5 days is deemed necessary in order to standardize the food 
effect (omeprazole administration under fasting conditions) prior to the PK study of 
nifedipine ER tablets. Since the omeprazole PD effect can be eliminated after 3-5 
days of discontinuing the drug, a wash-out period of at least 7 days is sufficient to 
allow the complete elimination of the drug before subsequent dosing and to avoid 
carry-over effects. In this study, a wash-out period of at least 14 days is chosen to 
ensure the scientific and logistic conduct of the study.  
Nifedipine (Procardia XL, Pfizer) is a cardiovascular drug that is used for the 
long-term treatment of hypertension and angina. Nifedipine is a weak acid (pKa 
3.9) which is practically insoluble in water and has a pH-dependent solubility across 
pH 1-7. According to the Biopharmaceutical Classification System (BCS), it is a 
Class II compound with an oral bioavailability determined by aqueous solubility. 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 20 of 74 
Nifedipine (Procardia XL) was approved by the FDA in 1989. After loss of patent 
protection, the FDA approved several generic nifedipine ER tablets manufactured 
by Osmotica (2005), Mylan (2010), Matrix Laboratories (2010), and others. 
Although several in vivo and in vitro methods are available to measure product 
bioavailability and bioequivalence for orally administered drug products, the FDA 
guidelines recommend reliance on pharmacokinetic measures such as the rate (i.e., 
maximum concentration [Cmax]) and extent (i.e., area under the concentration-time 
curve 
[AUC]) 
of 
absorption 
as 
these 
best 
reflect 
systemic 
exposure(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinfor
mation/guidances/ucm320010.pdf ). Nifedipine should be administered orally and 
may be given with or without food [6]. Omeprazole/sodium bicarbonate should be 
taken orally on empty stomach at least one hour before meal2. Therefore, the 
investigational medicinal products (IMPs) will be administered orally under fasting 
conditions to better distinguish possible differences between the IMPs. This is in 
compliance with the Guidance for Industry [15]. 
The specific aim of this research is to conduct a randomized, single-dose, four-
treatment, four-period cross-over in vivo bioequivalence study in 65-66 healthy 
adult volunteers (males and non-gravid females) (The sample size is discussed in 
Section 7.1 of this Study Protocol) to evaluate the in vivo performance of brand and 
generic nifedipine ER tablets with or without co-administration of multiple-dose 
PPIs. The pharmacokinetics of nifedipine as Procardia XL and generic nifedipine 
ER tablets, Procardia XL with PPIs and generic nifedipine ER tablets with PPIs 
will be determined and compared in healthy volunteers under fasting conditions.   
3.3 
Product Information 
PROCARDIA XL [6]  
Nifedipine is a calcium ion influx inhibitor (slow-channel blocker or calcium ion 
antagonist) and inhibits the transmembrane influx of calcium ions into cardiac muscle 
and smooth muscle. The contractile processes of cardiac muscle and vascular smooth 
muscle are dependent upon the movement of extracellular calcium ions into these cells 
through specific ion channels. Nifedipine selectively inhibits calcium ion influx across 
the cell membrane of cardiac muscle and vascular smooth muscle without altering 
serum calcium concentrations. The indications of nifedipine include: 
I. 
Vasospastic Angina  
Procardia XL is indicated for the management of vasospastic angina confirmed by any 
of the following criteria: 1) classical pattern of angina at rest accompanied by ST 
segment elevation, 2) angina or coronary artery spasm provoked by ergonovine, or 3) 
angiographically demonstrated coronary artery spasm. In those patients who have had 
angiography, the presence of significant fixed obstructive disease is not incompatible 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 21 of 74 
with the diagnosis of vasospastic angina, provided that the above criteria are satisfied. 
Procardia XL may also be used where the clinical presentation suggests a possible 
vasospastic component, but where vasospasm has not been confirmed, e.g., where pain 
has a variable threshold on exertion, or in unstable angina where electrocardiographic 
findings are compatible with intermittent vasospasm, or when angina is refractory to 
nitrates and/or adequate doses of beta blockers.  
II. 
Chronic Stable Angina (Classical Effort-Associated Angina)  
Procardia XL is indicated for the management of chronic stable angina (effort-
associated angina) without evidence of vasospasm in patients who remain 
symptomatic despite adequate doses of beta blockers and/or organic nitrates or who 
cannot tolerate those agents.  
In chronic stable angina (effort-associated angina), nifedipine has been effective in 
controlled trials of up to eight weeks duration in reducing angina frequency and 
increasing exercise tolerance, but confirmation of sustained effectiveness and 
evaluation of long-term safety in these patients is incomplete. 
Controlled studies in small numbers of patients suggest concomitant use of nifedipine 
and beta-blocking agents may be beneficial in patients with chronic stable angina, but 
available information is not sufficient to predict with confidence the effects of 
concurrent treatment, especially in patients with compromised left ventricular function 
or cardiac conduction abnormalities. When introducing such concomitant therapy, 
care must be taken to monitor blood pressure closely, since severe hypotension can 
occur from the combined effects of the drugs (See WARNINGS).  
III. Hypertension  
Procardia XL is indicated for the treatment of hypertension. It may be used alone or in 
combination with other antihypertensive agents. 
 
Omeprazole/sodium bicarbonate [18]  
Omeprazole/sodium bicarbonate is a proton pump inhibitor (PPI) indicated for,  
− Short-term treatment of active duodenal ulcer.  
− Short-term treatment (4-8 weeks) of active benign gastric ulcer.  
− The treatment of heartburn and other symptoms associated with GERD for 
up to 4 weeks [Symptomatic GERD] 
− The short-term treatment (4-8 weeks) of erosive esophagitis which has 
been diagnosed by endoscopy.  
− Maintaining healing of erosive esophagitis. 
− Capsules 40 mg/1100 mg (omeprazole/sodium bicarbonate) is indicated for 
the reduction of risk of upper gastrointestinal bleeding in critically ill 
patients. 
 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 22 of 74 
Mechanism of Action: 
Omeprazole belongs to a class of anti-secretory compounds, the substituted 
benzimidazoles, that do not exhibit anticholinergic or H2 histamine antagonistic 
properties, but that suppress gastric acid secretion by specific inhibition of the 
H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell. 
Because this enzyme system is regarded as the acid (proton) pump within the 
gastric mucosa, omeprazole has been characterized as a gastric acid‑pump 
inhibitor, in that it blocks the final step of acid production. This effect is dose 
related and leads to inhibition of both basal and stimulated acid secretion 
irrespective of the stimulus. Animal studies indicate that after rapid disappearance 
from plasma, omeprazole can be found within the gastric mucosa for a day or 
more. 
Omeprazole is acid labile and thus rapidly degraded by gastric acid. Capsules are 
immediate‑release formulations that contain sodium bicarbonate which raises the 
gastric pH and thus protects omeprazole from acid degradation. 
 
Pharmacokinetics: 
Absorption 
In separate in vivo bioavailability studies, when omeprazole/sodium bicarbonate 
Oral Suspension and Capsules are administered on an empty stomach 1 hour prior 
to a meal, the absorption of omeprazole is rapid, with mean peak plasma levels (% 
CV) of omeprazole being 1954 ng/mL (33%) and 1526 ng/mL (49%), respectively, 
and time to peak of approximately 30 minutes (range 10-90 min) after a single-
dose 
or 
repeated-dose 
administration. 
Absolute 
bioavailability 
of 
omeprazole/sodium bicarbonate Powder for Oral Suspension (compared to I.V. 
administration) is about 30-40% at doses of 20 – 40 mg, due in large part to pre-
systemic metabolism. 
When omeprazole/sodium bicarbonate Oral Suspension 40 mg/1680 mg was 
administered in a two-dose loading regimen, the omeprazole AUC (0-inf) 
(ng⋅hr/mL) was 1665 after Dose 1 and 3356 after Dose 2, while Tmax was 
approximately 30 minutes for both Dose 1 and Dose 2. Following single or 
repeated once daily dosing, peak plasma concentrations of omeprazole are 
approximately proportional from 20 to 40 mg doses, but a greater than linear mean 
AUC (three-fold increase) is observed when doubling the dose to 40 mg. The 
bioavailability of omeprazole increases upon repeated administration. When 
omeprazole/sodium bicarbonate is administered 1 hour after a meal, the 
omeprazole AUC is reduced by approximately 24% relative to administration 1 
hour prior to a meal.  
 


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Distribution 
Omeprazole is bound to plasma proteins. Protein binding is approximately 95%.  
 
Metabolism  
Following single-dose oral administration of omeprazole, the majority of the dose 
(about 77%) is eliminated in urine as at least six metabolites. Two metabolites 
have been identified as hydroxyomeprazole and the corresponding carboxylic acid. 
The remainder of the dose was recoverable in feces. This implies a significant 
biliary excretion of the metabolites of omeprazole. Three metabolites have been 
identified in plasma – the sulfide and sulfone derivatives of omeprazole, and 
hydroxyomeprazole. These metabolites have very little or no antisecretory activity.  
Excretion  
Following single-dose oral administration of omeprazole, little if any, unchanged 
drug is excreted in urine. The mean plasma omeprazole half-life in healthy 
subjects is approximately 1 hour (range 0.4 to 3.2 hours) and the total body 
clearance is 500-600 mL/min.  
SMARTPILLTM  
The SmartPill™ motility testing system is an ingestible capsule that offers a 
convenient and radiation-free way to assess motility by measuring pressure, pH, 
and temperature throughout the entire gastrointestinal (GI) tract for patients with 
unexplained GI symptoms, such as nausea, bloating, constipation, abdominal pain, 
and vomiting. As it moves through the GI tract, it wirelessly and continuously 
transmits data to a recorder worn on the belt or lanyard for up to 5 days or when it 
passes with a regular bowel movement.  
In the current study, the SmartPill™ will be used to measure subjects’ gastric pH 
conditions (over a period of 8 hours) under which the nifedipine and co-
administered nifedipine and omeprazole/sodium bicarbonate is released in vivo. 
This direct measurement of gastric pH will confirm a positive pharmacologic 
response (i.e. increased gastric pH) to proton pump inhibitors in healthy volunteers 
and determine the extent of gastric pH elevation as a result of 7-day multiple-dose 
of omeprazole/sodium bicarbonate capsules. In contrast with conventional gastric 
or nasogastric intubation methods, subjects should feel significantly less pain or 
discomfort when swallowing the capsule or while the capsule moves through the 
GI tract. It is naturally passed during a bowel movement, usually within a few 
days. 
SmartPill™ uses MotiliGI® software to display and analyze the data, providing test 
results in both graphical and report formats. SmartPill™ provides valuable 
diagnostic information including: 
• 
Gastric emptying time 


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• 
Small bowel transit time 
• 
Colonic transit time 
• 
Whole gut transit time 
• 
Pressure patterns from the antrum and duodenum 
4.0 
STUDY OBJECTIVE  
4.1 
Study Objective 
The objective of this study is to compare pharmacokinetics of nifedipine from both 
generic Nifedipine oral extended-release tablets, 60 mg and reference listed drug 
PROCARDIA XL (nifedipine) extended-release tablets, 60 mg when co-
administered 
with 
or 
without 
proton 
pump 
inhibitor 
(PPI)/antacid, 
omeprazole/sodium bicarbonate capsules 40 mg/1100 mg capsules in healthy 
males and non-pregnant females under fasting conditions.  
The two one-sided t-tests procedure Schuirmann proposed will be used to construct 
the 90% confidence interval at the alpha=0.05 level of significance for the ratio of 
geometric mean of PK parameters AUCt, AUCinf and Cmax. The limits of the 
90% confidence intervals are 80.00%-125.00% which will be used for the 
statistical hypothesis testing. Therefore, it consists of decomposing the interval 
hypotheses into two sets of one-sided hypotheses.  
 
