Conditions: Hypertension
Keywords: High blood pressure Systolic blood pressure Diastolic blood pressure Antihypertensive
Allocation: RANDOMIZED | Intervention model: FACTORIAL
Enrollment: 105
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the effect of celecoxib on the efficacy and safety of amlodipine besylate on renal and vascular function in subjects with existing hypertension requiring antihypertensive therapy.

Kitov Pharma Ltd. (Kitov) is developing KIT-302, an oral fixed combination drug product (FCDP) consisting of the calcium channel blocker amlodipine besylate and the nonsteroidal anti-inflammatory drug (NSAID) celecoxib, as a "convenience reformulation" FCDP to facilitate and improve patient compliance with the once a day (qd) administration of its individual components, amlodipine and celecoxib.

The formulation of KIT-302 consists of amlodipine besylate and celecoxib co-formulated in a single immediate release tablet. However, for this study (KIT-302-03-02), commercial celecoxib capsules (Celebrex®) and commercial amlodipine besylate tablets (Norvasc®) were separately over-encapsulated (OE) and matched placebos were used to allow for blinding.

Kitov completed a phase 3 pivotal trial in subjects with newly diagnosed hypertension (KIT-302-03-01) demonstrating that the amlodipine + celecoxib combination was statistically non-inferior to amlodipine monotherapy with regard to reduction of blood pressure. Further, trends towards superior blood pressure lowering effects and improved renal function were observed for the combination. This study (KIT-302-03-02) was conducted to quantify the beneficial renovascular effects noted in the prior study in subjects with existing hypertension requiring antihypertensive therapy.

On May 31, 2018, the United States (US) Food and Drug Administration (FDA) approved KIT-302, under the brand name Consensi® (amlodipine and celecoxib) tablets \[New Drug Application (NDA) 210045\] for the following indication: "patients for whom treatment with amlodipine for hypertension and celecoxib for osteoarthritis are appropriate. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions."

Detailed description:
This was a multi-center, randomized, double blind, placebo controlled study to evaluate the effect of celecoxib on the efficacy, safety, and pharmacokinetics of amlodipine in subjects with existing hypertension requiring antihypertensive therapy. Approximately 105 eligible subjects were to be randomized 3:3:1 to one of three treatment arms.

Arm 1:OE 10 mg Norvasc tablet+OE 200 mg Celebrex capsule (amlodipine+celecoxib arm)

Arm 2:OE 10 mg Norvasc tablet+matched placebo for OE Celebrex capsule (amlodipine+placebo arm)

Arm 3:Matched placebo for OE Norvasc tablet+matched placebo for OE Celebrex capsule (placebo+placebo arm).

Following an up to 14-day screening phase, eligible subjects were randomized to one of the 3 treatment arms. All drugs were to be administered orally qd for 14 days for a total of 14 doses. Visits at the clinic took place at the start and at the end of the screening phase, at Study Day 0 (start of treatment), Day 6, Day 7, Day 13 (end of treatment), Day 14 and Day 28 (end of follow-up).

Arms:
arm 1: OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days arm 2: OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days arm 3: Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days

Interventions: intervention 1: OE 10 mg amlodipine besylate tablet intervention 2: OE 200 mg celecoxib capsule intervention 3: Matched placebo for OE amlodipine besylate tablet intervention 4: Matched placebo for OE celecoxib capsule
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol document:
Prot_000.pdf: 
Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 1 
CONFIDENTIAL 
TITLE: 
 
A Prospective Randomized Placebo Controlled Study to Evaluate 
the Effect of Celecoxib on the Efficacy and Safety of Amlodipine 
on Renal and Vascular Function in Subjects with Existing 
Hypertension Requiring Antihypertensive Therapy 
 
 
PROTOCOL NO.: 
KIT-302-03-02 
 
 
INVESTIGATIONAL 
DRUGS: 
Amlodipine besylate and celecoxib 
 
 
DOSAGE FORM: 
Capsule [over-encapsulated (OE) tablet and capsule, respectively] 
 
 
SPONSOR: 
Kitov Pharmaceuticals Ltd. 
 
One Azrieli Center 
 
Round Tower, Floor 23 
 
Derech Menachem Begin 132 
 
Tel Aviv, Israel 670110 
 
Telephone: 011 972 2 625 4124 
 
Fax: 011 972 72 257 8658 
 
 
MONITOR: 
J. Paul Waymack, M.D., Sc.D. 
 
1615 Suter’s Lane NW 
 
Washington, DC 20007 
 
Telephone: (202) 965-2215 
 
Fax: (202) 965-2376 
 
Email: paul@kitovpharma.com 
 
 
DATE OF VERSION: 
December 16, 2016 
 
 
VERSION: 
4 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 2 
CONFIDENTIAL 
TABLE OF CONTENTS 
 
PROTOCOL SIGNATURE SHEET .............................................................................................. 5 
INVESTIGATOR SIGNATURE SHEET ...................................................................................... 6 
LIST OF ABBREVIATIONS ......................................................................................................... 7 
PROTOCOL SYNOPSIS ............................................................................................................... 9 
1. BACKGROUND ...................................................................................................................... 19 
2. STUDY OBJECTIVES ............................................................................................................. 22 
2.1 Primary Objective ............................................................................................................ 22 
2.2 Secondary Objectives ...................................................................................................... 22 
3. STUDY DESIGN...................................................................................................................... 23 
4. ELIGIBILITY CRITERIA........................................................................................................ 27 
4.1 Inclusion Criteria ............................................................................................................. 27 
4.2 Exclusion Criteria ............................................................................................................ 27 
4.3 Withdrawal of Subjects .................................................................................................... 29 
4.4 Termination of Trial ........................................................................................................ 30 
5. STUDY DRUGS ....................................................................................................................... 31 
5.1 Description of Investigational Drugs ............................................................................... 31 
5.1.1 Active Pharmaceutical Ingredients ..................................................................... 31 
5.1.2 Drug Products ..................................................................................................... 31 
5.1.3 Packaging and Labeling ...................................................................................... 31 
5.1.4 Storage and Handling .......................................................................................... 32 
5.2 Randomization ................................................................................................................. 32 
5.3 Study Drug Administration .............................................................................................. 33 
5.4 Measuring Subject Compliance ....................................................................................... 33 
5.5 Drug Accountability ........................................................................................................ 34 
5.6 Concomitant Medications ................................................................................................ 34 
6. SCHEDULE OF EVENTS ....................................................................................................... 35 
6.1 Screening Visits ............................................................................................................... 35 
6.1.1 Initial Screening Visit (Day -14 to -10) .............................................................. 35 
6.1.2 Final Screening Visit (Day -1) ............................................................................ 36 
6.2 Study Day 0 ..................................................................................................................... 36 
6.3 Study Day 6 ..................................................................................................................... 38 
6.4 Study Day 7 ..................................................................................................................... 38 
6.5 Study Day 13 ................................................................................................................... 40 
6.6 Study Day 14 ................................................................................................................... 40 
6.7 Study Day 28 ................................................................................................................... 41 
6.8 Duration of Participation ................................................................................................. 42 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 3 
CONFIDENTIAL 
7. ASSESSMENT OF EFFICACY............................................................................................... 43 
7.1 Continuous Recording of Blood Pressure........................................................................ 43 
7.2 Body Weight .................................................................................................................... 43 
7.3 Renal Function ................................................................................................................. 43 
8. ASSESSMENT OF SAFETY ................................................................................................... 44 
8.1 Adverse Events ................................................................................................................ 44 
8.1.1 Definitions ........................................................................................................... 44 
8.1.1.1 Adverse Event ...................................................................................... 44 
8.1.1.2 Serious Adverse Event ......................................................................... 44 
8.1.2 Severity of Adverse Events ................................................................................. 45 
8.1.3 Relationship of Treatment Emergent Adverse Events to the Study Drug .......... 45 
8.1.4 Expectedness of Adverse Events ........................................................................ 46 
8.1.5 Monitoring of Adverse Events ............................................................................ 46 
8.1.6 Routine Reporting of Adverse Events ................................................................ 46 
8.1.7 Reporting of Serious Adverse Events, Including Death ..................................... 47 
8.2 Physical Examination ...................................................................................................... 50 
8.3 Vital Signs ....................................................................................................................... 50 
8.4 Orthostatic Hypotension Evaluations .............................................................................. 51 
8.5 ECG ................................................................................................................................. 51 
8.6 Hematology, Serum Chemistry, and Urinalysis .............................................................. 51 
9. ASSESSMENT OF PHARMACOKINETICS ......................................................................... 53 
9.1 Blood Collection .............................................................................................................. 53 
9.2 Bioanalytical Method ....................................................................................................... 53 
9.3 Pharmacokinetic Analysis ............................................................................................... 53 
10. STATISTICS .......................................................................................................................... 54 
10.1 Data Sets ........................................................................................................................ 54 
10.1.1 Intent-to-Treat (ITT) ........................................................................................ 54 
10.1.2 Per-protocol (PP) .............................................................................................. 54 
10.2 Statistical Analysis of Efficacy Data ............................................................................. 54 
10.2.1 Primary Efficacy Endpoint ............................................................................... 54 
10.2.2 BP Change Comparisons ................................................................................. 55 
10.2.3 Primary Efficacy Endpoint Analysis ................................................................ 55 
10.2.4 Secondary Efficacy Endpoints ......................................................................... 55 
10.2.5 Secondary Efficacy Endpoints Analysis .......................................................... 56 
10.3 Statistical Analysis of Pharmacokinetic Data ................................................................ 58 
10.4 Statistical Analysis of Safety Data ................................................................................ 58 
10.5 ABPM Measurement Weighting ................................................................................... 59 
10.6 ABPM Study Measurements ......................................................................................... 59 
10.7 ABPM Validity .............................................................................................................. 61 
10.8 ABPM Statistics............................................................................................................. 61 
10.9 Sample Size ................................................................................................................... 62 
11. ACCESS TO SOURCE DOCUMENTS ................................................................................ 63 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 4 
CONFIDENTIAL 
12. QUALITY CONTROL AND QUALITY ASSURANCE ...................................................... 65 
12.1 Data Collection .............................................................................................................. 65 
12.2 Study Monitoring ........................................................................................................... 65 
12.3 Data Management .......................................................................................................... 66 
12.4 Sponsor Audits............................................................................................................... 66 
12.5 Inspection by Regulatory Authorities ............................................................................ 66 
13. ETHICS................................................................................................................................... 67 
13.1 Declaration of Helsinki .................................................................................................. 67 
13.2 Good Clinical Practice and Regulatory Compliance ..................................................... 67 
13.3 Institutional Review Board/Independent Ethics Committee ......................................... 67 
13.4 Informed Consent .......................................................................................................... 67 
13.5 Emergency Departure from Protocol ............................................................................. 68 
14. PUBLICATION POLICY ...................................................................................................... 69 
15. PROTOCOL AMENDMENTS AND MODIFICATIONS .................................................... 70 
16. REFERENCES ....................................................................................................................... 71 
APPENDIX A: SCHEDULE OF EVENTS ................................................................................. 72 
APPENDIX B: CLINICAL LABORATORY TESTS ................................................................. 75 
APPENDIX C: WORLD HEALTH ORGANIZATION TOXICITY CRITERIA....................... 76 
APPENDIX D: ABPM PROCEDURE ......................................................................................... 81 
D.1 ABPM Fitting Procedure ................................................................................................ 81 
D.2 ABPM Removal Procedure ............................................................................................ 81 
APPENDIX E: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
(OCTOBER 2013) ........................................................................................................................ 82 
APPENDIX F: PACKAGE INSERT FOR NORVASC® (AMLODIPINE BESYLATE) 
TABLETS (MARCH 2015) .......................................................................................................... 91 
APPENDIX G: PACKAGE INSERT FOR CELEBREX® (CELECOXIB) CAPSULES 
(MAY 2016)................................................................................................................................ 107 
APPENDIX H: SAMPLE SIZE AND EFFICACY ANALYSIS ............................................... 129 
H.1 Results from Study No. KIT-302-03-01 ....................................................................... 129 
H.2 Margin ........................................................................................................................... 129 
H.3 Standard Deviation ....................................................................................................... 129 
H.4 Preliminary Estimate ..................................................................................................... 130 
APPENDIX I: CHILD-PUGH CLASSIFICATION OF LIVER CIRRHOSIS .......................... 131 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 5 
CONFIDENTIAL 
PROTOCOL SIGNATURE SHEET 
The undersigned has reviewed the format and content of this protocol and has approved 
Protocol No. KIT-302-03-02 for issuance. 
 
 
 
J. Paul Waymack, M.D., Sc.D. 
Chief Medical Officer 
Kitov Pharmaceuticals, Ltd. 
 
Date 
 
 
 
16 Dec 2016


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 6 
CONFIDENTIAL 
INVESTIGATOR SIGNATURE SHEET 
 
I have read the attached protocol and agree that it contains all the necessary details for performing 
the study. 
I will provide copies of the protocol and of the preclinical and clinical information on the test 
articles, which was furnished to me by the Sponsor, to all members of the study team responsible 
to me who participate in the study. I will discuss this material with them to assure that they are 
fully informed regarding the test articles and the conduct of the study. 
Once the protocol has been approved by the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC), I will not modify this protocol without obtaining the prior approval of the 
Sponsor and of the IRB/IEC. I will submit the protocol modifications and/or any informed consent 
form (ICF) modifications to the Sponsor and the IRB/IEC, and approval will be obtained before 
any modifications are implemented. 
I understand the protocol and will work according to it, the principles of Good Clinical Practice 
(GCP) [current International Conference of Harmonization (ICH) guidelines], and the Declaration 
of Helsinki (1964) including all amendments up to and including the October 2013 revision. 
 