For the drug interaction for both test and reference products, the calculated 90% 
confidence interval (CI) for the ratios of geometric means for AUCt, AUCinf and 
Cmax will be used for the following two PK comparisons to assess if the statistical 
significance of interaction effect between the product type effect (test or reference) 
and the effect of co-administrating PPI/antacid is or not.  
• Test with PPI (Study Arm C)/Test without PPI (Study Arm A)        
• Reference with PPI (Study Arm D)/Reference without PPI (Study Arm B) 
Hypothesis 1.1: The hypotheses for testing of the interaction effect between Test 
product and the effect of co-administrating PPI/antacid are as follows: 
• The null hypothesis (H01): there is statistical significance of the interaction 
effect if the 90% CI of the ratios of geometric means for AUCt, AUCinf and 
Cmax is less than 80.00%.  
• The alternative hypothesis (H11): there is no statistical significance of the 
interaction effect if the 90% CI of the ratios of geometric means for AUCt, 
AUCinf and Cmax is greater than or equal to 80.00%. 
• The null hypothesis (H02): there is statistical significance of the interaction 
effect if the 90% CI of the ratios of geometric means for AUCt, AUCinf and 
Cmax is greater than 125.00%. 


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• The alternative hypothesis (H12): there is no statistical significance of the 
interaction effect if the 90% CI of the ratios of geometric means for AUCt, 
AUCinf and Cmax is less than or equal to 125.00%. 
Hypothesis 1.2: The hypotheses for testing of the interaction effect between 
Reference product and the effect of co-administrating PPI/antacid are as follows: 
• The null hypothesis (H03): there is statistical significance of the interaction 
effect if the 90% CI of the ratios of geometric means for AUCt, AUCinf and 
Cmax is less than 80.00%. 
• The alternative hypothesis (H13): there is no statistical significance of the 
interaction effect if the 90% CI of the ratios of geometric means for AUCt, 
AUCinf and Cmax is greater than or equal to 80.00%. 
• The null hypothesis (H04): there is statistical significance of the interaction 
effect if the 90% CI of the ratios of geometric means for AUCt, AUCinf and 
Cmax is greater than 125.00%. 
• The alternative hypothesis (H14): there is no statistical significance of the 
interaction effect if the 90% CI of the ratios of geometric means for AUCt, 
AUCinf and Cmax is less than or equal to 125.00%. 
 
For the relative bioavailability between test and reference products under different 
conditions (with or without PPI), the calculated 90% confidence interval (CI) for 
the ratios of geometric means for AUCt, AUCinf and Cmax will be used for the 
following two PK comparisons to assess if the relative bioavailability is or not. 
• Test with PPI (Study Arm C)/Reference with PPI (Study Arm D)       
• Test without PPI (Study Arm A)/Reference without PPI (Study Arm B)  
Although the generic applicant has already confirmed the bioequivalence 
between Test and Reference in the absence of PPI, this study will confirm this 
result.  
Hypothesis 2.1: The hypotheses for the assessment of relative bioavailability for 
Test product with and without PPI are as follows: 
• The null hypothesis (H01): there is no comparable bioavailability if the 90% 
CI of the ratios of geometric means for AUCt, AUCinf and Cmax is less than 
80.00%. 
• The alternative hypothesis (H11): there is comparable bioavailability if the 
90% CI of the ratios of geometric means for AUCt, AUCinf and Cmax is 
greater than or equal to 80.00%. 
• The null hypothesis (H02): there is no comparable bioavailability if the 90% 
CI of the ratios of geometric means for AUCt, AUCinf and Cmax is greater 
than 125.00%. 


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• The alternative hypothesis (H12): there is comparable bioavailability if the 
90% CI of the ratios of geometric means for AUCt, AUCinf and Cmax is less 
than or equal to 125.00%. 
Hypothesis 2.2: The hypotheses for the assessment of relative bioavailability for 
Reference product with and without PPI are as follows: 
• The null hypothesis (H03): there is no comparable bioavailability if the 90% 
CI of the ratios of geometric means for AUCt, AUCinf and Cmax is less than 
80.00%. 
• The alternative hypothesis (H13): there is comparable bioavailability if the 
90% CI of the ratios of geometric means for AUCt, AUCinf and Cmax is 
greater than or equal to 80.00%. 
• The null hypothesis (H04): there is no comparable bioavailability if the 90% 
CI of the ratios of geometric means for AUCt, AUCinf and Cmax is greater 
than 125.00%. 
• The alternative hypothesis (H14): there is comparable bioavailability if the 
90% CI of the ratios of geometric means for AUCt, AUCinf and Cmax is less 
than or equal to 125.00%. 
 
 
 
 


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5.0 
STUDY DESIGN 
5.1 
Discussion of Study Design 
This will be a single-dose, randomized, open-label, four-way crossover, four-
period, four-sequence, single-center, drug-drug interaction (DDI) study of generic 
formulation of Nifedipine extended-release tablets, 60 mg and reference listed 
drug PROCARDIA XL extended-release tablets, 60 mg with or without co-
administration multiple-dose of PPI/antacid, omeprazole/sodium bicarbonate 
capsules 40 mg/1100 mg capsule under fasting conditions.  
The generic nifedipine ER tablets based on a matrix design are available at only 
two strengths (30 and 60 mg), and the higher dose of 60 mg was chosen for its 
sensitivity of PK metrics in bioequivalence studies as per FDA guidance 
(Guidance for Industry: Bioequivalence studies with pharmacokinetic endpoints 
for drugs submitted under an ANDA, Dec 2013). The safety concern of 
administrating 60-mg single-dose nifedipine is minimal, considering that the 
existing product-specific bioequivalence guidance recommends generic applicants 
to conduct fasting and fed single-dose crossover BE studies administering 90-mg 
nifedipine ER tablets in healthy volunteers. On the other hand, the higher dose of 
40mg/1100mg omeprazole/sodium bicarbonate capsules between the two strengths 
(20 or 40 mg omeprazole) was selected for a more significant gastric pH elevation. 
Administering 40 mg omeprazole daily for 7 consecutive days in healthy 
volunteers should be considered safe as shown in the past clinical studies [12, 19, 
20]. In addition, omeprazole/sodium bicarbonate at the lower strength (20 mg 
omeprazole) is an OTC product. 
The products will be studied using a crossover design with 65-66 healthy, non-
smoking male and non-pregnant female volunteers being administered an oral dose 
of 1 × 60 mg extended-release tablet with or without co-administration multiple-
dose of omeprazole / sodium bicarbonate, 1 x 40 mg/1100 mg once daily for 7 
consecutive days under fasting conditions (i.e. subjects are dosed every 24 hrs). 
There will be at least a 14-day washout after Nifedipine only dosing (Study arms A 
or B) and for Study arms C and D (e.g., omeprazole/sodium bicarbonate followed 
with Nifedipine), at least 14 days after the last dose with omeprazole/sodium 
bicarbonate until the next study arm dose. Blood samples will be collected at pre-
dose (0 hour) and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 20, 24, 36, and 48 hours 
after nifedipine dosing for Study arm A and B on Day 2 and on Day 7 for Study 
arm C and D in each study period. 


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5.2 
Study Duration and Confinement  
Study arm A and B: Subjects will be confined to the clinic from at least 10 hours 
prior (e.g., 5 pm Friday) to dosing (e.g., 8:00 am Saturday) until at least 48-hours 
post-dose of nifedipine, for a total of at least 58 hours in each study period.  
Study arm C and D: 
Subjects will be confined to clinic from at least 1 hour prior to dosing 
omeprazole/sodium bicarbonate capsules on Day 1 and Day 2 and then the subjects 
will be discharged 1 hour post-dose.  
Subjects will be returning to the clinic 1 hour prior to dosing on Day 3 and can 
check-in after dosing or may check-in the evening to be confined to the clinic until 
at least 48 hours post-dose (test and reference) nifedipine dosing on Day 7. Total 
confinement from Day 1 to Day 9 will be of at least 148 hours (approximately 6 
days) in each study period.  
This study will consist of four study periods with a washout period of at least 14 
days after Nifedipine only dosing (Study arms A or B) and for Study arms C and D 
(e.g., omeprazole/sodium bicarbonate followed with Nifedipine), at least 14 days 
after the last dose with omeprazole/sodium bicarbonate until the next study arm 
dose. The total anticipated duration of the clinical part of the study will be 
approximately 9 weeks (since signing the ICF by the first subject up to the last 
planned study procedure of the last subject).  
5.3 
Randomization and Blinding 
In this study, the assignment of study arm groups (randomization scheme) will be 
generated by a computer program designed and run in SAS® Version 9.4 
. 
This is an open-label study and subjects as well as clinic staff will not be blinded 
to the randomization. The bioanalytical laboratory will not have access to the 
randomization scheme until the bioanalytical analysis is complete. 
Subjects who meet the eligibility criteria will be randomly assigned equally into 
one of the following four sequence groups: 
 
 
Period 1 
Period 2 
Period 3 
Period 4 
Sequence 1 
A 
B 
C 
D 
Sequence 2 
B 
C 
D 
A 
Sequence 3 
C 
D 
A 
B 
Sequence 4 
D 
A 
B 
C 
 
Each subject is scheduled to receive four periods by the end of the study (See 
Appendix A). 


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Study arm A (Test): Nifedipine extended-release tablets 
 
 60 mg 
Study arm B (Reference): PROCARDIA XL extended-release tablets 
 
60 mg 
Study arm C (PPI/antacid + Test): omeprazole/sodium bicarbonate capsules, 40 
mg/1100 mg + Nifedipine extended-release tablets 
, 
, 60 mg. 
Study arm D (PPI/antacid + Reference): omeprazole/sodium bicarbonate capsules, 
40 mg/1100 mg + PROCARDIA XL extended-release tablets 
 60 mg. 
 
The trial will be performed as an open-label study as the pharmacokinetic profile 
should not be expected to be affected by having the knowledge of reference or 
generic nifedipine ER tablets was administered. Blinding of the subjects as well as 
clinic staff is not considered necessary. Only the bioanalytical laboratory staff will 
not have access to the randomization scheme until the bioanalytical analysis is 
complete. 
 
 


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6.0 
STUDY POPULATION 
A required number of healthy volunteers, male and non-pregnant female, aged 
between 18 and 55 years of age will be screened according to the inclusion and 
exclusion criteria listed in Sections 7.3 and 7.4 to be sure that about 65-66 are 
randomized. The volunteers will be selected at the participating clinical site. 
 
This study will be conducted in normal, healthy male and non-pregnant female 
volunteers, as intended for general population3.  No one racial group will exceed 
65% of total enrolled subjects. 
To assure subjects’ safety, eligibility will be assessed at the time of screening and 
upon entry into the clinic prior to first drug administration.   
 
 
 


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7.0 
SUBJECT SELECTION AND WITHDRAWAL/TERMINATION 
7.1 
Sample Size 
A sample size of 65-66 subjects (minimum of 52 subjects to complete the study) is 
estimated to attain at least 80% statistical power to demonstrate 2x2 crossover 
bioequivalence study with a margin of 80-125% between the Test and Reference 
products, assuming the mean Test to Reference difference is within 5% Type I 
error and the geometric mean ratio is 1.08, based on an estimated intra-subject 
variability of approximately 27%. Subjects who are dosed will not be replaced. 
 
The subjects will be dosed in two or more groups. 
7.2 
Inclusion Criteria 
Potential subjects meeting all of the following criteria may be included in the 
study: 
1. Healthy, males and non-pregnant (excluding nursing and lactating) female 
volunteers, 18 to 55 years of age, inclusive. 
2. Smoking status: Only non-tobacco/nicotine users (for at least 6 months 
prior to the clinical study) will be eligible to participate in this study. 
3. BMI that is within 18.5-35.0 kg/m², inclusive. 
4. Healthy, according to the medical history, ECG, vital signs, laboratory 
results and physical examination as determined by the PI/Sub-Investigator. 
5. Ability to comprehend and be informed of the nature of the study, as 
assessed by BPSI staff. Capable of giving written informed consent prior to 
receiving any study procedure. Must be able to communicate effectively 
with clinic staff. 
6. Ability to fast for at least 14 hours. 
7. Availability to volunteer for the entire study duration and willing to adhere 
to all protocol requirements. 
8. Female subjects must fulfill at least one of the following: 
• Be surgically sterile for a minimum of 6 months; 
• Post-menopausal for a minimum of 1 year; 
• Agree to avoid pregnancy and use medically acceptable method of 
contraception from at least 30 days prior to the study until 30 days 
after the study has ended (last study procedure). 


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Medically acceptable methods of contraception include contraceptives, 
intrauterine device, or double barrier method (condom with foam or vaginal 
spermicidal suppository, diaphragm with spermicide). Complete abstinence 
alone can be used as a method of contraception. 
7.3 
Exclusion Criteria 
Potential subjects meeting any of the following criteria will be excluded: 
1. Known history or presence of any clinically significant hepatic, 
renal/genitourinary, gastrointestinal (e.g., gastrointestinal obstruction, 
gastrointestinal ulcers), cardiovascular (e.g., severe obstructive coronary 
artery disease, myocardial infarction, angina, heart failure), cerebrovascular, 
pulmonary, endocrine, immunological, musculoskeletal, neurological, 
psychiatric, dermatological or hematological disease or condition unless 
determined as not clinically significant by the PI/Sub-Investigator. 
2. Clinically significant history or presence of any clinically significant 
gastrointestinal pathology (e.g. chronic diarrhea, inflammatory bowel 
disease), unresolved gastrointestinal symptoms (e.g. diarrhea, vomiting, 
swallowing disorder), or other conditions known to interfere with the 
absorption, distribution, metabolism or excretion of the drug experienced 
within 7 days prior to first dosing, as determined by the PI/Sub-
Investigator.  
3. QTc interval > 430 milliseconds for males and > 450 milliseconds for 
females, unless deemed otherwise by the PI/Sub-Investigator. 
4. Abnormal clinical laboratory values, unless values are deemed by the 
PI/Sub-Investigator as “Not Clinically Significant”. 
5. Hemoglobin values less than 11.5 g/dl. 
6. Abnormal vital signs (blood pressure [BP], heart rate [HR], respiratory rate 
[RR] and temperature) measurements, unless deemed otherwise by the 
PI/Sub-Investigator. 
7. Presence of any clinically significant illness within 30 days prior to first 
dosing, as determined by the PI/Sub-Investigator. 
8. Presence of any significant physical or organ abnormality as determined by 
the PI/Sub-Investigator. 
9. Individuals who have implanted or portable electro-mechanical medical 
device such as a cardiac pacemaker, defibrillator or infusion pump. 


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10. A positive test result for any of the following: HIV, Hepatitis B surface 
antigen, Hepatitis C, drugs of abuse (marijuana, amphetamines, 
barbiturates, cocaine, opiates, phencyclidine and benzodiazepines), alcohol 
test and cotinine. Positive pregnancy test for female subjects. 
11. Known history or presence of: 
• Alcohol abuse or dependence within one year prior to first study 
period; 
• Drug abuse or dependence; 
• Hypersensitivity 
or 
idiosyncratic 
reaction 
to 
nifedipine, 
omeprazole/sodium bicarbonate, its excipients, and/or related 
substances; 
• Hypotension; 
• Bartter’s syndrome; 
• Gastric bezoar; 
• Crohn’s disease or diverticulitis; 
• severe dysphagia to food or pills; 
• Food allergies and/or presence of any dietary restrictions; 
• Severe allergic reactions (e.g. anaphylactic reactions, angioedema). 
12. History of intolerance to and/or difficulty with blood sampling through 
venipuncture. 
13. Abnormal diet patterns (for any reason) during the four weeks preceding 
the study, including fasting, high protein diets, vegan, etc. 
14. Individuals who have donated, in the days prior to first study period: 
• 50-499 mL of blood in the previous 30 days; 
• 500 mL or more in the previous 56 days. 
15. Donation of plasma by plasmapheresis within 7 days prior to first study 
period. 
16. Individuals who have participated in another clinical trial or who received 
an investigational drug within 30 days prior to first study period.  
17. Use of any enzyme-modifying drugs and/or other products, including 
strong inhibitors of cytochrome P450 (CYP) enzymes (e.g. cimetidine, 
fluoxetine, 
quinidine, 
fluconazole, 
ketoconazole, 
voriconazole, 


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itraconazole, 
clarithromycin, 
erythromycin, 
nefazodone, 
atazanavir, 
saquinavir, indinavir, and nelfinavir) and strong inducers of CYP enzymes 
(e.g. barbiturates, carbamazepine, glucocorticoids, phenytoin, St. John´s 
Wort and rifampin) in the previous 30 days before first study period. 
18. Use of drugs such as, proton pump inhibitors, clopidogrel, tacrolimus, 
digoxin, cyclosporine, disulfiram, benzodiazepines, diazepam, warfarin, 
methotrexate, iron salts, erlotinib, and mycophenolate mofetil (MMF) in 
the previous 30 days before first study period, or individuals with vitamin 
B-12 deficiency (as long-term dosing (more than 3 years) of 
omeprazole/sodium bicarbonate may lead to vitamin B-12 deficiency) 
19. Individuals having undergone gastrointestinal (GI) surgery within 3 months 
prior to first study period, unless deemed otherwise by PI/Sub-Investigator. 
20. Use of any prescription medication within 14 days prior to first study 
period (except for contraceptives). 
21. Use of any over-the-counter medications (including oral multivitamins, 
herbal and/or dietary supplements and/or teas) within 14 days prior to first 
study period (except for spermicidal/barrier contraceptive products). 
22. Consumption of food or beverages containing grapefruit and grapefruit 
juice and/or pomelo within 10 days prior to first study period. 
23. Consumption of food or beverages containing caffeine/methylxanthines, 
poppy seeds and/or alcohol within 48 hours before dosing. 
24. Use of diuretics (drugs or food, see Appendix D) within 24 hours before 
dosing of SmartPillTM. 
25. Individuals having undergone any major surgery within 6 months prior to 
the start of the study, unless deemed otherwise by PI/Sub-Investigator. 
26. Difficulty with swallowing whole tablets or large capsules. 
27. Have had a tattoo or body piercing within 30 days prior to first study 
period and during the study. 
7.4 
Informed Consent Procedure 
The Investigator is responsible for ensuring that the informed consent is obtained 
before any protocol specific procedures are carried out.  The decision of a subject 
to participate in clinical research is voluntary and should be based on a clear 
understanding of what is involved.   


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Subjects must receive adequate oral and written information. The oral explanation 
to the participant should be performed by the Investigator or a designated person, 
and must cover all the elements specified in the informed consent form.   
The subject must be given every opportunity to clarify any points they do not 
understand and, if necessary, to ask for more information.  The subject must be 
given sufficient time to consider the provided information.  It should be 
emphasized that the subjects may withdraw their consent to participate at any time 
without loss of benefits to which they otherwise would be entitled. 
The subjects should be informed and agree that their names will not be disclosed 
outside the site. 
The Investigator or delegated member of the trial team and the subject should sign 
and date the Informed Consent Form to confirm that consent has been obtained.  
The participant should receive a copy of this document and the original should be 
filed in the subject binder.  In case of a screen failure, it will be filed separately in 
the designated binder.   
7.5 
Screening Procedures 
Subjects will review and sign the ICF prior to medical screening procedures. 
Screening procedures will be conducted within thirty (30) days prior to dosing in 
Period 1. Screening procedures can be performed on the day of check-in prior to 
conducting check-in procedures. The physician (Principal Investigator (PI) or Sub-
Investigator) will review all screening results/data to assess eligibility of each 
potential subject. 
The Screening procedures will include (but is not limited to): demographic data, 
medical and medication histories, physical examinations, body measurements, 
vital signs (seated blood pressure [BP], heart rate [HR], respiratory rate [RR] and 
temperature.), electrocardiogram (ECG), hematology, biochemistry, serology, 
urinalysis, urine screening for drugs of abuse and cotinine, alcohol test and serum 
pregnancy test (female subjects only). For a complete listing of all tests to be 
performed, please refer to Appendix B - Clinical Laboratory Assessment.  
7.6 
Study Restrictions 
If any subject does not comply with these restrictions, at any time prior to or 
during the study, continued participation will be re-assessed by the PI/Sub-
Investigator, BPSI PK Scientist and/or the Sponsor. 
1. No food will be allowed from at least 8 hours before dosing until at least 6 
hours after dosing (Study arm A and B). Following the administration of 
omeprazole/sodium bicarbonate capsules on Day 6, subjects will be required 


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to fast for at least an 8-hour overnight fasting period before dosing of 
nifedipine together with omeprazole/sodium bicarbonate capsules on Day 7, 
and will continue to fast for at least 6 hours after dosing (Study arm C and D). 
Except for water given with study medication (nifedipine, omeprazole/sodium 
bicarbonate, SmartPillTM), no fluid will be allowed from 8 hours before 
dosing until 6 hours post-dose. Water will be allowed up to ½ cup (4 fl. oz.) 
during the six (6) hours post-dose and then water will be allowed/provided ad 
libitum at all other times. 
2. For Study arm C and D, no food will be allowed from at least 8 hours before 
dosing of omeprazole/sodium bicarbonate capsules from Day 1 to Day 6 until 
at least 1 hour after dosing. Except for water given with study medication, no 
fluid will be allowed from 1 hour before dosing and 1 hour post-dose. Water 
will be allowed up to ½ cup (4 fl. oz.) during the six (6) hours post-dose and 
then water will be allowed/provided ad libitum at all other times. 
3. Subjects will be required to abstain from smoking or use of tobacco products 
from 6 months prior to the first study period and for the entire duration of the 
study based on self-reporting and the cotinine test. 
4. Use of any enzyme-modifying drugs and/or other products, including strong 
inhibitors of cytochrome P450 (CYP) enzymes (e.g., cimetidine, fluoxetine, 
quinidine, 
fluconazole, 
itraconazole, 
clarithromycin, 
erythromycin, 
nefazodone, saquinavir, indinavir, and nelfinavir) and strong inducers of CYP 
enzymes (e.g., barbiturates, carbamazepine, glucocorticoids, phenytoin, St. 
John´s Wort and rifampicin) within 30 days prior to first study period until 
the last blood draw in the final study period. 
5. Use of drugs such as, proton pump inhibitors, clopidogrel, tacrolimus, 
digoxin, cyclosporine, disulfiram, benzodiazepines, diazepam, warfarin 
methotrexate, iron salts, antibiotics containing ampicillin, erlotinib, and 
mycophenolate mofetil (MMF) in the previous 30 days before first study 
period until the last blood draw in the final study period. 
6. Any concomitant medication [prescription medications (e.g., prescription 
pills, topical systemic creams, inhalants, sprays [except for contraceptives]) 
or over-the-counter (e.g., acetaminophen, Ricola, oral multivitamins) (except 
for spermicidal/barrier contraceptive products)], any herbal and/or dietary 
supplements will not be permitted for 14 days prior to first study drug 
administration until the last blood draw in the final study period unless 
deemed otherwise by the PI/Sub-Investigator for treatment of any adverse 
events (AEs).  
Any use of concomitant medication or herbal/dietary supplement during the 
restriction period will be reported as soon as possible to the PI/Sub-


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Investigator, BPSI PK Scientist and/or the Sponsor. In each case, the decision 
whether to continue or discontinue the subject’s participation in the study will 
be made by the PI/Sub-Investigator and/or by the BPSI PK Scientist and/or 
by the Sponsor. 
7. The consumption of foods and/or beverages containing grapefruit and/or 
pomelo (e.g., grapefruit, grapefruit juice, grapefruit candies, pomelo, etc.) 
will be prohibited for 10 days prior to first study period until the last blood 
draw in the final study period. 
8. The consumption of alcohol of any kind (e.g., wine, beer, liquor, cocktails), 
products containing caffeine/methylxanthines [e.g., coffee, tea, chocolate, 
caffeine-containing soft drinks (e.g., Coke, Pepsi, Red Bull)] and poppy seeds 
containing products (poppy seed cake, cookies, bagels) will be prohibited for 
48 hours prior to study period until after the last blood draw in each study 
period. 
9. Use of diuretics (drugs or food, see Appendix D) will be prohibited for 24 
hours prior to SmartPillTM administration until after the last blood draw in 
each study period. 
10. Physical activity: For the SmartPillTM administration (Study arm A and B on 
Day 2) (Study arm C and D on Day 7), subjects will remain awake and seated 
in an upright position for the first 4 hours following SmartPillTM 
administration where possible. Subjects are allowed to rise under supervision 
only for brief periods of time during the first 4 hours post-dose to assure 
subjects’ safety and to use the washroom, after which they will be allowed to 
ambulate freely within the clinic. However, if a medical event (i.e. AE) 
occurs, subjects may be placed in an appropriate position at any time. 
Subjects will be required to abstain from strenuous activities for the duration 
of the study period(s).  
11. For Study arm A and B on Day 2 and for Study arm C and D on Day 7, for 1 
hour after each nifedipine administration, subject visits to the washroom will 
be monitored and recorded by clinic staff. Subjects will be restricted from 
flushing the toilet to allow staff to inspect the content during this time. 
7.7 
Withdrawal/Termination 
A subject is free to withdraw from participation in the study at any time, for any 
reason. An Investigator may terminate a study subject’s participation in the study 
if: 
• Any clinical adverse event (AE), laboratory abnormality, or other medical 
condition or situation occurs such that continued participation in the study 
would not be in the best interest of the subject. 