 
Investigator’s Signature:  
 
Date:   
Investigator’s Printed Name:   
 
Investigational Site Name: 
 
 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 7 
CONFIDENTIAL 
LIST OF ABBREVIATIONS 
 
ABPM 
ambulatory blood pressure monitor 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
bd 
twice a day 
BE 
bioequivalence 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
Ca 
calcium 
CFR 
Code of Federal Regulations 
COX-2 
cyclooxygenase-2 
CRF 
case report form 
CRO 
contract research organization 
CYP2C9 
cytochrome P450 2C9 
DBP 
diastolic blood pressure 
DBP24h 
average 24-hour ambulatory diastolic blood pressure 
DBPday 
average daytime (9:00 to 21:00) diastolic blood pressure 
DBPnight 
average night-time (01:00 to 06:00) diastolic blood pressure 
ECG 
electrocardiogram 
FCDP 
fixed combination drug product 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR 
heart rate 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug application 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IUD 
intrauterine device 
LC-MS/MS 
liquid chromatography tandem mass spectroscopy 
LLOQ 
lower limit of quantification 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
millimetres of mercury 
MMRM 
mixed model for repeated measures 
NSAID 
non-steroidal anti-inflammatory drug 
OBP 
office blood pressure 
OE 
over-encapsulated 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 8 
CONFIDENTIAL 
OTC 
over-the-counter 
PHI 
Protected Health Information 
PK 
pharmacokinetic 
PP 
per-protocol 
PTAE 
pretreatment adverse event 
qd 
once a day 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SBP24h 
average 24-hour ambulatory systolic blood pressure 
SBPday 
average daytime (9:00 to 21:00) ambulatory systolic blood pressure 
SBPnight 
average night-time (01:00 to 06:00) ambulatory systolic blood pressure 
TBD 
to be determined 
TEAE 
treatment emergent adverse event 
US 
United States 
WCBP 
women of childbearing potential 
WHO 
World Health Organization 
 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 9 
CONFIDENTIAL 
PROTOCOL SYNOPSIS 
Name of Sponsor/ 
Company: 
Kitov Pharmaceuticals, Ltd. 
Name of Finished 
Products: 
Norvasc® (amlodipine besylate) tablets (10 mg amlodipine besylate base) 
Celebrex® (celecoxib) capsules (200 mg celecoxib) 
Each of the formulations will be individually over-encapsulated (OE) and matched 
placebos will be used to allow for blinding. 
Name of Active 
Ingredients: 
Amlodipine besylate and celecoxib  
Title of Study: 
A Prospective Randomized Placebo Controlled Study to Evaluate the Effect of Celecoxib 
on the Efficacy and Safety of Amlodipine on Renal and Vascular Function in Subjects 
with Existing Hypertension Requiring Antihypertensive Therapy 
Protocol No.: 
KIT-302-03-02 
Investigators/Study 
Centers/Locations: 
TBD/TBD/TBD 
Phase of 
Development: 
Phase 3 
Study Period: 
Up to 6 weeks per subject (initial Screening visit to Final visit); approximately 
8 months for the entire trial (first subject enrolled to last subject completed) 
Primary Objective: 
To demonstrate that the mean reduction in average daytime (9:00 to 21:00) ambulatory 
systolic blood pressure (SBPday) after oral administration of amlodipine tablets (10 mg) and 
celecoxib capsules (200 mg) given together once a day (qd) for 14 days in adult subjects 
with existing hypertension is no less than half the mean reduction in SBPday after oral 
administration of amlodipine tablets (10 mg) given alone (i.e., with matched celecoxib 
placebo) qd for 14 days in the same population. 
Secondary 
Objectives: 
To evaluate the effect of amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given 
together qd for 14 days in adult subjects with existing hypertension on secondary efficacy 
endpoints using a serial gatekeeping strategy. If and only if the primary efficacy endpoint is 
statistically achieved, a secondary hierarchical analysis will be used to evaluate the 
endpoints listed below, and will only proceed to the next endpoint in the list if the alpha is 
met for the prior analyses. 
1. Difference in mean change in body weight from baseline to end of treatment 
between treatment arms [amlodipine tablets (10 mg) and celecoxib capsules 
(200 mg) given together, amlodipine tablets (10 mg) given alone (with matched 
celecoxib placebo), and placebo]; 
2. Difference in the mean reduction in average 24-hour ambulatory systolic blood 
pressure (SBP24h) from baseline to end of treatment between amlodipine tablets 
(10 mg) and celecoxib capsules (200 mg) given together and amlodipine tablets 
(10 mg) given alone (with matched celecoxib placebo) treatment arms; 
3. Difference in the mean reduction in average 24-hour ambulatory diastolic blood 
pressure (DBP24h) from baseline to end of treatment between amlodipine tablets 
(10 mg) and celecoxib capsules (200 mg) given together and amlodipine tablets 
(10 mg) given alone (with matched celecoxib placebo) treatment arms;  
4. Difference in the mean change in creatinine clearance from baseline to end of 
treatment between amlodipine tablets (10 mg) and celecoxib capsules (200 mg) 
given together and amlodipine tablets (10 mg) given alone (with matched 
celecoxib placebo) treatment arms.  


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 10 
CONFIDENTIAL 
To evaluate the safety of amlodipine tablets (10 mg) and celecoxib capsules (200 mg) 
given together qd for 14 days in adult subjects with existing hypertension. 
To evaluate the effect of celecoxib on the mean plasma concentrations of amlodipine in 
adult subjects with existing hypertension after 14 days of treatment with amlodipine tablets 
(10 mg) and celecoxib capsules (200 mg) given together compared to amlodipine tablets 
(10 mg) given alone (with matched celecoxib placebo). 
Methodology: 
This is a multi-center, randomized, double blind, placebo controlled trial to evaluate the 
effect of celecoxib on the efficacy, safety, and pharmacokinetics of amlodipine in subjects 
with existing hypertension requiring antihypertensive therapy. 
Approximately 105 adult subjects with existing hypertension who require and are currently 
using pharmacological therapy with a single agent that is not a calcium channel blocker to 
control their hypertension will be randomized 3:3:1 to one of three treatment arms: 
 
1. OE Norvasc® tablet (10 mg amlodipine besylate) + OE Celebrex® capsule (200 mg 
celecoxib); 
 
2. OE Norvasc® tablet (10 mg amlodipine besylate) + matched placebo for OE 
Celebrex® capsule; 
 
3.  Matched placebo for OE Norvasc® tablet + matched placebo for OE Celebrex® 
capsule. 
All drugs will be administered orally qd for 14 days (Days 0-13) for a total of 14 doses.  
The total number of subjects planned (105) is an approximation.  Once the 105th subject is 
randomized to treatment (Day 0), any subject that is currently participating in the washout 
period will be allowed to complete the washout period and if found eligible will be enrolled 
into the trial.  These subjects will continue to be randomized 3:3:1 as noted above.  No 
further subjects will be brought in for the Initial Screening Visit once the 105th subject is 
randomized.   
Initial Screening Visit (Day -14 to -10): Each subject will be provided with oral and 
written information (ICF) describing the study and will have any questions answered. 
Subjects that consent in writing to participate in the study will undergo eligibility 
assessments, including complete medical history, comprehensive physical examination, 
height, body weight in underwear and a light gown, body mass index (BMI), vital signs 
(BP, pulse rate, respiration rate, and oral body temperature), 12-lead electrocardiogram 
(ECG), hematology, serum chemistry, urinalysis, serum pregnancy test for women of 
childbearing potential (WCBP), urine drug screen, and record medications taken within 
30 days prior to initial screening visit.   
Subjects who meet eligibility criteria based on the above initial screening visit 
procedures will be instructed to cease taking their current BP medication.  Monitoring 
for pretreatment adverse events (PTAEs) will begin upon completion of the initial 
screening visit procedures and will continue through the 9 to 13 days of washout, the 
final screening visit on Day -1, and the baseline procedures on Day 0 (i.e., prior to the 
administration of the first dose of study drugs). Any untoward medical occurrence that 
initiates or worsens after completion of the initial screening visit procedures and before 
administration of the first dose of study drugs will be recorded as a PTAE. Subjects will 
be instructed to return to the clinic in 9 to 13 days. 
Final Screening Visit (Day -1) Subjects will return to the clinic after 9 to 13 days of 
washout for their final screening visit (Day -1). They will undergo the following 
procedures: solicit for history of PTAEs since the previous visit and record medications 
taken since prior visit. Those who continue to meet eligibility criteria will be given an 
ambulatory blood pressure monitor (ABPM), instructed in its use, and have the positioning 
of their ABPM checked. They will be instructed to wear it at all times for the next 25 hours 
and to return to the clinic the following day.  


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 11 
CONFIDENTIAL 
Study Day 0: When the subjects return to clinic the following day, the ABPM will be 
collected and the data contained therein downloaded and analysed. If subjects are found to 
be hypertensive, based upon their ABPM measurement, they will undergo additional 
baseline procedures as described below. If the subject’s BP is too elevated for them to 
continue safely in the study (i.e., SBP24h > 169 mmHg or DBP24h > 110 mmHg), the subject 
will not be enrolled and they will be instructed to resume taking their prescribed BP 
medication as directed by the study doctor or general practitioner.  If the subject is found to 
be normotensive (SBPday ≤ 135 mmHg), the subject will not be enrolled. The subject’s 
primary care doctor will be informed that he/she has been found not to be hypertensive.  
No subject will be randomized until these baseline ABPM data have been reviewed and it 
has been documented that the subject meets entry BP criteria.  
Subjects who meet the BP criteria (SBPday > 135 and ≤ 169 mmHg and 
DBPday ≤ 110 mmHg) following completion of the 10- to 14-day washout period will 
undergo the following additional baseline procedures: solicit for history of PTAEs since 
the previous visit, targeted physical examination, body weight in underwear and a light 
gown, vital signs, orthostatic hypotension evaluation, serum chemistry, and record 
medications taken since last visit. Subjects that continue to meet all eligibility requirements 
will be enrolled in the study and randomized 3:3:1 to one of three treatment arms. The 
subjects will then be administered their first dose of study drugs in the clinic.  
Monitoring for treatment emergent adverse events (TEAEs) will begin immediately 
following administration of the first dose of study drugs and will continue throughout the 
study. Any untoward medical occurrence that initiates or worsens after the first dose of 
study drugs and within 14 days of the last dose of study drugs will be recorded as a TEAE. 
Subjects will remain in the clinic under observation for one hour following their first dose 
and will be solicited for TEAE history prior to leaving the clinic. Subjects will be provided 
with sufficient study drugs for the remainder of the 2-week treatment period, and instructed 
to take the study drugs qd in the morning. Subjects will be provided with a diary and 
instructed to record any concomitant medications taken and details of study drug 
administration. Subjects will be instructed to return to clinic the morning of Day 6. 
Study Day 6: Subjects will return to clinic on the morning of Day 6 and will be solicited 
for history of TEAEs since the previous visit. The study drug containers will be collected 
and unused study drug counted and recorded. The diary will be reviewed for details of 
study drug administration and any concomitant medications taken since the previous visit. 
Subjects will be given an ABPM, instructed in its use, and have the positioning of their 
ABPM checked. The subjects will then be administered their Day 6 dose of study drugs, 
and instructed to wear the ABPM at all times for the next 25 hours. Subjects will be given 
back their remaining study drug supply and diary, instructed to record any concomitant 
medications taken and details of study drug administration, and instructed to return to 
clinic the following day.  
Study Day 7: The Day 7 study drugs will be self-administered at home within 
24 hours ± 1 hour from the Day 6 dose. Subjects will return to clinic on the morning of 
Day 7 (after the home administration of study drugs). The diary will be reviewed for any 
concomitant medications taken and for details of study drug administration since the 
previous visit. The study drug containers will be collected and unused study drug 
counted and recorded. Subjects will be solicited for history of TEAEs since the previous 
visit. A targeted physical examination will be performed and body weight in underwear 
and light gown and vital signs will be measured. An orthostatic hypotension test will be 
performed. Subjects will have BP as measured by the ABPM recorded and the ABPM 
collected. Subjects will have blood collected for measurement of creatinine (and 
calculation of creatinine clearance) and electrolytes. 
If the Investigator determines that it is safe for the subject to continue in the study, the 
subject will have their remaining study drug supply returned to them, and instructed to take 
the study drugs at home on Days 8-12, between 0700 and 1000 hours, and preferably at 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 12 
CONFIDENTIAL 
approximately the same time each day. Subjects will be given back their diary and 
instructed to record any concomitant medications taken and details of study drug 
administration, and instructed to return to the clinic in 6 days (on the morning of Day 13). 
If the subject’s BP is too elevated for them to continue safely in the study (i.e., 
SBP24h > 169 mmHg or DBP24h > 110 mmHg), blood will be drawn for renal profile 
testing. The subject will be instructed to cease taking study drugs, instructed to resume 
taking their prescribed BP medication as directed by the study doctor or general 
practitioner, given back their diary and instructed to record any concomitant medications 
taken between visits, and instructed to return to the clinic in 7 days (Day 14). 
Study Day 13: Subjects will return to clinic on the morning of Day 13 (except for those 
discontinued from study drug due to excessive hypertension or other safety reasons) and 
will be solicited for history of TEAEs since the previous visit. The diary will be reviewed 
for details of study drug administration and any concomitant medications taken since the 
previous visit. The study drug containers will be collected and any unused study drug 
counted and recorded. Subjects will be given an ABPM, instructed in its use, and have the 
positioning of their ABPM checked. The subjects will then be administered their Day 13 
dose of study drugs (final dose), and instructed to wear the ABPM at all times for the next 
25 hours. Subjects will be given back their diary and instructed to record any concomitant 
medications taken between visits, and instructed to return to clinic the following day.  
Study Day 14: Subjects will return to clinic on the morning of Day 14. The diary will be 
reviewed for any concomitant medications taken since the previous visit. Subjects will be 
solicited for history of TEAEs since the previous visit. A comprehensive physical 
examination will be performed and body weight in underwear and a light gown and vital 
signs will be measured. BP as measured by the ABPM will be recorded and the ABPM 
collected, and an orthostatic hypotension evaluation will be performed. The following 
additional evaluations will be performed: 12-lead ECG, hematology, serum chemistry, 
urinalysis, and urine pregnancy test for WCBP. 
In addition, subjects will have a blood sample collected 24 hours ± 1 hour post-dose for 
measurement of amlodipine concentrations.  Only subjects enrolled at Investigational Sites 
that have UV-shielded lights will participate in the pharmacokinetic (PK) blood 
collections.  Due to the design of the trial (randomized, double-blind, placebo-controlled), 
this blood sample will be collected and analyzed for all participating subjects, regardless of 
whether they are in a treatment arm that receives amlodipine. 
Following the Day 14 evaluations, the subjects will be instructed to resume taking their 
prescribed BP medication as directed by the study doctor or general practitioner, given 
back their diary and instructed to record any concomitant medications taken between visits, 
and instructed to return to the clinic in 14 days (Day 28). 
Study Day 28: Subjects will return to clinic on Day 28 for their final study visit (follow-
up visit). The diary will be reviewed for any concomitant medications taken since the 
prior visit. Subjects will be solicited for history of TEAEs since the previous visit. A 
targeted physical examination will be performed and vital signs will be measured. For 
subjects whose study drugs are discontinued at Day 7, this follow-up visit will still occur 
on Day 28 (i.e., these subjects will return to the clinic for both the Day 14 and Day 28 
visits). 
Number of Subjects 
(planned): 
Approximately 105 randomized subjects.  Once the 105th subject is randomized to 
treatment (Day 0), any subject that is currently participating in the washout period will be 
allowed to complete the washout period and if found eligible will be randomized.   
Diagnosis and Main 
Criteria for 
Inclusion: 
Inclusion Criteria 
1. 
Adult 40 to 75 years of age;  
2. 
Existing hypertension that is being treated using pharmacological therapy with a 
single agent that is not a calcium channel blocker; 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 13 
CONFIDENTIAL 
3. 
SBPday > 135 and ≤ 169 mmHg and DBPday ≤ 110 mmHg at Day 0 (i.e., after the 10- 
to 14-day washout from prior BP medication); 
4. 
Body Mass Index (BMI) of 18.5 to 34.9 kg/m2; 
5. 
Healthy (other than hypertension) as determined by the Investigator based on medical 
history, physical examination, vital signs, 12-lead ECG, and clinical laboratory tests; 
6. 
A negative pregnancy test at initial screening visit; 
7. 
If WCBP, agree to use a highly effective form of birth control while on study (from 
Screening through final study visit); 
Highly effective methods of birth control are defined as those, alone or in 
combination, that result in a low failure rate (i.e., less than 1% per year) when used 
consistently and correctly. Forms of birth control include intrauterine device (IUD), 
birth control patch or vaginal ring, oral, or injectable or implanted contraceptives, or a 
vasectomized partner, or abstinence from sexual intercourse. Abstinence is acceptable 
only as true abstinence: when this is in line with the preferred and usual lifestyle of 
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
A woman that is postmenopausal (≥2 years since last menstrual period) or 
permanently sterilized (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy) is 
not considered a WCBP. 
8. 
Able to comprehend and sign an ICF. 
Exclusion Criteria  
1. Resting systolic BP > 169 mmHg or a resting diastolic BP > 110 mmHg at initial 
screening visit while on their standard antihypertensive therapy (where resting is 
defined as supine for at least 10 minutes with minimal interaction); 
2. Weight < 55 kg; 
3. Fragile health; 
4. Evidence of clinically significant findings on screening evaluations (clinical, 
laboratory, and ECG) which, in the opinion of the Investigator would pose a safety risk 
or interfere with appropriate interpretation of safety data; 
5. Current or recent history (within four weeks prior to initial screening visit) of a 
clinically significant bacterial, fungal, or mycobacterial infection; 
6. Current clinically significant viral infection; 
7. History of malignancy, with the exception of cured basal cell or squamous cell 
carcinoma of the skin; 
8. Major surgery within four weeks prior to initial screening visit;  
9. Presence of a malabsorption syndrome possibly affecting drug absorption (e.g., 
Crohn’s disease or chronic pancreatitis); 
10. Active peptic ulceration or history of gastrointestinal bleeding; 
11. History of myocardial infarction, congestive heart failure, or stroke; 
12. Any current cardiovascular disease (other than hypertension); 
13. History of psychotic disorder; 
14. History of alcoholism or drug addiction or current alcohol or drug use that, in the 
opinion of the Investigator, will interfere with the subject’s ability to comply with the 
dosing schedule and study evaluations; 
15. History of any illicit drug use within one year prior to initial screening visit; 
16. Positive drug screen at initial screening visit.  A positive drug screen for opiates only 
(with all other drug tests negative) will not be a basis for exclusion if the subject took 
over-the-counter narcotics as indicated on the product label within 24 hours prior to the 
drug screen;  
17. Current treatment or treatment within 30 days prior to first dose of study drugs with 
another investigational drug or current enrollment in another clinical trial;  