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• The subject meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation. 
The cause, date and time of withdrawal or termination will be documented in the 
source documents and in the final study report. If a subject’s participation is 
terminated prematurely, the cause for the early termination date and time of the 
termination will be documented on the source documents and in the final study 
report. 
Subjects experiencing emesis or diarrhea after dosing will be evaluated on a case-
by-case basis by the PI/Sub-Investigator (to assess subject safety) and the BPSI 
Pharmacokinetic Scientist (for assessment of impact on PK) and the Sponsor and a 
decision on their continued participation will be made. All decisions will be made 
prior to the bioanalytical laboratory commencing bioanalysis. 
Withdrawn and dismissed subjects are not required to adhere to the study specific 
procedures (e.g., study restrictions). If withdrawn or dismissed following 
administration of any drug product in the study, these subjects will be asked to 
adhere to the study restrictions in regards to the safety, prescription medication, 
over-the-counter medication, dietary and/or herbal supplements and/or teas for the 
expected duration of the restriction relevant to the study period the subject 
withdrew or was dismissed from (where that period becomes the subject’s last 
study period).  
This study may be suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study 
suspension or termination, will be provided by the suspending or terminating party 
to the investigator, sponsor and regulatory authorities. If the study is prematurely 
terminated or suspended, the principal investigator will promptly inform the IRB 
and will provide the reason(s) for the termination or suspension.  
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to subjects. 
• Insufficient adherence to protocol requirements. 
• Data that are not sufficiently complete and/or evaluable.  
• Determination of futility. 
Subjects whose participation in the study is discontinued (for any reason) will not 
be replaced. If a subject withdraws or is dismissed from the study, a post-study 
symptom-directed physical exam with the possibility for a full physical exam if 
deemed necessary by the PI/Sub-Investigator will be conducted and post-study 
testing will be completed, where possible.  
 
 


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8.0 
STUDY PROCEDURES 
8.1 
Study Period Check-in Procedures 
At check-in for Period 1, subjects will review the study specific ICF and document 
their consent by signing the ICF. At check-in for each study period, subjects will 
be questioned about whether they have complied with the study restrictions. 
If drug therapy other than that specified in the protocol was used, a decision to 
continue or discontinue the subject’s participation will be made by the PI/Sub-
Investigator and/or by the BPSI PK Scientist and/or by the Sponsor. 
Subjects will be required to provide blood and urine samples for laboratory testing 
(hematology, serum biochemistry and urinalysis) at check-in for each study period. 
For Study arm C and D blood samples will be taken on Day 3 check-in. 
Urine tests for drugs of abuse and cotinine and an alcohol test will be performed 
on all subjects at each study period check-in. In addition, urine hCG testing will be 
performed on all female subjects at each study period check-in. 
Clinical staff reserves the right to conduct random testing (urine drugs of abuse, 
cotinine, urine hCG [females only], or alcohol) on any subject at any time during 
the study to ensure subject compliance and/or safety. Any subjects with a positive 
test for urine drugs of abuse, cotinine, alcohol or urine hCG (females only) will be 
withdrawn immediately from the study. 
8.2 
Food and Fluid Intake 
SmartPillTM Administration, Study arm A and Study arm B 
Following at least an 8-hour overnight fasting period, subjects will be dosed with 
nifedipine ER tablets and will be required to continue to fast for at least 6 hours 
after dosing. 
Following the fasting period of at least 6-hours after dosing, subjects will be given 
standardized meals and caffeine/methylxanthine-free beverages at scheduled times. 
In this study, meals will be served at approximately 6.5, 10.5, 14.0, 24.5, 28.5, 
33.5, and 37.5 hours after dosing. Meals and beverages during confinement will be 
identical for all study periods. 
Except for water given with study medication, no fluid will be allowed from 8 
hours before dosing until 6 hours post-dose. Water will be allowed up to ½ cup (4 
fl. oz.) during the six (6) hours post-dose and then water will be allowed/provided 
ad libitum at all other times. 
 
 
 


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Study arm C and Study arm D 
No food will be allowed from at least 8 hours before dosing of omeprazole/sodium 
bicarbonate capsules from Day 1 to Day 6 until at least 1 hour after dosing. 
Following the administration of omeprazole/sodium bicarbonate capsules on Day 
6, subjects will be required to fast for at least an 8-hour overnight fasting period 
before dosing of nifedipine together with omeprazole/sodium bicarbonate capsules 
on Day 7, and will continue to fast for at least 6 hours after dosing. 
Subjects will be given standardized meals and caffeine/methylxanthine-free 
beverages at scheduled times during their confinement. In this study, meals will be 
served at approximately 4.5, 9.5, 13.5, 24.5, 28.5, 33.5, 37.5, 48.5, 52.5, 57.5, 
61.5, 72.5, 76.5, 81.5, and 85.5 hours after capsules dosing on Day 3. Following 
the fasting period of at least 6-hours after dosing of nifedipine together with 
omeprazole/sodium bicarbonate capsules on Day 7, subjects will be given 
standardized meals and caffeine/methylxanthine-free beverages at approximately 
6.5, 10.5, 14.0, 24.5, 28.5, 33.5, and 37.5 hours after dosing. Meals and beverages 
during confinement will be identical between each study period. 
On dosing Day 1 to Day 6, except for water given with study medication, no fluid 
will be allowed from 1 hour before dosing and 1 hour post-dose. Water will be 
allowed/provided ad libitum at all other times. On Day 7, except for water given 
with study medication, no fluid will be allowed from 8 hours before dosing until 6 
hours post-dose. Water will be allowed up to ½ cup (4 fl. oz.) during the six (6) 
hours post-dose and then water will be allowed/provided ad libitum at all other 
times. 
8.3 
Dosing 
Study arm A and Study arm B 
Subjects will take their assigned formulation of nifedipine with 8 fl. oz. of ambient 
temperature water at their scheduled time point after a fast of at least 8-hours. 
 
Study arm C and Study arm D 
Subjects will take omeprazole/sodium bicarbonate capsules from Day 1 to Day 6 
after a fast of at least 8 hours with 8 fl. oz. of ambient temperature water at their 
scheduled time point.  
Also, subjects will take their assigned formulation of nifedipine together with 
omeprazole/sodium bicarbonate capsules on Day 7 after a fast of at least 8-hours 
with 8 fl. oz. of ambient temperature water at their scheduled time point. 
Subjects will take their Day 1 to Day 2 doses of omeprazole/sodium bicarbonate 
capsules at the clinic and will be released 1 hour post-dose. 


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SmartPillTM Administration 
Subjects will take SmartPillTM with 8 fl. oz. of water approximately 30 minutes 
prior to nifedipine (Study arm A and B) dosing and on Day 7 before 
omeprazole/sodium bicarbonate capsules and nifedipine dosing (Study arm C and 
D) to monitor the gastric pH. If subjects cannot swallow SmartPill™ with 8 fl. oz. 
of water, a maximum of 16 fl. oz. of additional water will be given to the subjects 
by increments of 4 fl. oz. (i.e. no more than 24 fl. oz. water in total). The total 
amount of water consumption will be recorded.  
 
Immediately after ingesting a SmartPill™ capsule, subjects are fitted with the 
wireless Data Recorder to wear on a belt or lanyard until the SmartPill™ capsule 
passes with a regular bowel movement. The participant will wear the Data 
Recorder at all time between SmartPill™ dosing and the last pharmacokinetic 
sampling (i.e., 48 hrs after administering nifedipine ER tablets) in each of the 
Periods, except while bathing or sleeping. The recorder should be removed while 
bathing and placed close by where it will not get wet. While sleeping, the 
participant will be instructed to place the data recorder under the pillow or on a 
nightstand by the bed. The SmartPill™ is expected to pass within 5 days of 
ingestion, and participants will be asked to return the Data Recorder before being 
discharged.  
 
The procedure of dosing and instructions on SmartPillTM will be described in the 
study directive. 
 
For all periods (Study arms A, B, C, and D), subjects will be instructed not to 
touch, chew, bite or break the drug products (nifedipine, omeprazole/sodium 
bicarbonate, SmartPills). If a subject chews, bites or breaks any of the drug 
products, that subject will be removed from the study. If the subject touches 
nifedipine or omeprazole/sodium bicarbonate, a replacement dose will be 
administered. Subjects must consume the drug products and finish the water 
provided within a few minutes, and the actual time will be recorded. 
A hand and mouth check will be conducted by clinic staff immediately following 
dosing. 
8.4 
Gastric pH  
The gastric pH will be monitored through SmartPillTM Technology. The pH will be 
measured at 0, 1, 2, 3, 4, 5, 6, 7, and 8 hours in each study period. The pH will be 
monitored continuously for 24 hours post-dose. 


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8.5 
Safety Monitoring 
In the interest of the subject safety the following safety parameters will be 
conducted on all subjects. 
8.5.1 Vital Signs 
Vital signs (BP, HR, RR and temperature) will be monitored for Study arm A and 
B and on Day 7 for Study arm C and D at pre-dose∗ and at 4, 12 and 24 hours after 
dosing in each study period and at pre-dose and at 1 hour after omeprazole/sodium 
bicarbonate capsules dosing from Day 1 to Day 6 in each study period for Study 
arm C and D. 
Pre-Dose and Post-Dose (all periods): 
Acceptable Range - systolic blood pressure between 95-140 mmHg, diastolic 
blood pressure between 55-90 mmHg, inclusive, and heart rate between 50-100 
bpm, inclusive. 
All subjects with vital signs outside of the acceptable range will have their vital 
signs repeated up to two times. If vitals are still outside of acceptable range, the 
PI/Sub-Investigator will determine appropriate course of action. 
 
Additional vital signs measurements will be taken if deemed necessary by the 
PI/Sub-Investigator. Blood draws at pre-determined time (+/- 5 min) will take 
precedence over vital signs measurements and other scheduled activities, should a 
timing conflict arise unless deemed necessary by the PI/Sub-Investigator.  
8.5.2 ECG 
ECG measurements are not required during this study unless deemed necessary by 
the PI/Sub-Investigator. 
8.5.3 Health Monitoring 
For Study arm A and B, the PI/Sub-Investigator will be present approximately 30 
minutes prior to SmartPillTM administration until at least 6 hours after the last 
subject is dosed with nifedipine.  
For Study arm C and D, from Day 1 to Day 6, the PI/Sub-Investigator will be 
present from approximately 30 minutes prior to omeprazole/sodium bicarbonate 
capsules until at least 1 hour after dosing in each study period. On Day 7, the 
PI/Sub-Investigator will be present from approximately 30 minutes prior to 
SmartPillTM administration until at least 6 hours after the last subject is dosed with 
nifedipine together with omeprazole/sodium bicarbonate capsules in each study 
period. 
                                                 
∗Within 12 hours prior to nifedipine administration. 


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The PI/Sub-Investigator will remain on-call throughout the duration of the study. 
Health monitoring will be conducted throughout the study or as needed. Adverse 
events will be monitored throughout the study. 
8.6 
Post-Study Tests 
Clinical laboratory tests (hematology, serum chemistry and urinalysis), as per 
Appendix B – Clinical Laboratory Assessment, will be repeated prior to discharge 
at the end of the study or after withdrawal/dismissal of a subject from the study.  
At exit, a symptom-directed physical exam with the possibility for a full physical 
exam if deemed necessary by the PI/Sub-Investigator including vital signs (BP, 
HR, Temperature and RR) will be conducted upon completion of the study or after 
withdrawal/dismissal of a subject from the study, where possible. 
8.7 
Sample Collection and Processing 
Blood will be obtained by direct venipuncture in the arm, or via an indwelling 
cannula. Subjects may use up to 1 indwelling cannula in each study period. If the 
cannula fails to work (i.e. it becomes clogged), the remaining samples will be 
taken by direct venipuncture. If catheter will be used, the residual volume in the 
dead space will be washed with saline each time before taking the sample. Subjects 
who use cannulas will have them removed: 
• After the last blood sample collection of confinement (not later than the 
24 hour time point); 
• If deemed necessary by clinic staff (for any reason); 
• If subject requests removal. 
Blood sample collection times will be recorded on the appropriate source 
documents and reported for each subject. 