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 14 
CONFIDENTIAL 
18. Known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C;  
19. Known hypersensitivity to amlodipine or celecoxib; 
20. Known hypersensitivity to the inactive ingredients in the OE study drugs; 
21. Asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic 
type reactions after taking acetylsalicylic acid or NSAIDs including cyclooxygenase-2 
(COX-2) inhibitors; 
22. Subjects who, in the opinion of the Investigator, are unable or unlikely to comply with 
the dosing schedule and study evaluations; 
23. Pregnant or lactating; 
24. Unable to correctly use ABPM after instruction on its use; 
25. Subjects with Child-Pugh Class B or C cirrhosis; 
26. Subjects currently taking a calcium channel blocker or any NSAID for any reason will 
be excluded. Subjects will not be withdrawn from these drugs to be enrolled in the 
trial; 
27. Subjects that took a calcium channel blocker in the past for any indication; 
28. Creatinine clearance < 50 ml/min as estimated by the Cockroft-Gault equation; 
29. Known cytochrome P450 2C9 (CYP2C9) poor metabolizer; 
30. Subjects with allergy or hypersensitivity to sulfonamides. 
Test Product, Dose 
and Mode of 
Administration: 
Active Pharmaceutical Ingredients 
Amlodipine is a calcium (Ca) channel blocker. The chemical name of amlodipine is 3-
ethyl-5-methyl (±) 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)- 1,4-dihydro-6 methyl-
3,5-pyridinedicarboxylate, monobenzenesulphonate. Amlodipine besylate has a molecular 
weight of 567.06 and a molecular formula of C20H25ClN2O5•C6H6O3S. 
Celecoxib is a sulfa NSAID and selective COX-2 inhibitor. The chemical name of 
celecoxib is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide. Celecoxib has a molecular weight of 381.38 and a molecular 
formula of C17H14F3N3O2S. 
Drug Products 
Two commercial formulations will be used for this trial. This study is a double blind, 
placebo controlled study. Therefore, the commercial formulations will be OE and matched 
placebos will be used to allow for blinding. The two commercial formulations are as 
follows: 
1. Norvasc® (amlodipine besylate) tablets (10 mg amlodipine besylate, Pfizer): Each 
tablet contains 10 mg amlodipine besylate (base equivalent) and the following inactive 
ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium 
starch glycolate, and magnesium stearate.  
2. Celebrex® (celecoxib) capsules (200 mg celecoxib, GD Searle): Each capsule contains 
200 mg celecoxib and the following inactive ingredients: croscarmellose sodium, 
edible inks, gelatin, lactose monohydrate, magnesium stearate, povidone, and sodium 
lauryl sulfate. 
Dose and Mode of Administration 
All subjects will take study drugs by mouth qd for 14 days (Days 0-13) for a total of 
14 doses. With the exception of Days 6 and 13, when study drug intake is at the time of 
fitting the ABPM and of Day 7, when study drug intake is 24 hours ± 1 hour later, the 
subjects should be instructed to take their study drugs between 0700 and 1000 hours, and 
preferably at approximately the same time each day. Subjects will be randomized 3:3:1 to 
one of three treatment arms: 
 
1. OE Norvasc® tablet (10 mg amlodipine besylate) + OE Celebrex® capsule (200 mg 
celecoxib); 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 15 
CONFIDENTIAL 
 
2. OE Norvasc® tablet (10 mg amlodipine besylate) + matched placebo for OE 
Celebrex® capsule; 
 
3.  Matched placebo for OE Norvasc® tablet + matched placebo for OE Celebrex® 
capsule. 
Duration of 
Treatment: 
14 days (qd on Days 0-13) 
 
Criteria for 
Evaluation: 
Primary Endpoint 
The primary efficacy endpoint for this trial will be the difference in the mean change in 
SBPday from baseline (Day -1 to Day 0) to end of treatment (Day 13 to Day 14) between 
subjects treated with amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given 
together (arm 1) and amlodipine tablets (10 mg) given alone (i.e., with matched celecoxib 
placebo) (arm 2).  
Secondary Endpoints 
The effect of amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together 
on secondary efficacy endpoints will be evaluated using a serial gatekeeping strategy. If 
and only if the primary blood pressure efficacy endpoint is statistically achieved, a 
secondary hierarchical analysis will be used to evaluate the endpoints listed below, and 
will only proceed to the next endpoint in the list if the alpha is met for the prior analyses. 
1. Difference in mean change in body weight from baseline (Day 0) to end of 
treatment (Day 14) between treatment arms [amlodipine tablets (10 mg) and 
celecoxib capsules (200 mg) given together (arm 1), amlodipine tablets (10 mg) 
given alone (with matched celecoxib placebo) (arm 2), and placebo (arm 3)]; 
2. Difference in the mean reduction in SBP24h from baseline (Day -1 to Day 0) to 
end of treatment (Day 13 to Day 14) between subjects treated with amlodipine 
tablets (10 mg) and celecoxib capsules (200 mg) given together (arm 1) and 
amlodipine tablets (10 mg) given alone (with matched celecoxib placebo) 
(arm 2); 
3. Difference in the mean reduction in DBP24h from baseline (Day -1 to Day 0) to 
end of treatment (Day 13 to Day 14) between subjects treated with amlodipine 
tablets (10 mg) and celecoxib capsules (200 mg) given together (arm 1) and 
amlodipine tablets (10 mg) given alone (with matched celecoxib placebo) 
(arm 2); 
4. Difference in the mean change in creatinine clearance from baseline (Day 0) to 
end of treatment (Day 14) between subjects treated with amlodipine tablets 
(10 mg) and celecoxib capsules (200 mg) given together (arm 1) and amlodipine 
tablets (10 mg) given alone (with matched celecoxib placebo) (arm 2). 
The safety of amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together 
qd for 14 days in adult subjects with existing hypertension (arm 1) is a secondary endpoint 
of this trial.  Safety will be assessed primarily based on reported TEAEs. The severity of 
both PTAEs and TEAEs will be graded according to World Health Organization (WHO) 
Toxicity Criteria. Secondary safety assessments will include physical examination, body 
weight, vital signs, orthostatic hypotension evaluations, ECG, hematology, serum 
chemistry, and urinalysis.  
The effect of celecoxib on plasma levels of amlodipine in adult subjects with existing 
hypertension is a secondary endpoint of this trial. Mean plasma concentrations of 
amlodipine after 14 days of treatment with amlodipine tablets (10 mg) and celecoxib 
capsules (200 mg) given together (arm 1) and amlodipine tablets (10 mg) given alone (with 
matched celecoxib placebo) (arm 2) will be compared to evaluate for a PK drug-drug 
interaction. 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 16 
CONFIDENTIAL 
Statistical Methods 
for Primary Efficacy 
Analysis: 
The primary efficacy endpoint for this trial will be the difference in the mean reduction in 
SBPday from Day 0 to Day 14 between subjects treated with amlodipine tablets (10 mg) and 
celecoxib capsules (200 mg) given together (arm 1) and amlodipine tablets (10 mg) given 
alone (with matched celecoxib placebo) (arm 2), and specifically that the lower limit of the 
95% confidence interval for the arm 1 subjects is at least 50% of the mean reduction in the 
arm 2 subjects.  
A two-sample t-test will be used to test the one-sided hypothesis that treatment with 
amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together (arm 1) is non-
inferior to the control treatment with amlodipine tablets (10 mg) given alone (with matched 
celecoxib placebo) (arm 2). 
H0: ∆SBPday,1 – 0.5(∆SBPday,2) ≥ 0 
H1: ∆SBPday,1 – 0.5(∆SBPday,2 < 0 
Where ∆SBPday,1 is the reduction in SBPday for subjects in arm 1. 
 