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Number of Samples 
17 samples from 17 time points in each study 
period 
Total Volume of Blood (for all periods, 
including approximately 29 mL for pre- and 
post-study 
procedures 
and 
44 
mL 
for 
laboratory testing at check-in for each study 
period) 
Approximately 345 mL of blood 
Type of Vacutainer 
Pre-chilled K2EDTA Vacutainer®, 4 mL 
Blood Sampling Time Points 
Pre-dose (0 hour) and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 
10, 12, 16, 20, 24, 36 and 48 hours after 
nifedipine dosing in each study period. 
 
The blood samples collected from each subject will be processed and divided into 
2 aliquots. The blood sampling and processing will be performed as per the 
laboratory directive. 
8.8 
Sample Shipment 
One set of aliquots from all subjects will be shipped to the bioanalytical facility 
packed on dry ice. Once the initial set has been confirmed to have been received 
by the bioanalytical facility, the second set of aliquots will then be shipped.  
All shipments will be accompanied by an inventory list and delivered to the 
bioanalytical facility:  
 
 
 
 
 
Clinic personnel will notify the analytical laboratory prior to shipment by phone, 
fax or e-mail. The bioanalytical laboratory will notify BPSI by either e-mail or fax 
of confirmation of receipt of each aliquot. 
 
 
                                                 
 Pre-dose samples to be obtained within 2 hours prior to nifedipine administration. 


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9.0 
DRUG PRODUCTS 
9.1 
Drug Information  
Treatment Code 
A (Test) 
B (Reference) 
PPI/antacid  
Drug Name: 
Nifedipine 
PROCARDIA XL 
(nifedipine) 
omeprazole/sodium 
bicarbonate  
Strength: 
60 mg 
60 mg 
40 mg / 1100 mg  
Dosage Form: 
Extended-release 
tablets 
Extended-release 
tablets 
Capsules  
 
 
 
 
 
 
Dose: 
1 x 60 mg  
1 x 60 mg  
1 x 40 mg/1100 mg  
(once daily for 7 
consecutive days)  
 
Device Name: 
SmartPillTM  
Dosage Form: 
Capsule (26 mm x 13 mm) 
Manufactured by/for: 
Given Imaging 
Dose: 
1 capsule 30 minutes prior to SmartPillTM administration  
9.2 
Labeling, Maintenance, and Retention of Study Drugs (Nifedipine, 
omeprazole/sodium bicarbonate, SmartPillTM) 
Each investigational study drug will be labeled (in English) with a statement 
indicating that the drug is an investigational drug to be used only by a Qualified 
Investigator and will include but not limited to: Drug Name, Strength, Protocol 
Number, Sponsor’s Name and Address, the recommended storage conditions for 
the drug, Expiry/Retest Date (when available) and Lot/Batch Number. 
9.3 
Drug Inventory 
The Sponsor will supply sufficient quantities of the study formulation for the 
following: (1) completion of this study and (2) retention, as per applicable 
regulations. All drug supplies provided for this study will be stored in a secure area 
with restricted access, under controlled storage conditions described in the product 
package labelling, unless otherwise instructed per protocol. 
Records will be made of receipt and dispensing of nifedipine, omeprazole/sodium 
bicarbonate, and SmartPillTM supplied. It is the responsibility of the Sponsor to 


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ensure that all drug supplies provided for the study are manufactured under current 
Good Manufacturing Practices (cGMP) and are suitable for human use. 
9.4 
Disposition of Unused Study Drug (Nifedipine, omeprazole/sodium bicarbonate, 
SmartPillTM) 
Upon completion or termination of the study, all remaining study supplies will be 
retained according to applicable regulations. Once the retention period has elapsed, 
any remaining unused drug will be returned to the Sponsor in the original 
containers, or destroyed, as directed in writing by the Sponsor. 
 
 


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10.0 Potential Risks and Benefits  
10.1 Potential Risks 
Nifedipine 
The controlled and open trials with chronic dosing of nifedipine extended-release 
tablets in hypertension and angina patients were included in the evaluation of 
adverse experiences. It is noteworthy that these potential risks derived from 
clinical studies with chronic multiple-dose administration of nifedipine in subjects 
with cardiovascular (e.g. hypertension and angina) diseases. 
− The most common side effect reported with PROCARDIA XL was edema 
which was dose related and ranged in frequency from approximately 10% 
to about 30% at the highest dose studied (180 mg).  
− Other common adverse experiences reported in patients in a placebo-
controlled trials include, headache (15.8%), fatigue (5.9%), dizziness 
(4.1%), constipation (3.3%), and nausea (3.3%). 
− Other adverse reactions were reported sporadically with an incidence of 
1.0% or less.  
− Gastrointestinal obstruction resulting in hospitalization and surgery, 
including the need for bezoar removal, has occurred in association with 
nifedipine extended-release tablets, even in patients with no prior history of 
gastrointestinal disease. 
− Cases of tablet adherence to the gastrointestinal wall with ulceration have 
been reported, some requiring hospitalization and intervention. 
 
Other serious side effects reported with PROCARDIA XL (nifedipine) use 
were: 
− Myocardial infarction [heart attack] (4%) 
− Pulmonary edema [fluid accumulation in the lungs] (2%) 
− Ventricular arrhythmias [abnormal heartbeat] or conduction disturbances 
(0.5%) 
Omeprazole/sodium bicarbonate  
Each capsule contains omeprazole and sodium bicarbonate. Subjects will be asked 
to consult the Investigator if on a sodium restricted diet or have Bartter’s 
Syndrome (a rare kidney disorder) or at risk of developing congestive heart failure 
(CHF). 


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− Omeprazole/sodium bicarbonate may increase risk of getting severe 
diarrhea caused by an infection (Clostridium difficile) in intestines. 
− Multiple daily doses of proton pump inhibitor medicines for a long period 
of time (a year or longer) may  
• Have an increased risk of fractures of the hip, wrist or spine. 
• Increase the risk of inflammation to your stomach lining. 
− Possibility of vitamin B-12 deficiency if you have been on 
omeprazole/sodium bicarbonate for a long time (more than 3 years). 
− Low magnesium can happen in some people who take a proton pump 
inhibitor medicine for at least 3 months.  
− The most common side effect reported in patients include, headache, 
abdominal pain, nausea, vomiting and gas.  
− Additional adverse reactions that could be caused by sodium bicarbonate 
include metabolic alkalosis, seizures, and tetany. 
− Other adverse reactions were reported sporadically with an incidence of 
1.0% or less.  
 
A long term use of omeprazole/sodium bicarbonate may cause serious side effects 
including chronic inflammation of the stomach lining (Atrophic Gastritis).  
 
SmartPillTM 
The risk involved for subjects with the SmartPillTM Capsule Motility procedure is 
non-passage of the capsule through the intestinal tract. If there is delay in passage 
of the capsule, and the capsule is located in the stomach, a pro-motility drug could 
be administered to assist in emptying the capsule from the stomach. Alternatively, 
endoscopy could be performed in order to retrieve the capsule. If located in the 
colon, laxative therapy could be administered to facilitate capsule movement, or a 
colonoscopy could be performed in order to retrieve the capsule. This can occur 
when a subject has a blockage. Subjects must inform study staff or study doctor in 
such instance.  
Subjects must avoid MRI machines during the SmartPillTM Capsule Motility 
procedure until 7 days after the study. 
10.2 Potential Benefits 
While it may not provide direct benefit to subjects, the importance of the 
knowledge that may result from the study may enhance regulatory review on oral 
modified-release drug products in which the controlled release rate of drug delivery 
into the gastrointestinal lumen is a function of gastric pH.  
 


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11.0 SAFETY ASSESSMENT 
BioPharma Services USA Inc. has established SOPs in conformity with regulatory 
requirements to ensure the timely, accurate and complete reporting of safety 
information. 
PI/Sub-Investigators at BPSUSA are responsible for monitoring the safety and for 
providing appropriate medical care for subjects who have entered this trial (i.e., 
from the signing of ICF onwards). In addition, the PI/Sub-Investigator remains 
responsible for following-up all AEs.  
Each subject will be carefully questioned and/or examined by the PI/Sub-
Investigator or a medically qualified delegate (i.e., authorized by the Investigator, 
in a separate form, to record AEs) to obtain information regarding AEs. All AEs 
will be reported and documented as stated below 
11.1 Definitions 
Adverse Event (AE) – is any untoward medical occurrence in clinical trial subject 
who are administered with any of study drugs (nifedipine, omeprazole/sodium 
bicarbonate and SmartPillTM) and which does not necessarily have a causal 
relationship with this treatment. An adverse event can therefore be any unfavorable 
and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a study drug, whether or not considered 
related to the study drug. 
Adverse Drug Reaction (ADR) of study drug any of study drugs (nifedipine, 
omeprazole/sodium bicarbonate and SmartPillTM) is any untoward and unintended 
response to any of study drugs (nifedipine, omeprazole/sodium bicarbonate and 
SmartPillTM) related to any dose administered. 
Unexpected Adverse (Drug) Reaction – is an adverse reaction, the nature or 
severity of which is not consistent with the applicable product information (e.g., 
Prescribing Information for an authorized product). 
Serious Adverse Event (SAE) / Reaction – a serious adverse event (experience) 
or reaction is any untoward medical occurrence or effect that at any dose can: 
• result in death, 
• be life-threatening, 
• require hospitalization or prolongation of existing inpatient hospitalization, 
• result in persistent or significant disability or incapacity, 
• cause a congenital anomaly/birth defect, 


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• be considered to be other medically important event that may not be 
immediately life-threatening or result in death or hospitalization, but may 
jeopardize the participant or may require intervention to prevent one of the 
above-listed outcomes. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) – is all suspected 
adverse reactions related to PROCARDIA XL, generic nifedipine ER tablets  
omeprazole/sodium bicarbonate, and SmartPillTM, which can occur in the 
concerned trial, and that are both unexpected and serious. 
Unanticipated Problems – The unanticipated problems involving risks to subjects 
or others to include, in general, any incident, experience, or outcome that meets all 
of the following criteria: 
• unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) 
the characteristics of the subject population being studied; 
• related or possibly related to participation in the research (“possibly 
related” means there is a reasonable possibility that the incident, 
experience, or outcome may have been caused by the procedures involved 
in the research); and 
• suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
Subjects will be instructed to inform clinic personnel of any untoward medical 
symptoms and/or events that may arise during the course of the study. 
11.2 Characteristics of an Adverse Event 
11.2.1 Relationship to Study Drug 
The PI/Sub-Investigator will assess the relationship of all adverse reactions to any 
of study drugs (nifedipine, omeprazole/sodium bicarbonate and SmartPillTM), 
using the following scale: 
Probable 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to drug administration, unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and 
which follows a clinically reasonable response on withdrawal. 
Possible 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to drug administration, but which 


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could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or 
unclear. 
Unlikely 
A clinical event, including laboratory test abnormality, with a 
temporal relationship to drug administration which makes a 
causal relationship improbable, and which other drugs, chemicals 
or underlying disease provide plausible explanation. 
Unrelated 
This category is applicable to AEs which are judged to be clearly 
and incontrovertibly due to extraneous causes (diseases, 
environment, etc.) and do not meet the criteria for drug 
relationship listed for the above-mentioned conditions. 
 
All AEs will be evaluated by the PI/Sub-Investigator, who must approve the 
subject for subsequent dosing. 
Any AEs, whether serious or non-serious, will be monitored throughout the study 
and followed to resolution, when possible, regardless of whether the subject is still 
participating in the study. 
11.2.2 Expectedness of SAE 
The Study PI will be responsible for determining whether an SAE is expected or 
unexpected as per drug labels. An adverse event will be considered unexpected if 
the nature, severity, or frequency of the event is not consistent with the risk 
information previously described for the intervention.   
11.2.3 Severity Assessment 
The term "severe" describes the intensity (severity) of a specific event; the event 
itself, however, may be of relatively minor medical significance (such as severe 
headache). This means it is not the same as "serious", which is based on 
patient/event outcome or action criteria usually associated with events that pose a 
threat to a patient's life or functioning3. 
The severity of all AEs will be graded by the PI/Sub-Investigator or a medical 
qualified delegate according to the following definitions: 
Mild 
Adverse event resulting in discomfort, but not sufficient to cause 
interference in normal daily activities. 
Moderate 
Adverse event resulting in discomfort that is sufficient to cause 
interference in daily activities.  
Severe 
Adverse event resulting in discomfort causing an inability to carry 


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E
v
ery effort will be made to obtain an adequate evaluation of the severity. 
11.3 Adverse Events Reporting  
An Adverse Event as defined above generally includes any condition that was: 
1) Not present prior to administration of study drugs (nifedipine, 
omeprazole/sodium bicarbonate, SmartPillTM) but appeared after initiation 
of administration of study drug;  
2) Present 
prior 
to 
administration 
of 
study 
drugs 
(nifedipine, 
omeprazole/sodium 
bicarbonate, 
SmartPillTM) 
but 
worsened 
after 
administration of study drug; or   
3) Reported as part of the subject's history, and while not present immediately 
prior 
to 
initiating 
administration 
of 
study 
drugs 
(nifedipine, 
omeprazole/sodium 
bicarbonate, 
SmartPillTM), 
reappeared 
after 
administration of study drug.  
 
Planned hospital admissions and/or surgical operations/procedures for an illness or 
disease that existed before the investigational product was given or the participant 
was enrolled in a clinical trial are not to be considered AEs. 
 
Clinical laboratory data collected during the course of the study, which exceeds or 
drops below the acceptable limits for the participant population and which, based 
on baseline values, are considered by the Investigator to be clinically significant, 
will be reported as an AE. If clinically significant abnormal ECGs and/or 
laboratory values lead to, or are associated with clinical symptom(s), the diagnosis 
should be reported as an AE. 
If a participant discontinue from the study as a result of an AE, study site 
personnel must clearly document the circumstances and data leading to the reason 
for discontinuation. 
The investigator/designee is responsible for recording all AEs which have occurred 
during the study (including clinically important deviations of laboratory values 
from normal ranges), regardless of their relationship to the study drugs (nifedipine, 
omeprazole/sodium bicarbonate, SmartPillTM). This includes AEs spontaneously 
reported by the patient, observed by the investigator/designee or elicited by general 
questioning. All AEs will be determined as Serious or Non-Serious. Treatment of 
any AEs will be administered under the direction of a physician, either at BPSUSA 
or at a nearby hospital emergency room 
 
out normal daily activities.  


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All symptoms will be recorded by clinic staff and will be reviewed by the PI/Sub-
Investigator prior to any subsequent dosing. When appropriate, medical tests and 
examinations will be performed to document resolution of the event(s).  
All reported adverse events will be documented in the Clinical Report. 
The Investigator will monitor the subject's condition until recovery to a 
satisfactory state or stabilization. Thus, follow-up visits may be required even after 
the administration of the study drugs (nifedipine, omeprazole/sodium bicarbonate, 
SmartPillTM) has been discontinued.   
Serious Adverse Events  
All serious adverse events (SAEs), whether or not the event is deemed study drug-
related, will be reported to the Sponsor by telephone within 24 hours of BPSUSA 
being aware of SAE, followed by a written report within five business days.  
Reports of all SAEs must be communicated as soon as possible to the appropriate 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) and/or 
reported in accordance with local laws and regulations. 
Adverse events will be coded into the Preferred Term (PT), classified according to 
the Medical Dictionary for Regulatory Activities (MedDRA) with System Organ 
Classification (SOC) and reported with severity, duration, onset time and 
relationship 
to 
study 
drug 
(nifedipine, 
omeprazole/sodium 
bicarbonate, 
SmartPillTM) and action taken. 
The Principal Investigator will report to the RIHSC (FDA IRB) through the FDA 
Sponsor any unanticipated problems involving risk to human subjects or others 45 
CFR 46.103(b)(5)(i). Certain adverse events must be reported to the RIHSC within 
10 working days of the discovery of the event. The RIHSC defines these adverse 
events as including, but not limited to the following:  
− An adverse event that is not expected, i.e. not listed in the informed consent 
document or the investigator’s brochure;  
− An expected adverse event that occurs at a greater frequency or duration 
than expected;  
− Any adverse event that would require modification of the protocol and/or 
informed consent document 


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The following Sponsor personnel are to be contacted on the occurrence of a SAE: 
 
 
  
  
 
 
 
 
 
  
 
  
 
 
 
11.4 Procedures for Reporting Pregnancy 
A positive urine pregnancy test or any hCG level ≥ 5 IU/L for females of child-
bearing potential and ≥ 8 IU/L for post-menopausal females will be assessed as 
clinically significant and will result in the immediate dismissal of the subject from 
the study, unless deemed otherwise by the Investigator. The elevated hCG will be 
investigated as a potential pregnancy and will be followed up in the same manner 
as an AE.  A confirmatory hCG blood test will be required for any elevated values. 
If pregnancy is confirmed, any out of range hCG levels will not be considered an 
adverse event 
Once notified that pregnancy has occurred during the course of the study or within 
30 days of study completion, clinic personnel will report the pregnancy within 24 
hours of the confirmatory hCG blood test, to the PI/Sub-Investigator, the IRB, and 
appropriate Sponsor representative. A Pregnancy Notification Form will be 
completed as per BPSUSA internal Standard Operating Procedures and will be 
included alongside any pertinent information at the time of pregnancy reporting. 
The confirmed pregnancy will be followed to birth of the child or 
elective/spontaneous termination of the pregnancy. Follow up will occur at 
minimum once every three months (i.e. once per trimester) until the end of the 
pregnancy (birth, termination, etc.).  
Elective termination will not be considered an adverse event; however supporting 
documentation detailing the outcome of the procedure will be required. 


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Spontaneous termination of the pregnancy will be considered a Serious Adverse 
Event and will be followed up accordingly (as per Section 11.1).  
Although elevated hCG and pregnancy will not be considered adverse events, both 
will be treated as AEs. As such, for safety purposes, the samples collected from 
any subject who has elevated hCG levels or is confirmed to be pregnant will be 
analyzed accordingly. Furthermore, the results will not be included in the 
pharmacokinetic and statistical analysis, but rather will be presented separately.  
 
 
 


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12.0 BIOANALYTICAL ANALYSIS 
12.1 Analytical Procedures 
Data management, quality review and reporting of study data pertaining to 
laboratory analysis of study data will be the responsibility of the bioanalytical 
facility.  
12.1.1 Samples to be assayed 
Samples from subjects fulfilling at least one of the following criteria will be 
analyzed for drug concentration: 
1. Subjects who complete at least two study periods. 
2. Subjects who have missed samples that have been pre-determined prior to 
the start of bioanalytical analysis to not significantly impact the overall 
outcome of the study, as per BPSI PK Scientist and/or Sponsor 
recommendation. 
3. Subjects who do not complete the study due to AE(s). 
The samples from subjects who were dismissed due to non-compliance will not be 
analyzed. 
12.1.2 Analyte(s) in Biological Matrix 
Plasma samples will be assayed for nifedipine using a validated analytical method 
according to the principles of Good Laboratory Practice.  
 
 


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13.0 PHARMACOKINETIC AND STATISTICAL ANALYSIS 
13.1 Pharmacokinetic Analysis Data Set 
The data from the following subjects meeting one of the criteria will be included in 
the final PK and statistical analysis: 
1. Subjects who complete at least two study periods with both test and 
reference administered alone; or two study periods with the same product 
administered with and without PPI. 
2. Subjects who have missed samples that have been pre-determined prior to 
the start of bioanalytical analysis to not significantly impact the overall 
outcome of the study. 
Data from subjects who were dismissed or withdrew due to AE(s) will not be 
included in the PK and statistical analysis. The data for these subjects will be 
presented separately. 
 
Any decision for excluding data from the final data set will be provided with a 
detailed explanation and will be properly recorded and dated. 
13.2 Pharmacodynamic (PD) Analysis Data Set 
The data from the following subjects meeting one of the criteria will be included in 
the final PD and statistical analysis: 
Subjects who were dosed with SmartPillTM and have collected Gastric pH samples 
up to 4 hours’ time point in any given period.  
Any decision for excluding data from the final pharmacokinetic and 
pharmacodynamics data set will be provided with a detailed explanation and will 
be properly recorded and dated. 
13.3 Analysis of Data  
Pharmacokinetic, pharmacodynamic and statistical analysis will be performed on 
all data from all subjects in the final data set.  
The PK, PD and statistical analysis will be performed at BPSI using SAS® Version 
9.4. The PK, PD and/or statistical analyses outlined in this protocol may be altered 
with appropriate justification. 


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13.3.1 Pharmacokinetic Analysis 
Pharmacokinetic parameters will be calculated using non-compartmental analysis 
(NCA) method. The following PK parameters will be estimated (where possible) 
for nifedipine and included in the PK and statistical analysis for the subjects in the 
final data set: 
 
AUCinf: 
Area under the concentration-time curve from time zero to 
infinity, calculated as AUCt + Clast/λ, where Clast is the last 
measurable concentration. 
AUCt: 
Area under the concentration-time curve from time zero until the 
last measurable concentration or last sampling time t, whichever 
occurs first. AUCt is estimated using the trapezoidal method. 
Cmax: 
The maximal observed plasma concentration. 
T1/2: 
Terminal elimination half-life, estimated as ln(2)/λ. 
Tmax: 
Time when the maximal plasma concentration is observed. 
λ: 
Terminal elimination rate constant, estimated by linear 
regression analysis of the terminal portion of the ln-
concentration vs. time plot. 
 
If nifedipine concentration in the subject’s plasma before administering any 
nifedipine (i.e. pre-dose) in any given period is less than or equal to 5% of the Cmax 
value for that subject in the given period, then the subject’s data without any 
adjustments can be included in all PK measurements and calculations. If the pre-
dose value is greater than 5% of the Cmax, data from that subject may be dropped 
from the PK and statistical analysis based on the assessment of the 
pharmacokinetic scientist and sponsor. Data for subjects dropped due to higher 
than 5% of Cmax pre-dose concentrations will be included in a separate appendix in 
the final study report. 
During PK and statistical analyses, drug concentrations below the lower limit of 
quantitation (BLQ) of an assay will be considered as zero except when they occur 
between two non-BLQ concentrations where they will be considered as missing 
during PK calculations and estimations. 
Missed samples and non-reportable concentrations (e.g. quantity not sufficient) 
from the analytical laboratory will be treated in the pharmacokinetic analysis as if 
they have not been scheduled for collection. 
 


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The λ, T1/2, and AUCinf parameters will not be estimated for plasma concentration-
time profiles where the terminal linear phase is not clearly defined. 
For subjects with missing or non-reportable nifedipine concentrations for three or 
more of the last samples, only the Cmax and Tmax will be presented and included in 
the statistical analysis. Other PK parameters will not be reported. 
13.3.2 Pharmacodynamic Analysis 
Pharmacodynamic (PD) parameters of omeprazole/sodium bicarbonate (i.e. proton 
pump inhibitors) will be evaluated for all subjects with at least 4 hours pH 
measurement. The PD parameters include gastric pH, change of gastric pH from 
baseline. 
13.3.3 Statistical Analysis 
Descriptive statistics (min, max, median, mean, standard deviation and coefficient 
of variability) of all PK parameters will be provided for nifedipine for all study 
arm groups. 
ANOVA including sequence, subjects nested within sequence, period and study 
arm will be performed on the ln-transformed data for AUCt, AUCinf and Cmax and 
on the untransformed data for Tmax, λ and T1/2.  
Tmax will be analyzed using an additional non-parametric test (Wilcoxon test). 
The 90% CI of the ratios of geometric means for AUCt, AUCinf and Cmax will be 
calculated based on the LSMEANS and ESTIMATE of the ANOVA. 
 
The following PK comparisons will be carried out: 
− Test with PPI (Study arm C)/Test without PPI (Study arm A)        
− Reference with PPI (Study arm D)/Reference without PPI (Study arm B) 
− Test with PPI (Study arm C)/Reference with PPI (Study arm D)       
− Test without PPI (Study arm A)/Reference without PPI (Study arm B) 
 
For Pharmacodynamic Data: 
The descriptive statistics (min, max, median, mean, standard deviation and 
coefficient of variability) of the gastric pH and change of gastric pH will be 
calculated for both test and reference products. 
Analysis of Variance (ANOVA) for gastric pH and change of gastric pH from 
baseline will be carried out. 
The following gastric pH comparisons will be carried out: 
− 
Study arm C PPI (Day7) – Study arm A (Day2) 


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− 
Study arm D PPI (Day7) – Study arm B (Day2) 
− 
The comparison of the change between test and reference can be assessed 
 
Additional statistical and alternate tests will be performed if necessary. 
 