∆SBPday,2 is the reduction in SBPday for subjects in arm 2. 
For the primary analysis, an intent-to-treat (ITT) data set will be used comprising of 
randomized subjects with a valid ABPM measurement from Day –1 to Day 0 and also 
either a valid ABPM measurement from Day 13 to Day 14, where a subject completes the 
14-day treatment plan, or a valid ABPM measurement from Day 6 to Day 7, where a 
subject is withdrawn from treatment at Day 7 because of an SBP24h > 169 mmHg and/or a 
DBP24h > 110 mmHg. 
Statistical Methods 
for Secondary 
Efficacy Analysis: 
A serial gatekeeping strategy will be used to evaluate the effect of amlodipine tablets 
(10 mg) and celecoxib capsules (200 mg) given together on secondary efficacy endpoints.  
If and only if the primary blood pressure efficacy endpoint is statistically achieved, a 
secondary hierarchical analysis will be used to evaluate the endpoints listed below, and 
will only proceed to the next endpoint in the list if the alpha is met for the prior analyses.  
1. Difference in mean change in body weight from baseline (Day 0) to Day 14 (or 
Day 7 for subjects withdrawn from treatment at Day 7) between treatment arms 
[amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together 
(arm 1), amlodipine tablets (10 mg) given alone (with matched celecoxib 
placebo) (arm 2), and placebo (arm 3)]; 
2. Difference in the mean reduction in SBP24h from the baseline (Day –1 to Day 0) 
ABPM measurement to the Day 13 to Day 14 ABPM measurement (or to the 
Day 6 to Day 7 ABPM measurement for subjects withdrawn from treatment at 
Day 7) between subjects treated with amlodipine tablets (10 mg) and celecoxib 
capsules (200 mg) given together (arm 1) and amlodipine tablets (10 mg) given 
alone (with matched celecoxib placebo) (arm 2); 
3. Difference in the mean reduction in DBP24h from the baseline (Day –1 to Day 0) 
ABPM measurement to the Day 13 to Day 14 ABPM measurement (or to the 
Day 6 to Day 7 ABPM measurement for subjects withdrawn from treatment at 
Day 7) between subjects treated with amlodipine tablets (10 mg) and celecoxib 
capsules (200 mg) given together (arm 1) and amlodipine tablets (10 mg) given 
alone (with matched celecoxib placebo) (arm 2); 
4. Difference in the mean change in creatinine clearance from baseline (Day 0) to 
Day 14 (or Day 7 for subjects withdrawn from treatment at Day 7) between 
subjects treated with amlodipine tablets (10 mg) and celecoxib capsules (200 mg) 
given together (arm 1) and amlodipine tablets (10 mg) given alone (with matched 
celecoxib placebo) (arm 2). 
Analysis of variance (ANOVA) will be utilized to compare body weight changes among 
the three treatment arms.  Change in body weight will be the response with treatment arm 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 17 
CONFIDENTIAL 
as the predictive factor.  There will be no covariate adjustments.  Post-hoc comparisons for 
individual differences will use the Bonferroni Method. 
H0: ∆BW1 = ∆BW2 = ∆BW3 
H1: At least one difference. 
Where ∆BW1 is the reduction in body weight for subjects in arm 1 
 
∆BW2 is the reduction in body weight for subjects in arm 2 
 
∆BW3 is the reduction in body weight for subjects in arm 3 
A two-sample t-test for superiority will be used for the secondary blood pressure efficacy 
analyses to test the one-sided hypotheses that treatment with amlodipine tablets (10 mg) 
and celecoxib capsules (200 mg) given together (arm 1) lowers SBP24h to a greater degree 
than amlodipine tablets (10 mg) given alone (with matched celecoxib placebo) (arm 2). 
H0: ∆SBP24h,1 – ∆SBP24h,2 = 0 
H1: ∆SBP24h,1 – ∆SBP24h,2 > 0 
Where ∆SBP24h,1 is the reduction in SBP24h for subjects in arm 1 
 
∆SBP24h,2 is the reduction in SBP24h for subjects in arm 2 
For the next endpoint, SBP24h will be replaced with DBP24h. 
For the creatinine clearance endpoint, a two-sample t-test for superiority will be used for 
the analysis to test the one-sided hypothesis that treatment with amlodipine tablets 
(10 mg) and celecoxib capsules (200 mg) given together (arm 1) improves creatinine 
clearance to a greater degree than amlodipine tablets (10 mg) given alone (with matched 
celecoxib placebo) (arm 2).  
Statistical Methods 
for PK Drug-Drug 
Interaction 
Analysis: 
Only subjects enrolled at Investigational Sites that have UV-shielded lights will participate 
in the PK blood collections.   
Blood samples will be collected on Day 14, approximately 24 hours after receiving the 
final dose of study drugs. The plasma concentration of amlodipine will be determined by a 
validated liquid chromatography tandem mass spectroscopy (LC-MS/MS) method. 
A t-test will compare the plasma concentration of amlodipine in those subjects who receive 
amlodipine tablets (10 mg) given alone (with matched celecoxib placebo) (arm 2) with 
those who receive amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given 
together (arm 1). 
Statistical Methods 
for Safety Analysis: 
Data from all subjects who receive at least one dose of study drug will be incorporated into 
the final safety analysis. 
Safety will be assessed primarily based on reported TEAEs. Clinically significant 
laboratory abnormalities will be reported as adverse events (AEs) [i.e., either as PTAEs or 
TEAEs, depending on when they initiate or worsen]. The incidence of TEAEs will be 
tabulated by Medical Dictionary for Regulatory Activities (MedDRA) system organ class 
and preferred term, and will be further categorized by treatment arm, severity, and assigned 
relationship to study drug. The incidence of PTAEs will be tabulated by MedDRA system 
organ class and preferred term, and will be further categorized by severity. 
The incidence for each PTAE and TEAE will be provided as the total number of subjects 
that experienced the PTAE or TEAE, as well as the percentage of the population that this 
represents. If a PTAE or TEAE is reported more than once for a given subject, the greatest 
severity and the worst-case attribution will be presented in the summary tables. 
Chi-square analysis or an exact binomial test will be used to compare TEAE rates between 
treatment arms.  


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 18 
CONFIDENTIAL 
PTAEs and TEAEs will be separately listed for individual subjects, along with information 
regarding onset and end dates, onset time where available, severity, seriousness, 
relationship to study drug (only in the case of TEAEs), action taken, and outcome. Separate 
listings and tabular summaries of PTAEs and TEAEs that lead to withdrawal from the 
study will be generated. Separate listings and tabular summaries of serious PTAEs and 
TEAEs will also be generated. 
Secondary safety assessments, including physical examination, body weight, vital signs, 
orthostatic hypotension evaluations, ECG, hematology, serum chemistry, and urinalysis 
will be listed and summarized. Descriptive statistics will be generated as appropriate (i.e., 
mean, median, range, and standard deviation for continuous data and frequency for 
categorical data). The clinical laboratory results will also be summarized with respect to 
laboratory normal ranges and absolute changes from baseline. Comparisons among 
treatment arms will be performed using chi-square, binomial, and logistic analyses for 
dichotomous variables (e.g. normal/abnormal) and analysis of covariance (ANCOVA) for 
continuous variables. 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 19 
CONFIDENTIAL 
1. BACKGROUND 
KIT-302 is an oral fixed combination drug product (FCDP) consisting of the calcium (Ca) channel 
blocker antihypertensive drug amlodipine besylate and the non-steroidal anti-inflammatory drug 
(NSAID) celecoxib. Amlodipine besylate and celecoxib are marketed in the United States (US) 
and worldwide as individual branded and generic prescription drug products, and as combination 
drug products with other prescription drugs, in the case of amlodipine. Kitov Pharmaceuticals, Ltd. 
(Kitov) is developing KIT-302 as a “convenience reformulation” FCDP intended to facilitate and 
improve patient compliance with the once a day (qd) administration of its individual components, 
amlodipine besylate and celecoxib, when used together for the intended patient population.  
Long-term treatment with celecoxib is most commonly used in treating patients with osteoarthritis. 
This population is generally more aged than an average cross-section of people. It is therefore to 
be expected that a significant percentage of these patients will also have hypertension. Thus, it can 
be anticipated that a significant number of patients requiring chronic celecoxib therapy will also 
require chronic antihypertensive therapy. KIT-302 is intended to treat these patients. 
The proposed indications for KIT-302 are a subset of those for the combined labeling of the 
individual marketed prescription drug products (i.e., amlodipine besylate tablets and celecoxib 
capsules), and in particular, a subset of those for which qd administration is an option. Thus, the 
proposed indications in the usage section of the KIT-302 product labeling are anticipated to read 
as follows: “KIT-302 is indicated for the treatment of hypertension, to lower blood pressure, in 
patients who also require the use of a NSAID for relief of the signs and symptoms of osteoarthritis.  
Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily 
strokes and myocardial infarctions.” 
The formulation of KIT-302 consists of amlodipine besylate and celecoxib co-formulated in a 
single immediate release tablet. The dosage form was developed so that it will show 
bioequivalence (BE) to the individually marketed prescription amlodipine besylate tablets and 
celecoxib capsules given together. The strengths of the KIT-302 tablets reflect the three different 
possible combinations of the strengths of individual marketed prescription drug products for the 
proposed indications. 
The previous human experience with the KIT-302 formulation (i.e., the FCDP) is limited to 
bioavailability studies in healthy volunteers under fasted (Study No. DXE-P6-039) and fed states 
(Study No. DXE-P6-127 and Study No. TRC 009/10219).  However, an efficacy study (Study No. 
KIT-302-03-01) was conducted using the individual components, amlodipine besylate and 
celecoxib, and the latter have been approved and marketed in the US and worldwide for many 
years (amlodipine besylate tablets were first approved in 1992 and celecoxib capsules were first 
approved in 1998), and have well-established clinical safety profiles.  
Amlodipine besylate tablets are recognized as being generally safe for patients.  Post-marketing 
surveillance has confirmed the safety of amlodipine besylate tablets.  While generally regarded as 
safe, celecoxib and other NSAIDs can cause gastrointestinal ulcerations and cardiovascular 
problems.  Copies of the prescribing information for prescription amlodipine besylate [Norvasc® 
(amlodipine besylate) tablets] and prescription celecoxib [Celebrex® (celecoxib) capsules] are 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 20 
CONFIDENTIAL 
included in Appendices F and G, respectively.  These product labelings list the adverse events 
(AEs) that can be expected from the drug substances. 
The concomitant oral administration of labeled doses of amlodipine besylate and celecoxib does 
not appear to present any new safety issues in terms of potential additive or synergistic 
pharmacodynamic, pharmacokinetic (PK), or toxicological interactions.  The FCDP is not 
anticipated to produce systemic exposures to either drug greater than those associated with current 
clinical use of either drug administered alone or in combination. 
Study No. DXE-P6-039 and Study No. DXE-P6-127 demonstrated that a single oral dose of the 
highest strength KIT-302 dosage form (10 mg amlodipine besylate/200 mg celecoxib) is BE to the 
individual commercially available products given together (10 mg amlodipine besylate tablet + 
200 mg celecoxib capsule) in healthy volunteers under fasted and fed conditions, respectively.  
The combination was well tolerated, and no new AE findings occurred relative to the individual 
prescribing information for amlodipine besylate tablets and celecoxib capsules. 
The findings of Study No. DXE-P6-127 were consistent with the earlier pilot BE study in healthy 
males under fed conditions (Study No. TRC 009/10219).  In the latter study, two prototype 
formulations of KIT-302 were evaluated, and prototype formulation 1 was shown to be BE to the 
individual commercial drugs given together.  Prototype formulation 1 was pursued for the 
manufacture of registration stability lots of KIT-302 FCDP and one of the resulting lots was used 
for the full BE studies (Study Nos. DXE-P6-039 and DXE-P6-127).  As with the full BE studies, 
the pilot BE study showed the formulation to be well tolerated, with no new AE findings.   
In November 2015, Kitov completed a phase 3 pivotal study (KIT-302-03-01) comparing 
amlodipine monotherapy at a dose of 10 mg/day, with the combination of the components of KIT-
302 at a dose of 10 mg amlodipine plus 200 mg celecoxib/day.  The study also included a double 
placebo arm and a celecoxib monotherapy arm (200 mg/day).  For the combination arm, two 
separate capsules were used, one containing the commercial amlodipine tablet and one containing 
the commercial celecoxib capsule.  Each of the commercial formulations were individually OE, as 
were the matched placebo tablets and capsules to allow for blinding. 
One hundred fifty-two (152) adult subjects with newly diagnosed hypertension who required 
pharmacological therapy to control their hypertension were randomized 1.5:1.5:1:1 to one of the 
four treatment arms (amlodipine/celecoxib:  10/200 mg, 10/0 mg, 0/200 mg, and 0/0 mg) and were 
administered study drug once a day for 14 days.  Subjects underwent 24-hour ambulatory blood 
pressure monitoring at baseline, during the initial 24 hours of therapy, after one week of therapy, 
and after two weeks of therapy.   
The mean changes in average daytime (9:00 to 21:00) ambulatory systolic blood pressure (SBPday), 
average daytime (9:00 to 21:00) diastolic blood pressure (DBPday), average night-time (01:00 to 
06:00) ambulatory systolic blood pressure (SBPnight), and average night-time (01:00 to 06:00) 
diastolic blood pressure (DBPnight) from baseline to end of therapy are listed below. Subjects in the 
amlodipine monotherapy arm had a mean reduction in SBPday of 8.8 ± 8.1 mm Hg after 14 days of 
treatment, whereas subjects in the amlodipine + celecoxib arm had a mean reduction of 10.6 ± 9.2 
mm Hg.  The combination was shown to be statistically non-inferior to amlodipine alone (p 
<0.001), and the primary efficacy endpoint of the study was successfully achieved.  Further, the 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 21 
CONFIDENTIAL 
change in SBPday showed a synergistic effect with the combination over amlodipine monotherapy. 
The change in DBPday showed a similar synergistic effect with the combination over amlodipine 
monotherapy and this synergy was even greater with respect to the SBPnight and DBPnight changes.  
Celecoxib monotherapy did tend to raise blood pressure (BP), not lower it, as expected, although 
statistical significance was not achieved. 
Changes in Blood Pressure from Baseline to End of Therapy  
(Mean ± Standard Deviation mm Hg) 
 