Missing data will not be included in the statistical analysis. There are potential two 
kinds of unbalanced designs for the analysis: (1) unequal number of subjects 
across groups, (2) missing cells: there are not available data for some subjects. The 
Type 3 method will be used for the calculation of sums of squares using SAS 
software. All the fixed effects will be tested using the Type 3 in the ANOVA to 
detect statistically significant differences (α=0.05) if applicable. A mixed effects 
ANOVA model for gastric pH with fixed factors of sequence, period, and study 
arm and random effects of subject will be fit. A compound-symmetric or other 
appropriate covariance structure will be used in the analysis. 
 
The null hypotheses for gastric pH comparisons for different study arms are: 
- 
For the comparison of Study Arm A and Study Arm C 
• H01: There is no difference between Study Arm A and Study Arm C 
• H11: There is a difference between Study Arm A and Study Arm C   
- 
For the comparison of Study Arm D and Study Arm B 
• H02: There is no difference between Study Arm D and Study Arm B 
• H12: There is a difference between Study Arm D and Study Arm B 
- 
For the comparison of Study Arm A and Study Arm B 
• H03: There is no difference for the change of median between Study Arm A 
and Study Arm B 
• H13: There is a difference for the change of median between Study Arm A 
and Study Arm B 
 
 
 


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14.0 ETHICAL CONSIDERATIONS / PROTECTION OF HUMAN SUBJECTS 
14.1 Basic Principles 
This research will be carried out in accordance with Good Clinical Practice (GCP) 
as set out by the International Conference on Harmonization (ICH), the basic 
principles defined in the U.S. Code of Federal Regulations (21 CFR Part 312), the 
Belmont Report, Directive 2001/20/EC (Europe), and the principles enunciated in 
the most recent version of the World Medical Association Declaration of Helsinki. 
14.2 Institutional Review Board 
Both Chesapeake IRB and FDA Research Involving Human Subjects Committee 
(RIHSC) will be the Institutional Review Board (IRB) for this study. This Protocol 
and the ICF will be reviewed and approved by the IRB prior to the initiation of the 
study. Termination / suspension of any prior approval / favorable opinion can be 
done by IEC/IRB. 
The board is constituted and operates in accordance with Division 5 of the Food 
and Drug Regulations, ICH Harmonized Tripartite Guideline (GCP Consolidated 
Guideline), and 21 CFR Parts 56 and 50. 
14.3 Informed Consent Form 
Subjects will sign the ICF prior to starting any screening procedures. Each subject 
will be provided with verbal and written information, in non-technical terms, 
which will describe the nature of the screening procedures as well as conduct of 
the study. Prior to signing the ICF, subjects will be allowed adequate time to 
consider the potential benefits and risks associated with their participation in the 
study. Signed and dated ICFs will be retained with the study records and a copy 
will be provided to the subject. 
14.4 Confidentiality 
The information in this study protocol is confidential. This document contains 
trade secrets and commercial information that is confidential and may not be 
disclosed to third parties (except to the IRB, FDA and/or relevant regulatory 
agencies). These restrictions will apply as well to all future communications if 
deemed privileged or confidential. 
Sponsor, study monitors, auditors, the IRB, FDA and applicable regulatory 
authorities will be granted direct access to the subject’s original medical records 
for verification of clinical trial procedure and/or data, without violating the 
confidentiality of the subject, to the extent permitted by applicable laws and 


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regulations and that, by signing a written informed consent form, the subject or the 
subjects legally acceptable representative is authorizing such access. 
All documentation collected by the Sponsor or by BPSI/BPSUSA Inc. will be kept 
confidential. The name and identity of the subjects will remain confidential. If 
documents containing the subjects’ names are photocopied, the name will be 
omitted from the photocopied version. 
All of the subject’s data obtained through data receiver will not be identified by 
name and the identity will remain confidential. The data obtained from the data 
receiver will be transferred to the computer that is password protected and have 
authorized access to the computer. 
14.5 Compensation for Participation 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.6 In Case of an Injury Related to this Research 
 
 
 
 
 
 
  
 
 


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15.0 ADMINISTRATIVE CONSIDERATIONS 
15.1 Revisions and/or Amendments to the Protocol 
Revisions and/or amendments to the protocol must be documented and approved 
by the Principal Investigator and Sponsor. If the revision/amendment will affect 
subject safety and/or study design, then the amendment will be re-submitted to the 
IRB for approval. Administrative changes (i.e. change of analytical facility, 
typographical errors, discrepancies, clarifications) will also be submitted to the 
IRB, but may not require approval. A copy of the IRB’s approval documents will 
be included in the final report. 
For revisions or amendments to the protocol that substantially alter the study 
design after initiation of the study, the Principal Investigator and Sponsor will 
decide whether a revised informed consent form will be needed for continued 
participation. 
It is the Sponsor’s responsibility to submit, or to assign responsibility to submit, all 
revisions and amendments to the appropriate regulatory authorities when 
necessary. If an amended or revised version of the ICF is introduced during the 
study, each subject’s further consent should be obtained. 
15.2 Investigator Responsibilities 
The Principal Investigator is responsible for ensuring that the clinical study is 
performed in accordance with the protocol, the current revision of the Declaration 
of Helsinki, ICH - GCP guidelines and applicable regulatory requirements. 
15.3 Study Completion/Termination 
BioPharma Services USA Inc. and/or the Sponsor reserve the right to terminate the 
study at any time, and for any reason. 
15.4 Sponsor Visits 
The Sponsor is encouraged to visit BioPharma Services USA Inc., if desired, and 
at their convenience. The PI and staff will provide, if requested, all source 
documents and/or other study-related documents. The PI will maintain regular 
written and telephone communication with the Sponsor. 
 
 


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16.0 DATA MANAGEMENT/RECORD KEEPING 
16.1 Source Data 
All data will be recorded in accordance with GCP to ensure accuracy, 
completeness, legibility, and timeliness of the data reported. 
 
All data will be recorded directly on the source documents and will be considered 
source data. The source documents will serve as the Case Report Forms. 
16.2 Quality of Data 
All source documents and laboratory reports will be Quality Control reviewed to 
ensure accuracy and completeness. Adverse events will be reviewed and assessed 
for severity and causality by the PI/Sub-Investigator. Specific processes of the 
study, its source documentation and any reports (if applicable) will be audited by 
the Quality Assurance (QA) unit of BPSI/BPSUSA. 
16.3 Retention of Documents 
All records and documents pertaining to the study will be retained by BioPharma 
Services USA Inc. for at least 5 years from the completion of the study, and will be 
available for inspection by the Sponsor and/or Regulatory Agencies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Page 66 of 74 
17.0 REFERENCES 
1. 
Wen H, Park K. Introduction and overview of oral controlled release formulation 
design. Oral Controlled Release Formulation Design and Drug Delivery: Theory to 
Practice. 2010:1-19. 
2. 
Shamblin SL. Controlled release using bilayer osmotic tablet technology: reducing 
theory to practice. Oral Controlled Release Formulation Design and Drug Delivery: 
Theory to Practice. 2010:129-53. 
3. 
Verma RK, Krishna DM, Garg S. Formulation aspects in the development of 
osmotically controlled oral drug delivery systems. Journal of Controlled Release. 
2002;79(1):7-27. 
4. 
Lin H-P, Sun D, Zhang X, Wen H. Physiologically Based Pharmacokinetic 
Modeling for Substitutability Analysis of Venlafaxine Hydrochloride Extended-
Release Formulations Using Different Release Mechanisms: Osmotic Pump Versus 
Openable Matrix. Journal of Pharmaceutical Sciences. 2016;105(10):3088-96. 
5. 
Garbacz G, Golke B, Wedemeyer R-S, Axell M, Söderlind E, Abrahamsson B, et 
al. Comparison of dissolution profiles obtained from nifedipine extended release 
once a day products using different dissolution test apparatuses. European Journal 
of Pharmaceutical Sciences. 2009;38(2):147-55. 
6. 
PROCARDIA XL® (nifedipine) Extended Release Tablets, Product Information, 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019684s029lbl.pdf, 
Date of Revision: Sep-01-2015. Sep-19-2016. 
7. 
Schug BS, Brendel E, Wolf D, Wonnemann M, Wargenau M, Blume HH. 
Formulation-dependent food effects demonstrated for nifedipine modified-release 
preparations marketed in the European Union. European journal of pharmaceutical 
sciences. 2002;15(3):279-85. 
8. 
Wonnemann M, Schug B, Anschütz M, Brendel E, De Nucci G, Blume H. 
Comparison of two marketed nifedipine modified-release formulations: an 
exploratory clinical food interaction study. Clinical therapeutics. 2008;30(1):48-58. 
9. 
Schug B, Brendel E, Chantraine E, Wolf D, Martin W, Schall R, et al. The effect of 
food on the pharmacokinetics of nifedipine in two slow release formulations: 
Pronounced lag‐time after a high fat breakfast. British journal of clinical 
pharmacology. 2002;53(6):582-8. 
10. 
Blume H, Donath F, Warnke A, Schug BS. Pharmacokinetic drug interaction 
profiles of proton pump inhibitors. Drug safety. 2006;29(9):769-84. 
11. 
Lahner E, Annibale B, Delle Fave G. Systematic review: impaired drug absorption 
related to the co‐administration of antisecretory therapy. Alimentary pharmacology 
& therapeutics. 2009;29(12):1219-29. 


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Protocol Version Date: August 3, 2017 
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Page 67 of 74 
12. 
Soons P, Van den Berg G, Danhof M, van Brummelen P, Jansen J, Lamers C, et al. 
Influence of single-and multiple-dose omeprazole treatment on nifedipine 
pharmacokinetics and effects in healthy subjects. European journal of clinical 
pharmacology. 1992;42(3):319-24. 
13. 
Nifedipine Extended-release tablets, USP Prescribing Information. Date of 
Revision May 2015. Sep-29-2016. 
14. 
Abrahamsson B, Alpsten M, Bake B, Jonsson UE, Eriksson-Lepkowska M, Larsson 
A. Drug absorption from nifedipine hydrophilic matrix extended-release (ER) 
tablet-comparison with an osmotic pump tablet and effect of food. Journal of 
controlled release. 1998;52(3):301-10. 
15. 
Guidance for Industry, 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. 
16. 
Prichard PJ, Yeomans ND, Mihaly GW, Jones DB, Buckle PJ, Smallwood RA, et 
al. Omeprazole: a study of its inhibition of gastric pH and oral pharmacokinetics 
after morning or evening dosage. Gastroenterology. 1985;88(1):64-9. 
17. 
Tolman KG, Sanders SW, Buchi KN, Karol MD, Jennings DE, Ringham GL. The 
effects of oral doses of lansoprazole and omeprazole on gastric pH. Journal of 
clinical gastroenterology. 1997;24(2):65-70. 
18. 
Omeprazole/sodium bicarbonate Capsules, Package Insert, Cipla USA Inc. Nov 
2016  
19. 
Gillen D, Wirz A, Neithercut W, Ardill J, McColl K. Helicobacter pylori infection 
potentiates the inhibition of gastric acid secretion by omeprazole. Gut. 
1999;44(4):468-75. 
20. 
Winston A, Back D, Fletcher C, Robinson L, Unsworth J, Tolowinska I, et al. 
Effect of omeprazole on the pharmacokinetics of saquinavir-500 mg formulation 
with ritonavir in healthy male and female volunteers. AidS. 2006;20(10):1401-6. 
 