SBPday 
DBPday 
SBPnight 
DBPnight 
Placebo 
-2.1 ± 8.2 
-0.3 ± 5.4 
-1.4 ± 9.2 
0.0 ± 6.2 
Celecoxib 
-0.5 ± 8.8 
-1.5 ± 5.1 
-1.7 ± 12.3 
0.3 ± 7.1 
Amlodipine 
-8.8 ± 8.1 
-5.5 ± 5.1 
-6.4 ± 11.4 
-3.2 ± 7.8 
Amlodipine + Celecoxib 
-10.6 ± 9.2 
-7.5 ± 6.4 
-10.5 ± 10.6 
-7.0 ± 8.6 
Consistent with the known potential of celecoxib to alter renal physiology, the celecoxib 
monotherapy arm showed a trend towards worsened function as measured by the change in serum 
creatinine from baseline to end of therapy relative to the placebo arm.  In contrast, the amlodipine 
monotherapy showed a trend towards improved renal function compared to placebo.  Further, the 
combination of the two (amlodipine + celecoxib) showed a trend towards improved renal function 
that was greater than that noted for amlodipine alone. 
The oral administration of 10 mg amlodipine besylate and 200 mg celecoxib, either individually 
(i.e., with a matched placebo) or in combination once daily for 14 days in adult subjects with newly 
diagnosed hypertension who required pharmacological therapy was well tolerated.  No deaths or 
serious adverse events (SAEs) were reported in Study No. KIT-302-03-01.  Of the AEs that were 
considered to be related to the study drugs (i.e., assigned as either a suspected adverse reaction or 
adverse reaction by the Investigator), all were mild in severity, except for a single incidence of 
headache that was moderate in severity.  Further, all of these AEs fully resolved. 
Study No. KIT-302-03-01 also included the collection of PK blood samples at the end of the study 
(i.e., steady state; Day 14) in a subset of the trial population to evaluate for drug-drug interactions.  
The analyses showed that amlodipine had no statistically significant effect on the plasma levels of 
celecoxib.  However, celecoxib reduced the plasma levels of amlodipine by approximately a third 
(p <0.001).  The mechanism for the enhancement in efficacy (lowering of BP) and trend towards 
improved renal function despite the reduction in the plasma concentration of amlodipine is 
currently unknown. Kitov hypothesizes that celecoxib prevents the fluid retention amlodipine 
causes (it acts in a manner similar to a diuretic) as evidenced by the reduced rate of oedema 
reported in patients receiving the combination therapy in the trial (8.2%) as opposed to those 
receiving amlodipine monotherapy (15.6%).  Such a diuretic type effect would be expected to 
lower BP. 
For further details regarding Study No. KIT-302-03-01 and the bioavailability studies, please refer 
to the most current version of the Investigator’s Brochure (IB) for KIT-302.   
This study will be performed in compliance with the current ICH guidelines for GCP and all 
applicable regulatory requirements. 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 22 
CONFIDENTIAL 
2. STUDY OBJECTIVES 
2.1 Primary Objective 
The primary efficacy objective of this study is to demonstrate that the mean reduction in SBPday 
after oral administration of amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given 
together qd for 14 days in adult subjects with existing hypertension is no less than half the mean 
reduction in SBPday after oral administration of amlodipine tablets (10 mg) given alone (i.e., with 
matched celecoxib placebo) qd for 14 days in the same population. 
2.2 Secondary Objectives 
The secondary objectives of this study are as follows: 
1. To evaluate the effect of amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given 
together qd for 14 days in adult subjects with existing hypertension on secondary efficacy 
endpoints using a serial gatekeeping strategy. If and only if the primary efficacy endpoint is 
statistically achieved, a secondary hierarchical analysis will be used to evaluate the endpoints 
listed below, and will only proceed to the next endpoint in the list if the alpha is met for the 
prior analyses. 
a. Difference in mean change in body weight from baseline to end of treatment between 
treatment arms [amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given 
together, amlodipine tablets (10 mg) given alone (with matched celecoxib placebo), and 
placebo]; 
b. Difference in the mean reduction in average 24-hour ambulatory systolic blood pressure 
(SBP24h) from baseline to end of treatment between amlodipine tablets (10 mg) and 
celecoxib capsules (200 mg) given together and amlodipine tablets (10 mg) given alone 
(with matched celecoxib placebo) treatment arms; 
c. Difference in the mean reduction in average 24-hour ambulatory diastolic blood pressure 
(DBP24h) from baseline to end of treatment between amlodipine tablets (10 mg) and 
celecoxib capsules (200 mg) given together and amlodipine tablets (10 mg) given alone 
(with matched celecoxib placebo) treatment arms;  
d. Difference in the mean change in creatinine clearance from baseline to end of treatment 
between amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together and 
amlodipine tablets (10 mg) given alone (with matched celecoxib placebo) treatment arms.  
2. To evaluate the safety of amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given 
together qd for 14 days in adult subjects with existing hypertension. 
3. To evaluate the effect of celecoxib on the mean plasma concentrations of amlodipine in adult 
subjects with existing hypertension after 14 days of treatment with amlodipine tablets (10 mg) 
and celecoxib capsules (200 mg) given together compared to amlodipine tablets (10 mg) given 
alone (with matched celecoxib placebo). 
 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 23 
CONFIDENTIAL 
3. STUDY DESIGN 
This is a multi-center, randomized, double blind, placebo controlled trial to evaluate the effect of 
celecoxib on the efficacy, safety, and pharmacokinetics of amlodipine in subjects with existing 
hypertension requiring antihypertensive therapy.  
Approximately 105 adult subjects who require and are currently using pharmacological therapy 
with a single agent that is not a calcium channel blocker to control their hypertension will be 
randomized 3:3:1 to one of three treatment arms:  
1. OE Norvasc® tablet (10 mg amlodipine besylate) + OE Celebrex® capsule (200 mg 
celecoxib); 
2. OE Norvasc® tablet (10 mg amlodipine besylate) + matched placebo for OE Celebrex® 
capsule; 
3. Matched placebo for OE Norvasc® tablet + matched placebo for OE Celebrex® capsule. 
All drugs will be administered orally qd for 14 days (Days 0-13) for a total of 14 doses.  The total 
number of subjects planned (105) is an approximation.  Once the 105th subject is randomized to 
treatment (Day 0), any subject that is currently participating in the washout period will be allowed 
to complete the washout period and if found eligible will be enrolled into the trial.  These subjects 
will continue to be randomized 3:3:1 as noted above.  No further subjects will be brought in for 
the Initial Screening Visit once the 105th subject is randomized. 
Initial Screening Visit (Day -14 to -10): Each subject will be provided with oral and written 
information (ICF) describing the study and will have any questions answered. Subjects that 
consent in writing to participate in the study will undergo eligibility assessments, including 
complete medical history, comprehensive physical examination, height, body weight in underwear 
and a light gown, body mass index (BMI), vital signs (BP, pulse rate, respiration rate, and oral 
body temperature), 12-lead electrocardiogram (ECG), hematology, serum chemistry, urinalysis, 
serum pregnancy test for women of childbearing potential (WCBP), urine drug screen, and record 
medications taken within 30 days prior to initial screening visit.  
Subjects who meet eligibility criteria based on the above initial screening visit procedures will be 
instructed to cease taking their current BP medication. Monitoring for pretreatment adverse events 
(PTAEs) will begin upon completion of the initial screening visit procedures and will continue 
through the 9 to 13 days of washout, the final screening visit on Day -1, and the baseline procedures 
on Day 0 (i.e., prior to the administration of the first dose of study drugs). Any untoward medical 
occurrence that initiates or worsens after completion of the initial screening visit procedures and 
before administration of the first dose of study drugs will be recorded as a PTAE. Subjects will be 
instructed to return to the clinic in 9 to 13 days. 
Final Screening Visit (Day -1) Subjects will return to the clinic after 9 to 13 days of washout for 
their final screening visit (Day -1). They will undergo the following procedures: solicit for history 
of PTAEs since the previous visit and record medications taken since prior visit. Those who 
continue to meet eligibility criteria will be given an ambulatory blood pressure monitor (ABPM), 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 24 
CONFIDENTIAL 
instructed in its use, and have the positioning of their ABPM checked. They will be instructed to 
wear it at all times for the next 25 hours and to return to the clinic the following day. 
Study Day 0: When the subjects return to clinic the following day, the ABPM will be collected 
and the data contained therein downloaded and analysed. If subjects are found to be hypertensive, 
based upon their ABPM measurement, they will undergo additional baseline procedures as 
described below. If the subject’s BP is too elevated for them to continue safely in the study (i.e., 
SBP24h > 169 mmHg or DBP24h > 110 mmHg), the subject will not be enrolled and they will be 
instructed to resume taking their prescribed BP medication as directed by the study doctor or 
general practitioner. If the subject is found to be normotensive (SBPday ≤ 135 mmHg), the subject 
will not be enrolled. The subject’s primary care doctor will be informed that he/she has been found 
not to be hypertensive. No subject will be randomized until these baseline ABPM data have been 
reviewed and it has been documented that the subject meets entry BP criteria.  
Subjects who meet the BP criteria (SBPday > 135 and ≤ 169 mmHg and DBPday ≤ 110 mmHg) 
following completion of the 10- to 14-day washout period will undergo the following additional 
baseline procedures: solicit for history of PTAEs since the previous visit, targeted physical 
examination, body weight in underwear and a light gown, vital signs, orthostatic hypotension 
evaluation, serum chemistry, and record medications taken since last visit. Subjects that continue 
to meet all eligibility requirements will be enrolled in the study and randomized 3:3:1 to one of 
three treatment arms. The subjects will then be administered their first dose of study drugs in the 
clinic. 
Monitoring for treatment emergent adverse events (TEAEs) will begin immediately following 
administration of the first dose of study drugs and will continue throughout the study. Any 
untoward medical occurrence that initiates or worsens after the first dose of study drugs and within 
14 days of the last dose of study drugs will be recorded as a TEAE. Subjects will remain in the 
clinic under observation for one hour following their first dose and will be solicited for TEAE 
history prior to leaving the clinic. Subjects will be provided with sufficient study drugs for the 
remainder of the 2-week treatment period, and instructed to take the study drugs qd in the morning. 
Subjects will be provided with a diary and instructed to record any concomitant medications taken 
and details of study drug administration. Subjects will be instructed to return to clinic the morning 
of Day 6. 
Study Day 6: Subjects will return to clinic on the morning of Day 6 and will be solicited for history 
of TEAEs since the previous visit. The study drug containers will be collected and unused study 
drug counted and recorded. The diary will be reviewed for details of study drug administration and 
any concomitant medications taken since the previous visit. Subjects will be given an ABPM, 
instructed in its use, and have the positioning of their ABPM checked. The subjects will then be 
administered their Day 6 dose of study drugs, and instructed to wear the ABPM at all times for the 
next 25 hours. Subjects will be given back their remaining study drug supply and diary, instructed 
to record any concomitant medications taken and details of study drug administration, and to return 
to clinic the following day.  
Study Day 7: The Day 7 study drugs will be self-administered at home within 24 hours ± 1 hour 
from the Day 6 dose. Subjects will return to clinic on the morning of Day 7 (after the home 
administration of study drugs). The diary will be reviewed for any concomitant medications taken 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 25 
CONFIDENTIAL 
and for details of study drug administration since the previous visit. The study drug containers will 
be collected and unused study drug counted and recorded. Subjects will be solicited for history of 
TEAEs since the previous visit. A targeted physical examination will be performed and body 
weight in underwear and light gown, and vital signs will be measured. An orthostatic hypotension 
test will be performed. Subjects will have BP as measured by the ABPM recorded and the ABPM 
collected. Subjects will have blood collected for measurement of creatinine (and calculation of 
creatinine clearance) and electrolytes. 
If the Investigator determines that it is safe for the subject to continue in the study, the subject will 
have their remaining study drug supply returned to them, and instructed to take the study drugs at 
home on Days 8-12, between 0700 and 1000 hours, and preferably at approximately the same time 
each day. Subjects will be given back their diary and instructed to record any concomitant 
medications taken and details of study drug administration, and instructed to return to the clinic in 
6 days (on the morning of Day 13). 
If the subject’s BP is too elevated for them to continue safely in the study (i.e., 
SBP24h > 169 mmHg or DBP24h > 110 mmHg), blood will be drawn for renal profile testing. The 
subject will be instructed to cease taking study drugs, instructed to resume taking their prescribed 
BP medication as directed by the study doctor or general practitioner, given back their diary and 
instructed to record any concomitant medications taken between visits, and instructed to return to 
the clinic in 7 days (Day 14). 
Study Day 13: Subjects will return to clinic on the morning of Day 13 (except for those 
discontinued from study drug due to excessive hypertension or other safety reasons) and will be 
solicited for history of TEAEs since the previous visit. The diary will be reviewed for details of 
study drug administration and any concomitant medications taken since the previous visit. The 
study drug containers will be collected and any unused study drug counted and recorded. Subjects 
will be given an ABPM, instructed in its use, and have the positioning of their ABPM checked. 
The subjects will then be administered their Day 13 dose of study drugs (final dose), and instructed 
to wear the ABPM at all times for the next 25 hours. Subjects will be given back their diary and 
instructed to record any concomitant medications taken between visits, and instructed to return to 
clinic the following day.  
Study Day 14: Subjects will return to clinic on the morning of Day 14. The diary will be reviewed 
for any concomitant medications taken since the previous visit. Subjects will be solicited for 
history of TEAEs since the previous visit. A comprehensive physical examination will be 
performed and body weight in underwear and a light gown and vital signs will be measured. BP 
as measured by the ABPM will be recorded and the ABPM collected. An orthostatic hypotension 
evaluation will be performed. The following additional evaluations will be performed: 12-lead 
ECG, hematology, serum chemistry, urinalysis, and urine pregnancy test for WCBP.  
In addition, subjects will have a blood sample collected 24 hours ± 1 hour post-dose for 
measurement of amlodipine concentrations. Only subjects enrolled at Investigational Sites that 
have UV-shielded lights will participate in the PK blood collections. Due to the design of the trial 
(randomized, double-blind, placebo-controlled), this blood sample will be collected and analyzed 
for all participating subjects, regardless of whether they are in a treatment arm that receives 
amlodipine. 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 26 
CONFIDENTIAL 
Following the Day 14 evaluations, the subjects will be instructed to resume taking their prescribed 
BP medication as directed by the study doctor or general practitioner, given back their diary and 
instructed to record any concomitant medications taken between visits, and instructed to return to 
the clinic in 14 days (Day 28). 
Study Day 28: Subjects will return to clinic on Day 28 for their final study visit (follow-up visit). 
The diary will be reviewed for any concomitant medications taken since the prior visit. Subjects 
will be solicited for history of TEAEs since the previous visit. A targeted physical examination 
will be performed and vital signs will be measured. For subjects whose study drugs are 
discontinued at Day 7, this follow-up visit will still occur on Day 28 (i.e., these subjects will return 
to the clinic for both the Day 14 and Day 28 visits). 
 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 27 
CONFIDENTIAL 
4. ELIGIBILITY CRITERIA 
4.1 Inclusion Criteria 
A subject may be included in this study if he or she meets all of the following criteria: 
1. Adult 40 to 75 years of age; 
2. Existing hypertension that is being treated using pharmacological therapy with a single 
agent that is not a calcium channel blocker; 
3. SBPday > 135 and ≤ 169 mmHg and DBPday ≤ 110 mmHg at Day 0 (i.e., after the 10- to 14-
day washout from prior BP medication);  
4. Body Mass Index (BMI) of 18.5 to 34.9 kg/m2; 
5. Healthy (other than hypertension) as determined by the Investigator based on medical 
history, physical examination, vital signs, 12-lead ECG, and clinical laboratory tests; 
6. A negative pregnancy test at initial screening visit; 
7. If WCBP, agree to use a highly effective form of birth control while on study (from 
Screening through final study visit); 
Highly effective methods of birth control are defined as those, alone or in combination, 
that result in a low failure rate (i.e., less than 1% per year) when used consistently and 
correctly.  Forms of birth control include intrauterine device (IUD), birth control patch 
or vaginal ring, oral, or injectable or implanted contraceptives, or a vasectomized 
partner, or abstinence from sexual intercourse. Abstinence is acceptable only as true 
abstinence: when this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception. 
A woman that is postmenopausal (≥2 years since last menstrual period) or permanently 
sterilized (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy) is not 
considered a WCBP. 
8. Able to comprehend and sign an ICF. 
4.2 Exclusion Criteria 
A subject will be excluded from this study if he or she meets any of the following criteria: 
1. Resting systolic BP > 169 mmHg or a resting diastolic BP > 110 mmHg at initial 
screening visit while on their standard antihypertensive therapy (where resting is defined 
as supine for at least 10 minutes with minimal interaction); 
2. Weight < 55 kg; 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 28 
CONFIDENTIAL 
3. Fragile health; 
4. Evidence of clinically significant findings on screening evaluations (clinical, laboratory, 
and ECG) which, in the opinion of the Investigator would pose a safety risk or interfere 
with appropriate interpretation of safety data; 
5. Current or recent history (within four weeks prior to initial screening visit) of a clinically 
significant bacterial, fungal, or mycobacterial infection; 
6. Current clinically significant viral infection; 
7. History of malignancy, with the exception of cured basal cell or squamous cell carcinoma 
of the skin; 
8. Major surgery within four weeks prior to initial screening visit;  
9. Presence of a malabsorption syndrome possibly affecting drug absorption (e.g., Crohn’s 
disease or chronic pancreatitis); 
10. Active peptic ulceration or history of gastrointestinal bleeding; 
11. History of myocardial infarction, congestive heart failure, or stroke; 
12. Any current cardiovascular disease (other than hypertension); 
13. History of psychotic disorder; 
14. History of alcoholism or drug addiction or current alcohol or drug use that, in the opinion 
of the Investigator, will interfere with the subject’s ability to comply with the dosing 
schedule and study evaluations; 
15. History of any illicit drug use within one year prior to initial screening visit; 
16. Positive drug screen at initial screening visit.  A positive drug screen for opiates only 
(with all other drug tests negative) will not be a basis for exclusion if the subject took 
over-the-counter narcotics as indicated on the product label within 24 hours prior to the 
drug screen;  
17. Current treatment or treatment within 30 days prior to first dose of study drugs with 
another investigational drug or current enrollment in another clinical trial;  
18. Known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C;  
19. Known hypersensitivity to amlodipine or celecoxib; 
20. Known hypersensitivity to the inactive ingredients in the OE study drugs; 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 29 
CONFIDENTIAL 
21. Asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic 
type reactions after taking acetylsalicylic acid or NSAIDs including cyclooxygenase-2 
(COX-2) inhibitors; 
22. Subjects who, in the opinion of the Investigator, are unable or unlikely to comply with 
the dosing schedule and study evaluations; 
23. Pregnant or lactating; 
24. Unable to correctly use ABPM after instruction on its use; 
25. Subjects with Child-Pugh Class B or C cirrhosis; 
26. Subjects currently taking a calcium channel blocker or any NSAID for any reason will be 
excluded. Subjects will not be withdrawn from these drugs to be enrolled in the trial; 
27. Subjects that took a calcium channel blocker in the past for any indication; 
28. Creatinine clearance < 50 ml/min as estimated by the Cockroft-Gault equation*; 
*Cockroft-Gault equation: 
estimated creatinine clearance = (140 – age) X body weight (kg)/72 X PCr (mg/dL) 
multiply by 0.85 for women 
29. Known cytochrome P450 2C9 (CYP2C9) poor metabolizer; 
30. Subjects with allergy or hypersensitivity to sulfonamides. 
4.3 Withdrawal of Subjects 
A subject may choose to withdraw from this study at any time for any reason without penalty of 
jeopardizing their health care or loss of benefits to which the subject is otherwise entitled.  
Subjects will be withdrawn from this study if one or more of the following events occur: 
1. Subject requests to be withdrawn from study; 
2. Allergic reaction or hypersensitivity reaction to the study drugs; 
3. The subject’s BP is too elevated for them to continue safely in the study (i.e., 
SBP24h > 169 mmHg or DBP24h > 110 mmHg); 
4. AE (PTAE or TEAE) that in the judgment of the Investigator poses unacceptable risk to 
the subject; 
5. Intercurrent illness that requires treatment that is not consistent with the protocol 
requirements, or intercurrent illness or the associated treatment that in the judgment of 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 30 
CONFIDENTIAL 
the Investigator poses a significant risk to the subject for continued participation in the 
study; 
6. Pregnant or suspected of being pregnant; 
7. Use of prohibited medication (listed in Section 5.6) that in the judgment of the 
Investigator and Sponsor’s Medical Monitor poses a significant risk to the subject for 
continued participation in the study or that will interfere with the interpretation of the 
results of this study; 
8. Significant protocol violation or noncompliance on the part of the subject or the 
Investigator including inability to correctly use the ABPM; 
9. Sponsor terminates the study or the Investigational Site terminates the study at their site; 
10. Any other reason that in the judgment of Investigator poses unacceptable risk to the 
subject. 
If a subject is withdrawn from the study, the date and reason will be recorded in the source 
documents and the case report form (CRF), and the Day 14 and Day 28 study evaluations will be 
performed if feasible. Any subject withdrawn due to a study drug-related TEAE (adverse reaction 
or suspected adverse reaction per the definitions in Section 8.1.3) will be followed until resolution 
or stabilization of the event. 
If subject becomes pregnant or is suspected of being pregnant, study drugs will be discontinued 
immediately, and the subject will be referred to an obstetrician/gynecologist experienced in 
reproductive toxicity for further evaluation and counseling. The subject will be followed until 
delivery or other termination of pregnancy for outcome. 
Subjects may choose to withdraw authorization to use and disclose their Protected Health 
Information (PHI) as defined by the Health Insurance Portability and Accountability Act (HIPAA) 
of 1996 or foreign equivalent where appropriate. Such withdrawal of authorization must be made 
to the Investigator in writing. Any PHI collected by the Investigator or Sponsor prior to the date 
of such withdrawal will continue to be used and disclosed.  
4.4 Termination of Trial 
The Sponsor has the right to terminate this study, and the Investigator/Investigational Site has the 
right to close the site, at any time, although this should occur only after consultation between 
involved parties. The Investigator must notify the IRB/IEC in writing of a premature termination 
of a study or closure of Investigational Site, and must send a copy of the notification to the Sponsor.  
Events that may trigger premature termination of a study or closure of an Investigational Site 
include, but are not limited to, a new toxicity finding, a request to discontinue the trial from a 
regulatory authority, non-compliance with the protocol, slow recruitment, or change in 
development plans for the study drugs.  
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 31 
CONFIDENTIAL 
5. STUDY DRUGS 
5.1 Description of Investigational Drugs 
5.1.1 Active Pharmaceutical Ingredients 
Amlodipine besylate is a Ca channel blocker. The chemical name of amlodipine is 3-ethyl-5-
methyl 
(±) 
2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)- 
1,4-dihydro-6 
methyl-3,5-
pyridinedicarboxylate, monobenzenesulphonate. Amlodipine besylate has a molecular weight of 
567.06 and a molecular formula of C20H25ClN2O5•C6H6O3S. 
Celecoxib is a sulfa NSAID and selective COX-2 inhibitor. The chemical name of celecoxib is 4-
[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide. Celecoxib has a 
molecular weight of 381.38 and a molecular formula of C17H14F3N3O2S.  
5.1.2 Drug Products 
Two commercial formulations will be used for this trial. The two formulations are as follows: 
1. Norvasc® (amlodipine besylate) tablets (10 mg amlodipine besylate, Pfizer): Each tablet 
contains 10 mg amlodipine besylate (base equivalents) and the following inactive 
ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium 
starch glycolate, and magnesium stearate.  
2. Celebrex® (celecoxib) capsules (200 mg celecoxib, GD Searle): Each tablet contains 
200 mg celecoxib and the following inactive ingredients: croscarmellose sodium, edible 
inks, gelatin, lactose monohydrate, magnesium stearate, povidone, and sodium lauryl 
sulfate.  
This study is a double blind, placebo controlled study. Therefore, the commercial formulations 
will be OE and matched placebos will be used to allow for blinding. The capsules used for OE will 
be back-filled with microcrystalline cellulose.  So as to aid in identifying the study drugs, opaque, 
white DB, AA hard gelatin capsules will be used to over-encapsulate the celecoxib capsules and 
the matched placebo. Opaque, Swedish Orange DB, AAA hard gelatin capsules will be used to 
over-encapsulate the amlodipine tablets and the matched placebo. 
Subjects will be required to take two capsules on a qd basis. One will be an OE Norvasc® tablet or 
matched placebo for the OE Norvasc® tablet. The second will be an OE Celebrex® capsule or 
matched placebo for the OE Celebrex® capsule. Each of the OE drug products will be supplied in 
a separate container. Subjects will therefore be instructed to take one capsule from each of the two 
containers on a qd basis. 
5.1.3 Packaging and Labeling  
The Sponsor will supply all study drugs for this trial. The Investigational Site personnel and the 
subjects will be blinded to the treatment.  


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 32 
CONFIDENTIAL 
The study drugs will be supplied in 15-count high-density polyethylene bottles with child resistant 
closures.  
The double-blind labeling kit (carton) will contain one 15-count bottle of OE Norvasc® tablet or 
matched placebo for the OE Norvasc® tablet and one 15-count bottle of OE Celebrex® capsule or 
matched placebo for the Celebrex® capsule.  
Medications will be labeled according to the requirements of local law and legislation. Each patient 
kit, and the two bottles of study drug within the kit, will be labeled with a randomization number. 
Label text will be approved according to agreed Kitov procedures, and a copy of the labels will be 
made available to the study site upon request. Copies of the labels will be available in the study 
files. 
Copies of the product labeling for the two commercial formulations (amlodipine tablets and 
celecoxib capsules) are included in Appendices F and G, respectively.  
5.1.4 Storage and Handling 
At the Investigational Site, all study drugs will be stored in a locked, secure area to prevent 
unauthorized access. The study drugs should be stored in compliance with the label requirements. 
The study drugs will be stored in the original packaging at controlled room temperature (15-30°C 
or 59-86°F) protected from light. The subjects will be instructed to store the study drug provided 
in the take home kits in the original packaging at controlled room temperature protected from light. 
5.2 Randomization 
This is a randomized, double blind, placebo controlled study. Subjects will be randomized 3:3:1 
to one of three treatment arms: 
1. OE Norvasc® tablet (10 mg amlodipine besylate) + OE Celebrex® capsule (200 mg 
celecoxib); 
2. OE Norvasc® tablet (10 mg amlodipine besylate) + matched placebo for OE Celebrex® 
capsule; 
3. Matched placebo for OE Norvasc® tablet + matched placebo for OE Celebrex® capsule. 
Randomization will take place on Day 0 when the subject returns to clinic and is found to have 
hypertension based upon the ABPM recordings and continues to meet eligibility criteria following 
baseline procedures.  
A computer-generated randomization schedule will be used for assigning the sequence in which 
subjects are assigned to treatment arms. The randomization code will be prepared in blocks of 7. 
Initial shipments to individual Investigational sites will include 5 patient kits with sequential 
randomization numbers. As subjects are enrolled, the Investigator will take the next sequential kit 
number in the block provided and assign it to the subject. The Investigational sites will be 
re-supplied in the same fashion (i.e., 5 patient kits). 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 33 
CONFIDENTIAL 
Approximately 105 subjects are to be randomized.  Therefore, a sufficient number of subjects will 
be screened so as to achieve approximately 105 subjects entering the randomization phase (starting 
at Day 0).  Once the 105th subject is randomized to treatment (Day 0), any subject that is currently 
participating in the washout period will be allowed to complete the washout period and if found 
eligible will be enrolled into the trial.  These subjects will continue to be randomized 3:3:1 as noted 
above.  No further subjects will be brought in for the Initial Screening Visit once the 105th subject 
is randomized. 
In the event of a medical emergency or a serious TEAE that is unexpected (as defined in Section 
8.1.4) and possibly related to the study drug(s) (i.e., an adverse reaction or suspected adverse 
reaction as defined in Section 8.1.3), the blind will be broken for the subject that experiences the 
event. An emergency code break envelope for each subject will be provided to each Investigational 
Site and also to the Pharmacovigilance Officer at PM Clinical LTD.  In the event that the 
Investigational Site personnel need to unblind the study treatment and cannot access the relevant 
code break envelope at the site, they can contact the Pharmacovigilance Officer at any time at: 
Pharmacovigilance Officer: Dr. Stefania De Santis 
Telephone: +39 0692919456 
Mobile: +39 3894547423 
5.3 Study Drug Administration 
All subjects will take study drugs by mouth qd for 14 days (Days 0-13) for a total of 14 doses. 
With the exception of Days 6 and 13, when study drug intake is at the time of fitting the ABPM 
and of Day 7, when study drug intake is 24 hours ± 1 hour later, the subjects shall be instructed to 
take the study drugs between 0700 and 1000 hours, and preferably at approximately the same time 
each day. At each dose, subjects will take one capsule from each of the two containers (i.e., an OE 
Norvasc® tablet or matched placebo for the OE Norvasc® tablet and an OE Celebrex® capsule or 
matched placebo for the OE Celebrex® capsule). 
The first dose of study drugs (morning dose on Day 0) will be taken in the clinic. Study Day 6 and 
Study Day 13 doses will also be taken in clinic. All remaining doses will be self-administered at 
home. Subjects will be provided with a diary to record the details of study drug administration 
including the time each dose is taken. 
Study drugs will only be dispensed to subjects randomized to treatment under this protocol, and 
only as directed by this protocol. Administration of study drugs will be accurately recorded in each 
subject’s source documents and CRF. 
5.4 Measuring Subject Compliance 
A total of 14 doses of study drugs will be administered. The first dose will be administered in the 
clinic on Study Day 0, as will Study Day 6 and Day 13 doses. The remainder of the doses will be 
self-administered at home. Subjects will be provided with a diary to record details of study drug 
administration for each dose (date, time, number of capsules), and will be instructed to return the 
completed diary at the Day 6, Day 7, and Day 13 clinic visits. 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 34 
CONFIDENTIAL 
Subjects will also be instructed to bring both of their study drug containers back to the clinic at 
Day 6, Day 7, and Day 13. The Investigational Site personnel will collect the study drug containers, 
and will count and record unused study drug. 
5.5 Drug Accountability 
In accordance with current GCP, the Investigational Site will account for all study drug supplies. 
Details of receipt, storage, administration, and return or destruction will be recorded in the study 
drug accountability record according to the standard operating procedure of the Investigational 
Site. Copies of the study drug accountability record will be provided to the Sponsor.  
Investigational supplies will be retained at the clinical site pending instructions for disposition by 
the Sponsor at the end of the study. 
5.6 Concomitant Medications 
All medications (or treatments) other than study drugs taken or received by the subject at any time 
during the study from the first dose of study drugs through the final study visit assessment will be 
considered concomitant medications. Use of all concomitant medications, including any change in 
therapy, must be recorded and updated in the source documentation and on the CRF. 
Subjects are not to consume any NSAIDs (other than study drug) from the initial screening visit 
to the final study visit (Day 28). Subjects will be instructed to take acetaminophen for any pain 
that develops from the time of enrollment until completion of the study or for the treatment of any 
fever that occurs and is deemed to require pharmacological therapy during the course of this study. 
Subjects are not to consume any calcium channel blocker (other than study drug) from the initial 
screening visit to Day 14. Further, a subject will not be eligible to participate in this trial if they 
have ever taken calcium channel blockers for any indication.   
Subjects are not to consume their current BP medication from the initial screening visit to Day 14. 
Following the Day 14 evaluations, subjects will be instructed to resume taking their prescribed BP 
medication as directed by the study doctor or general practitioner. If subjects are found to be too 
hypertensive to continue safely in the study after 7 days of study drug administration, they will be 
removed from the study and instructed to resume taking their prescribed BP medication as directed 
by the study doctor or general practitioner. 
Subjects are not to take any other investigational drugs beginning 30 days prior to the first dose of 
study drugs and continuing until the final study visit (Day 28).  
Information about the known drug interactions with amlodipine and celecoxib can be found in the 
product labelings for prescription amlodipine tablets and celecoxib capsules which are included in 
Appendices F and G, respectively. 
Subjects are to avoid consumption of grapefruit juice for the duration of the study. 
 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 35 
CONFIDENTIAL 
6. SCHEDULE OF EVENTS 
The schedule of events is provided in tabular format in Appendix A, and is summarized below by 
study visit. 
6.1 Screening Visits 
6.1.1 Initial Screening Visit (Day -14 to -10) 
The Investigator is responsible for keeping a record of all subjects screened for entry into the study 
and subsequently excluded. The reason(s) for exclusion will be recorded in the source documents.  
Each subject will be provided with oral and written information (ICF) describing the study and 
will have any questions answered. Written informed consent must be obtained prior to performing 
any screening evaluations. 
The initial screening visit will occur on Day -14 to -10. Subjects will undergo the following 
screening procedures: 
1. Record demographic data (date of birth/age at Screening, gender, and race); 
2. Complete medical history, including baseline concurrent illness assessment; 
3. Review and record medications taken within 30 days prior to initial screening visit; 
4. Height, body weight while only wearing underwear and a light gown, and BMI as 
determined by Weight (kg)/Height (m)2; 
5. Comprehensive physical examination (see Section 8.2); 
6. Vital signs (BP, pulse rate, respiration rate, and oral body temperature); 
7. 12-lead ECG; 
8. Blood sampling for hematology and serum chemistry (see Appendix B for list of tests);  
9. Serum pregnancy test for WCBP only; 
10. Collection of urine for urinalysis (see Appendix B for list of tests); 
11. Urine drug screen (see Appendix B for list of tests); 
12. Assessment of inclusion and exclusion criteria. 
Subjects who meet eligibility criteria based on the above initial screening assessments will be 
instructed as follows: 
1. Cease taking current BP medication; 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 36 
CONFIDENTIAL 
2. Do not take any NSAIDs (other than the study drug) for the duration of the study (through 
Day 28); 
3. Use acetaminophen for the treatment of any pain or fever that develops while on study 
and that is deemed to require pharmacological therapy; 
4. Do not take any calcium channel blocker (other than study drug) through the Day 14 
evaluations; 
5. Do not take any other investigational drugs for the duration of the study (through Day 28); 
6. For WCBP: Use adequate contraceptive methods for the duration of the study (through 
Day 28). For this study, a woman who has been surgically sterilized or who has been in a 
state of amenorrhea for more than two years will be deemed not to be of child bearing 
potential; 
7. Return to the clinic in 9 to 13 days (on the morning of Day -1); 
8. Do not consume any grapefruit juice for the remainder of the study. 
Monitoring for PTAEs will begin upon completion of the initial screening visit procedures and 
will continue through the 9 to 13 days of washout, the final screening visit on Day -1, and the 
baseline procedures on Day 0 (i.e., prior to the administration of the first dose of study drugs). Any 
untoward medical occurrence that initiates or worsens after completion of the initial screening visit 
procedures and before administration of the first dose of study drugs will be recorded as a PTAE. 
6.1.2 Final Screening Visit (Day -1) 
Subjects will return to clinic after 9 to 13 days of washout for their final screening visit (Day -1). 
They will undergo the following procedures:  
1. Solicit history of PTAEs since prior visit; 
2. Review and record medications taken since prior visit.  
Those subjects who continue to meet eligibility criteria will be given an ABPM, instructed in its 
use, and have the positioning of their ABPM checked. They will be instructed to wear it at all 
times for the next 25 hours and to return to the clinic the following day (Day 0). 
6.2 Study Day 0 
Subjects will return to clinic the morning of Day 0. The ABPM will be collected and the data 
contained therein will be downloaded and analyzed. A determination will be made based upon 
these ABPM data as to whether or not the subject meets the BP criteria for enrollment. No subject 
will be randomized until these baseline ABPM data have been reviewed and it has been 
documented that the subject meets entry BP criteria.  