 
 
 


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APPENDIX A – SCHEDULE OF EVENTS 
 
Screening 
Study arm A and B 
Study arm C and D 
Study Day 
-28 to 0 
1 
2 
3 
4 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Confinement 
 
 
X 
X 
X# 
 
 
X 
X 
X 
X 
X 
X 
X# 
Stay overnight 
 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
ICF 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Check-in 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Body weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sitting Vital Signs (BP, HR, 
PR and temperature) 
X 
X 
Xa 
Xb 
X 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xa 
Xb 
X 
Urine Drug Tests 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Alcohol Test 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Cotinine Test 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Pregnancy Test 
X* 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
Serum Chemistry 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
Urinalysis 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
Serology  
(HIV, Hepatitis B and C) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Compliance check 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
SmartPillTM Dosing 
 
 
Xd 
 
 
 
 
 
 
 
 
Xd 
 
 
Nifedipine ER Tablets 
Dosing 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Omeprazole/sodium 
bicarbonate Capsules 
Dosing 
 
 
 
 
 
Xe 
Xe 
Xe 
X 
X 
X 
X 
 
 
Gastric pH measurement 
 
 
Xf 
 
 
 
 
 
 
 
 
Xf 
 
 
PK Sampling 
 
 
Xg 
 
 
 
 
 
 
 
 
Xg 
 
 
Questioning subjects if use 
of any concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Meals 
 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Serum pregnancy test at screening and urine pregnancy test at each period check-in. 
# Study exit at 48 hours post-dose nifedipine 
a: 4 and 12 hours post-dose  
b: 24 hours post-dose 
c: 1 hour post-dose 
d: 30 minutes before nifedipine dosing 
e: Out-patient visit 1 hour prior to dosing until at least 1 hour post-dose 
f: 0, 1, 2, 3, 4, 5, 6, 7, and 8 hours after SmartPillTM administration 
g: Pre-dose (0 hour) and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 20, 24, 36, and 48 hours after nifedipine dosing 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 69 of 74 
An example of schedule events (note: the sequence of study arms A, B, C, and D may be 
in a random order). 
 
Study 
arm 
Day 
Overnight 
in clinic? 
Example time 
Items 
-28 to 0 
No 
Screening period 
A 
1 
Yes 
8:00 PM 
Arrive in the evening to check-in for check-in 
procedure 
2 
Yes 
(1) 7:00 AM 
(2) 7:30 AM 
(3) 7:30 AM  
(1) Administer SmartPill 
(2) Administer study drug generic nifedipine 
extended release tablets 
(3) Draw blood 
3 
Yes 
Throughout the day 
Draw blood 
4 
No 
7:30 AM 
After the last time point of blood draw, you will 
be released from the clinical site 
 
5 to 18 
No 
 
Washout period (break), at least 14 days 
B 
19 
Yes  
8:00 PM 
Arrive in the evening to check-in for check-in 
procedure 
20 
Yes 
(1) 7:00 AM 
(2) 7:30 AM 
(3) 7:30 AM  
(1) Administer SmartPill 
(2) Administer study drug brand-name 
nifedipine extended release tablets 
(3) Draw blood 
21 
Yes 
Throughout the day 
Draw blood 
22 
No 
 7:30 AM 
After the last time point of blood draw, you will 
be released from the clinical site 
 
23 to 36 
No 
 
Washout period (break), at least 14 days 
C 
37 
No 
(1) 6:30 AM 
(2) 7:30 AM 
(3) 8:30 AM 
(1) Arrive in the clinic 
(2) Omeprazole/sodium bicarbonate 
administration 
(3) Released from the clinic 
38 
No 
(1) 6:30 AM 
(2) 7:30 AM 
(3) 8:30 AM 
(1) Arrive in the clinic 
(2) Omeprazole/sodium bicarbonate 
administration 
(3) Released from the clinic 
39 
Yes 
(1) 6:30 AM 
(2) 7:30 AM 
(3) Afternoon 
(1) Arrive in the clinic to check-in 
(2) Omeprazole/sodium bicarbonate 
administration 
(3) Check-in procedure 
40 
Yes 
7:30 AM 
Omeprazole/sodium bicarbonate administration 
41 
Yes 
7:30 AM 
Omeprazole/sodium bicarbonate administration 
42 
Yes 
7:30 AM 
Omeprazole/sodium bicarbonate administration 
43 
Yes 
(1) 7:00 AM 
(2) 7:30 AM 
(3) 7:30 AM – 
(1) Administer SmartPill 
(2) Administer Omeprazole/sodium bicarbonate 
and study drug generic nifedipine extended-
release tablets 
(3) Draw blood 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 70 of 74 
44 
Yes 
Throughout the day 
Draw blood 
45 
No 
7:30 AM 
After the last time point of blood draw, you will 
be released from the clinical site 
 
46 to 59 
No 
 
Washout period (break), at least 14 days 
D 
60 
No 
(1) 6:30 AM 
(2) 7:30 AM 
(3) 8:30 AM 
(1) Arrive in the clinic 
(2) Omeprazole/sodium bicarbonate 
administration 
(3) Released from the clinic 
61 
No 
(1) 6:30 AM 
(2) 7:30 AM 
(3) 8:30 AM 
(1) Arrive in the clinic 
(2) Omeprazole/sodium bicarbonate 
administration 
(3) Released from the clinic 
62 
Yes 
(1) 7:00 AM 
(2) 7:30 AM 
(3) Afternoon 
(1) Arrive in the morning to check-in 
(2) Omeprazole/sodium bicarbonate 
administration 
(3) Check-in procedure 
63 
Yes 
7:30 AM 
Omeprazole/sodium bicarbonate administration 
64 
Yes 
7:30 AM 
Omeprazole/sodium bicarbonate administration 
65 
Yes 
7:30 AM 
Omeprazole/sodium bicarbonate administration 
66 
Yes 
(1) 7:00 AM 
(2) 7:30 AM 
(3) 7:30 AM – 
(1) Administer SmartPill 
(2) Administer Omeprazole/sodium bicarbonate 
and study drug brand-name nifedipine 
extended-release tablets 
(3) Draw blood 
67 
Yes 
Throughout the day 
Draw blood 
68 
No 
7:30 AM 
After the last time point of blood draw, you will 
be released from the clinical site 
 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 71 of 74 
APPENDIX B – CLINICAL LABORATORY ASSESSMENT 
TYPE OF 
TEST 
COMPONENTS 
Hematology 
• Hemoglobin 
• Hematocrit 
• RBC 
• Platelet count  
• WBC and differential  
• Peripheral blood smear 
Serum 
Chemistry 
• Glucose 
• Calcium 
• Sodium 
• Chloride 
• Albumin 
• Protein 
• Bilirubin 
• Lactate 
Dehydrogenase 
• AST 
• ALT 
• Potassium 
• Alkaline 
Phosphatase 
• Urea 
• Uric Acid 
• Creatinine 
• Creatine Kinase 
Urinalysis 
• Bilirubin 
• Blood  
• Glucose 
• pH  
• Ketones 
• Leukocytes 
• Nitrites 
• Protein 
• Specific Gravity 
• UBG  
Additional 
Tests 
Serology (HIV, Hepatitis B surface 
antigen, Hepatitis C antibody) 
Alcohol test 
Urine Cotinine 
Serum hCG (only females, at Screening) 
Urine hCG (only females, at each period 
check-in) 
Urine Tests 
for Drugs of 
Abuse  
Marijuana, Amphetamines, Phencyclidine, Barbiturates, Cocaine, Opiates, 
Benzodiazepines 
 
 
 
 
 
                                                 
 Only if deemed necessary by PI/Sub-Investigator 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 72 of 74 
APPENDIX C – LIST OF COMMON ABBREVIATIONS 
AE: 
Adverse Event 
kg/m2: 
Kilogram/Meter Squared 
ALT: 
Alanine Aminotransferase 
LC/MS/MS: 
Liquid Chromatography/Mass Spectrometry/ 
Mass Spectrometry 
ANDA: 
Abbreviated New Drug Application 
LLOQ: 
Lower Limit of Quantitation 
ANOVA 
Analysis of Variance 
LSMEANS: 
Least Square Means 
AST: 
Aspartate Aminotransferase 
MedDRA: 
Medical Dictionary for Regulatory Activities 
AUCt: 
Area under the concentration-time curve 
from time zero until the last measurable 
concentration or last sampling time t, 
whichever occurs first. AUCt is 
estimated using the trapezoidal method 
mg: 
Milligram 
AUCinf: 
Area under the concentration-time curve 
from time zero to infinity, calculated as 
AUCt + Clast/λ, where Clast is the last 
measurable concentration 
mL: 
Milliliters  
BLQ /BQL: 
Below the Limit of Quantitation / Below 
Quantitation Limit 
ms: 
Millisecond 
BMI: 
Body Mass Index (kg/m2) 
mmHg: 
Millimeter of Mercury 
BP: 
Blood Pressure 
MRI:  
Magnetic Resonance Imaging 
BPM: 
Beats Per Minute 
N/A or NA: 
Not applicable, Not Available 
BPSI: 
BioPharma Services Inc. 
NOL: 
No Objection Letter 
BPSUSA: 
BioPharma Services USA Inc. 
PI: 
Principal Investigator 
CI: 
Confidence Interval 
PK: 
Pharmacokinetic 
Cmax: 
The maximal observed-plasma 
concentration. 
PT: 
Preferred Term 
CTA: 
Clinical Trial Application 
QA: 
Quality Assurance 
CYP: 
Cytochrome P450 
RBC: 
Red Blood Cell 
ECG: 
Electrocardiogram 
RPM: 
Revolutions Per Minute 
EMA: 
European Medicine Agency 
RR: 
Respiratory Rate 
FDA: 
Food and Drug Administration 
RLD: 
Reference Listed Drug 
FSH: 
Follicle-Stimulating Hormone 
SAE: 
Serious Adverse Event 
g: 
Grams 
SAS®: 
Statistical Analysis System 
GCP: 
Good Clinical Practice 
SD or STD: 
Standard Deviation 
GLP: 
Good Laboratory Practice 
SOC: 
System Organ Classification 
HC: 
Health Canada 
SOP: 
Standard Operating Procedure 
hCG: 
Human Chorionic Gonadotropin 
T1/2: 
Terminal elimination half-life, estimated as 
ln(2)/λ 
HIV: 
Human Immunodeficiency Virus 
Temp: 
Temperature 
ICF: 
Informed Consent Form 
Tmax / tmax: 
Time when the maximal-plasma concentration 
is observed 
ICH: 
International Conference on 
Harmonization 
TPD: 
Therapeutic Products Directorate 
IRB: 
Institutional Review Board 
UBG: 
Urobilinogen 
IUD: 
Intrauterine Device 
WBC: 
White Blood Cell 
λ: 
Terminal elimination rate constant, 
estimated by linear regression analysis of 
the terminal portion of the ln-
concentration vs. time plot 
 
 
 
 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 73 of 74 
APPENDIX D – RESTRICTED LIST OF DIURETICS 
Examples of Diuretic Drugs 
Examples of Diuretic Foods 
Thiazides Diuretics 
Lemon 
chlorothiazide (Diuril)  
Oats 
chlorthalidone (Hygroton) 
Celery 
indapamide (Lozol) 
Brussels sprouts 
hydrochlorothiazide (Hydrodiuril) 
Ginger 
methyclothiazide (Enduron) 
Beets 
metolazone (Zaroxolyn, Diulo, Mykrox) 
Apple Cider Vinegar 
Loop Diuretics  
Cabbage 
bumetanide (Bumex) 
Cranberry Juice 
furosemide (Lasix)  
Eggplant 
ethacrynate (Edecrin) 
Parsley 
torsemide (Demadex)  
Caffeinated beverages 
Potassium sparing Diuretics 
Tomatoes 
Amiloride hydrochloride 
Cucumber 
spironolactone (Aldactone) 
Watermelon 
triamterene (Dyrenium) 
Carrots 
Carbonic anhydrase inhibitors 
Garlic 
Acetazolamide Injection/Tablets 
Artichokes 
Methazolamide 
Asparagus  
Osmotic diuretics 
 
glycerin (Glycerol) 
 
Isosorbide  
 
Mannitol IV 
 
Urea 
 
Nonprescription Diuretics 
 
Maximum Strength Aqua Ban 
 
 
 
 


BPSUSA Protocol Number: 2001 
Protocol Version Date: August 3, 2017 
Nifedipine Extended-release Tablets, 60 mg 
Fasting Conditions 
 
Page 74 of 74 
APPENDIX E – NIFEDIPINE LABEL 
(See attached) 
APPENDIX F – PROCARDIA XL LABEL 
(See attached) 
APPENDIX G –OMEPRAZOLE/SODIUM BICARBONATE LABEL 
(See attached) 
APPENDIX H – SMARTPILL™ 510(k) SUMMARY 
(See attached)