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 37 
CONFIDENTIAL 
If the SBPday is less than or equal to 135 mmHg, the subject will be deemed to be normotensive, 
from a clinical trial standpoint. The subject will not be enrolled in the study. The subject’s 
primary care doctor will be informed that he/she has been found not to be hypertensive. 
If the SBPday is greater than 135 mmHg and ≤ 169 mmHg and the DBPday ≤ 110 mmHg, the 
subject will be deemed to be hypertensive and to meet the BP criteria for this trial. These 
subjects will undergo additional baseline procedures as described below.  
If the subject’s BP is too elevated for them to continue safely in the study (i.e., 
SBP24h > 169 mmHg and/or DBP24h > 110 mmHg), the subject will be instructed to resume 
taking their prescribed BP medication as directed by the study doctor or general practitioner.  
The subject will not be enrolled in the study. 
Subjects who meet the BP criteria for the trial following completion of the 10- to 14-day washout 
period will undergo the following additional baseline procedures: 
1. Solicit history of PTAEs since prior visit; 
2. Review and record medications taken since last visit; 
3. Targeted physical examination (see Section 8.2); 
4. Body weight while only wearing underwear and a light gown; 
5. Vital signs (BP, pulse rate, respiration rate, and oral body temperature); 
6. Orthostatic hypotension evaluation (see Section 8.4); 
7. Blood sampling for serum chemistry (see Appendix B for list of tests); 
8. Review of inclusion/exclusion criteria. 
Subjects that continue to meet all eligibility requirements will be enrolled in the study and 
randomized 3:3:1 to one of three treatment arms. The subjects will then be administered their first 
dose of study drugs in the clinic.  
TEAE monitoring will begin immediately following administration of the first dose of study drugs 
and will continue throughout the study. Any untoward medical occurrence that initiates or worsens 
after the first dose of study drugs and within 14 days of the last dose of study drugs will be recorded 
as a TEAE. Subjects will remain in the clinic under observation for one hour following their first 
dose and will be solicited for TEAE history prior to leaving the clinic. Prior to leaving the clinic, 
the following procedures will be performed: 
1. Instruct subjects to continue to not take their prescribed BP medication; 
2. Instruct subjects to continue to not take any NSAIDs, calcium channel blockers, or 
investigational drugs (other than the study drugs); 
3. For WCBP: Instruct subjects to continue to use adequate contraceptive methods; 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 38 
CONFIDENTIAL 
4. Provide subjects with sufficient study drugs for the remainder of the 2-week treatment 
period and instruct subjects to take the study drugs qd in the morning at home, except for 
the mornings of Days 6 and 13 when the drug will be taken in the clinic. The subjects will 
be instructed to take the Day 1-5 study drugs between 0700 and 1000 hours, and preferably 
at approximately the same time each day; 
5. Provide subjects with a diary and instruct subjects to record any concomitant medications 
taken and details of study drug administration; 
6. Instruct subjects to return to the clinic in 6 days (the morning of Day 6), and to bring the 
completed diary and study drug containers with any unused study drug. 
6.3 Study Day 6 
Subjects will return to clinic on the morning of Day 6 and will undergo the following procedures: 
1. Solicit history of TEAEs since the previous visit; 
2. Collect study drug containers and count and record unused study drug; 
3. Review diary for details of study drug administration and any concomitant medications 
taken since the previous visit; 
4. Provide subjects with ABPM, instruct in its use, and check the positioning of the ABPM. 
Following the placement of the ABPM, the subjects will be administered their Day 6 dose of study 
drugs in the clinic.  Prior to leaving the clinic, the following procedures will be performed: 
1. Instruct subjects to wear the APBM at all times for the next 25 hours; 
2. Subjects will be given back their remaining study drug supply and instructed to take the 
Day 7 study drugs at home 24 hours ± 1 hour after the Day 6 study drugs; 
3. Subjects will be given back their diary and instructed to record any concomitant 
medications taken and details of study drug administration; 
4. Instruct subjects to return to the clinic the following day (on the morning of Day 7), and 
to bring the completed diary and study drug containers with any unused study drug.  
6.4 Study Day 7 
The Day 7 study drugs will be self-administered at home within 24 hours ± 1 hour from the Day 6 
dose. Subjects will return to clinic on the morning of Day 7 (after the home administration of study 
drugs). The following evaluations will be performed: 
1. Solicit history of TEAEs since the previous visit; 
2. Review diary for details of study drug administration and concomitant medications since 
the previous visit; 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 39 
CONFIDENTIAL 
3. Collect study drug containers, and count and record unused study drug; 
4. Targeted physical examination (see Section 8.2); 
5. Body weight while only wearing underwear and a light gown; 
6. Vital signs (BP, pulse rate, respiration rate, and oral body temperature); 
7. Orthostatic hypotension evaluation (see Section 8.4); 
8. Collect the ABPM and download the systolic and diastolic BP values obtained by the 
ABPM and incorporate into the subject’s medical record and CRF; 
9. Blood sampling for measurement of creatinine (and calculation of creatinine clearance) 
and electrolytes (sodium, bicarbonate, calcium, chloride, phosphorous, and potassium). 
If, after completing the Day 7 evaluations, the Investigator determines that it is safe for the subject 
to continue in the study, the following procedures will be performed: 
1. Instruct subjects to continue to not take their prescribed BP medication; 
2. Instruct subjects to continue to not take any NSAIDs, calcium channel blockers, or 
investigational drugs (other than the study drugs); 
3. For WCBP: Instruct subjects to continue to use adequate contraceptive methods; 
4. Subjects will be provided back their remaining study drug supply and instructed to take 
qd in the morning at home starting with the morning dose on Day 8, except for the study 
drugs on Day 13 which are to be taken in clinic. The subjects will be instructed to take the 
Day 8-12 study drugs between 0700 and 1000 hours, and preferably at approximately the 
same time each day; 
5. Subjects will be provided back their diary and instructed to record any concomitant 
medications taken and details of study drug administration; 
6. Instruct subjects to return to the clinic in 6 days (on the morning of Day 13), and to bring 
the completed diary and study drug containers with any unused study drug. 
If during the Day 7 visit, the subject’s BP is too elevated for them to continue safely in the study 
(i.e., SBP24h > 169 mmHg and/or DBP24h > 110 mmHg), blood will be drawn for renal profile 
testing (see Section 8.5). The subject will be instructed to cease taking study drugs, instructed to 
resume taking their prescribed BP medication as directed by the study doctor or general 
practitioner, given back their diary and instructed to record any concomitant medications taken 
between visits, and instructed to return to the clinic in 7 days (Day 14).  


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 40 
CONFIDENTIAL 
6.5 Study Day 13 
Subjects will return to clinic on the morning of Day 13 (except for those discontinued from study 
drug due to excessive hypertension or other safety reasons at Day 7) and will undergo the following 
procedures: 
1. Solicit history of TEAEs since the previous visit; 
2. Review diary for details of study drug administration and concomitant medications since 
the previous visit; 
3. Collect study drug containers and count and record any unused study drug; 
4. Provide subjects with an ABPM, instruct in its use, and check the positioning of the 
ABPM.  
Following the placement of the ABPM, the subjects will be administered their Day 13 dose of 
study drugs (final dose) in the clinic. Prior to leaving the clinic, the following procedures will be 
performed: 
1. Instruct subjects to wear the APBM at all times for the next 25 hours; 
2. Subjects will be given back their diary and instructed to record any concomitant 
medications taken between visits; 
3. Instruct subjects to return to clinic the following day (on the morning of Day 14), and to 
bring the completed diary to the clinic. 
6.6 Study Day 14 
Subjects will return to clinic on the morning of Day 14. The following evaluations will be 
performed: 
1. Solicit history of TEAEs since the previous visit; 
2. Review diary for details of concomitant medications since the previous visit; 
3. Comprehensive physical examination (see Section 8.2); 
4. Body weight while only wearing underwear and a light gown; 
5. Vital signs (BP, pulse rate, respiration rate, and oral body temperature); 
6. Collect the ABPM and download the systolic and diastolic BP values obtained by the 
ABPM and incorporate into the subject’s medical record and CRF; 
7. Orthostatic hypotension evaluation (see Section 8.4); 
8. 12-lead ECG; 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 41 
CONFIDENTIAL 
9. Blood sampling for hematology and serum chemistry (see Appendix B for list of tests); 
10. Collection of urine for urinalysis (see Appendix B for list of tests); 
11. Urine pregnancy test for WCBP only; 
12. Blood sample will be collected at 24 hours ± 1 hour post-dose for measurement of 
amlodipine concentrations. Only subjects enrolled at Investigational Sites that have 
UV-shielded lights will participate in the PK blood collections. Due to the design of the 
trial (randomized, double-blind, placebo-controlled), this blood sample will be collected 
and analyzed for all participating subjects, regardless of whether they are in a treatment 
arm that receives amlodipine. 
Following the Day 14 evaluations, the following procedures will be performed: 
1. Instruct subjects to resume taking their prescribed BP medication as directed by the study 
doctor or general practitioner; 
2. Instruct subjects to continue to not take any NSAIDs or investigational drugs for the 
remainder of the study (through Day 28); 
3. For WCBP: Instruct subjects to continue to use adequate contraceptive methods for the 
remainder of the study (through Day 28); 
4. Subjects will be provided back their diary and instructed to record any concomitant 
medications taken between visits; 
5. Subjects will be instructed to return to the clinic in 14 days (Day 28) for final study visit 
(follow-up visit), and to bring the completed diary to the visit. 
6.7 Study Day 28 
Subjects will return to clinic on Day 28 for their final study visit (follow-up visit). The following 
evaluations will be performed: 
1. Solicit history of TEAEs since last visit; 
2. Review diary for details of concomitant medications taken since last visit; 
3. Targeted physical examination (see Section 8.2); 
4. Vital signs (BP, pulse rate, respiration rate, and oral body temperature). 
For subjects whose study drug is discontinued at Day 7, this follow up-visit will still occur on Day 
28 (i.e., these subjects will return to the clinic for both the Day 14 and Day 28 visits). 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 42 
CONFIDENTIAL 
6.8 Duration of Participation 
The total duration of participation for subjects in this study will be up to 6 weeks (initial screening 
visit through follow-up visit). 
 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 43 
CONFIDENTIAL 
7. ASSESSMENT OF EFFICACY 
7.1 Continuous Recording of Blood Pressure 
BP will be recorded, using ABPM, on three 25-hour periods during the trial: Day -1 to Day 0, 
Day 6 to Day 7, and Day 13 to Day 14. Subjects deemed to be too hypertensive to continue in the 
study after 7 days of study drug administration, will only have one 25-hour ABPM measurement 
following randomization: Day 6 to Day 7. Those treated with study drugs for 14 days, will have 
two 25-hour ABPM measurements following randomization: Day 6 to Day 7 and Day 13 to 
Day 14.  
Subjects will have the ABPM fitted to their upper extremity with the greater BP (See Section 8.3). 
They will be instructed not to remove the monitor and will be shown how to refit it, in case it 
becomes dislodged. 
ABPM measurements will be recorded as described in Appendix D. The subject’s baseline systolic 
and diastolic BP values will be the SBPday, SBPnight, SBP24h, DBPday, DBPnight, and DBP24h obtained 
during the Day -1 to Day 0 ABPM measurement. 
Although BP will be manually taken during clinic visits as part of the safety assessments (Section 
8.3), it is the values obtained from the ABPM that will constitute the official BP values for all 
efficacy determinations and calculations for this study.   
7.2 Body Weight 
Body weight will be measured at Screening, Day 0, Day 7, and at Day 14.  The weight 
measurements will be made using a calibrated scale with the subject wearing only underwear and 
a light gown.   
The body weight measurements will serve a dual function as both a secondary efficacy endpoint 
and a secondary assessment for safety.  Further, the measurement of the change in body weight 
from baseline to the end of treatment will serve as an indirect measure of renal function. 
7.3 Renal Function 
Renal function as measured by estimated creatinine clearance is a secondary efficacy assessment 
of this trial.  Creatinine clearance will be estimated at the initial screening visit, Day 0, Day 7, and 
Day 14.  Creatinine clearance will be estimated by the Cockroft-Gault equation as follows: 
estimated creatinine clearance = (140 – age) X body weight (kg)/72 X PCr (mg/dL) 
multiply by 0.85 for women 
 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 44 
CONFIDENTIAL 
8. ASSESSMENT OF SAFETY 
Safety will be assessed primarily based on reported TEAEs. Secondary safety assessments will 
include the following: physical examination, body weight, vital signs, orthostatic hypotension 
evaluations, ECG, hematology, serum chemistry, and urinalysis. Refer to Appendix A (Schedule 
of Events) for the timing of these safety assessments. 
8.1 Adverse Events 
8.1.1 Definitions 
8.1.1.1 Adverse Event 
An AE is defined in the Guideline for Good Clinical Practice E6(R1) (ICH Harmonised Tripartite 
Guideline, dated June 10, 1996) as follows: 
Any untoward medical occurrence in a subject or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
Any untoward medical occurrence that initiates or worsens after completion of the initial screening 
visit procedures and before administration of the first dose of study drugs will be recorded as a 
PTAE. 
Any untoward medical occurrence that initiates or worsens after the first dose of study drugs and 
within 14 days of the last dose of study drugs will be recorded as a TEAE. 
8.1.1.2 Serious Adverse Event 
An SAE is defined in the Guideline for Good Clinical Practice E6(R1) (ICH Harmonised Tripartite 
Guideline, dated June 10, 1996) as follows: 
Any untoward medical occurrence that at any dose:  
• results in death,  
• is life-threatening,  
• requires inpatient hospitalization or prolongation of existing hospitalization,  
• results in persistent or significant disability/incapacity, or 
• is a congenital anomaly/birth defect. 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 45 
CONFIDENTIAL 
PTAEs meeting the above definition for SAE (disregarding the “at any dose” part of the definition) 
will be considered serious PTAEs.   
TEAEs meeting the above definition for SAE will be considered serious TEAEs 
8.1.2 Severity of Adverse Events 
The severity of PTAEs and TEAEs will be graded according to WHO Toxicity Criteria 
(Appendix C). 
The severity of PTAEs and TEAEs not classified by the above referenced toxicity grading scale 
will be categorized using the following definitions: 
Mild: discomfort noted, but no disruption of normal daily activity 
Moderate: discomfort noted of sufficient severity to reduce or adversely affect normal 
activity 
Severe: incapacitating, with inability to work or perform normal daily activity 
8.1.3 Relationship of Treatment Emergent Adverse Events to the Study Drug 
The Investigator should assess the relationship of TEAEs to the study drug and classify as one of 
the following:  
1. Adverse reaction: AE that is caused by the study drug.  
2. Suspected adverse reaction: AEs for which there is a reasonable possibility that the drug 
caused the AE. Reasonable possibility means there is evidence to suggest a causal 
relationship between the drug and the AE. A suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction. Examples of the types of 
evidence that would suggest reasonable possibility of a causal relationship between the 
drug and the AE are as follows: 
• 
A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
Syndrome) 
• 
One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug (e.g., 
tendon rupture)  
• 
An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other 
events that commonly occur in the study population independent of drug therapy) 
that indicates those events occur more frequently in the drug treatment group than in 
a concurrent or historical control group 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 46 
CONFIDENTIAL 
3. Unrelated: AE for which there is evidence that the AE definitely has an etiology other 
than the study drug. 
8.1.4 Expectedness of Adverse Events 
An unexpected AE is one for which the nature or severity of the event is not consistent with the 
applicable study drug information (i.e., the most current version of the IB, the current product 
labeling for amlodipine tablets, and the current product labeling for celecoxib capsules) or listed 
in this protocol.   
This study will enroll older subjects with existing hypertension. To that end, PTAEs and TEAEs 
can be expected due to the subjects’ age and underlying conditions. These include: hypertension, 
hypertensive crisis, myocardial infarction, congestive heart failure, stroke both hemorrhagic and 
ischemic, any adult forms of cancer, and gastrointestinal ulcerations with complications including 
hemorrhage and perforation. 
By definition, PTAEs initiate prior to administration of the first dose of study drugs, and thus a 
comparison against study drug specific risk information is inappropriate for determining 
expectedness of PTAEs.  Thus, only AEs that can be expected due to subject age and underlying 
conditions are relevant for the expectedness determination for PTAEs.   
8.1.5 Monitoring of Adverse Events 
Monitoring for PTAEs will begin upon completion of the initial screening visit procedures and 
will continue through the 9 to 13 days of washout, the final screening visit on Day -1, and the 
baseline procedures on Day 0 (i.e., prior to the administration of the first dose of study drugs). Any 
untoward medical occurrence that initiates or worsens after completion of the initial screening visit 
procedures and before administration of the first dose of study drugs will be recorded as a PTAE.  
Monitoring for TEAEs will begin immediately following administration of the first dose of study 
drugs and will continue throughout the study. Any untoward medical occurrence that initiates or 
worsens after the first dose of study drugs and within 14 days of the last dose of study drugs will 
be recorded as a TEAE. 
Subjects will be instructed to report all PTAEs and TEAEs experienced during the study, and 
subjects will be assessed for the occurrence of PTAEs and TEAEs throughout the study. In order 
to avoid bias in eliciting AEs, subjects will be asked general, non-leading questions such as "How 
are you feeling?"  
All study drug-related TEAEs (adverse reaction or suspected adverse reaction per the definitions 
in Section 8.1.3) will be followed until resolution or stabilization of the event. This may require 
additional clinical assessments and laboratory tests.  
8.1.6 Routine Reporting of Adverse Events 
PTAEs and TEAEs, whether or not associated with study drug administration, will be recorded on 
the AE form of the CRF and will be submitted to the Sponsor at regularly scheduled intervals. 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 47 
CONFIDENTIAL 
The information to be entered in the CRF will include: 
1. Medical diagnosis of the event in standard medical terminology (if a medical diagnosis 
cannot be determined, a description of each sign or symptom characterizing the event); 
2. Date of onset of any new AE or the worsening of a previously observed AE. For the days 
when the subject is in the clinic, the time (based on a 24-hour clock) of onset should be 
recorded if available; 
3. Date of resolution of the event (or confirmation ongoing).  For the days when the subject 
is in the clinic, the time (based on a 24-hour clock) of resolution should be recorded if 
available; 
4. Whether the event is serious (per definition in Section 8.1.1.2), and if so, the reason it is 
considered serious; 
5. Severity of AE (per definitions in Section 8.1.2); 
6. Assessment of the relationship of the AE to the study drug (per definitions in 
Section 8.1.3). Relationship assessments will only be made for TEAEs; 
7. Whether the event is expected (per definition in Section 8.1.4); 
8. Action taken in treating the AE (including concomitant medications or therapies 
administered) and/or change in study drug administration or dose (including whether the 
Study Drug was temporarily interrupted or discontinued); 
9. Outcome of AE (recovered/resolved, recovered/resolved with sequelae, not recovered/not 
resolved, fatal, or unknown). Fatal should only be used when death is possibly related to 
the AE. If an outcome for an AE is not available at the time of the initial report, follow-
up will proceed until an outcome is known or followed up to the final study visit.  Any 
subject with a possible study drug-related TEAE at the final study visit will be followed 
until resolution or stabilization of the event.  Further, any serious TEAE, whether or not 
related to study drugs that occurs within 14 days following the last dose of study drugs 
will be followed until resolution or stabilization of the event. 
8.1.7 Reporting of Serious Adverse Events, Including Death 
Serious PTAEs or serious TEAEs, including death due to any cause, which occur during this study 
or within 14 days following the last dose of the study drugs, whether or not related to the 
administration of study drugs, must be reported by the Investigator or other Investigational Site 
personnel directly to the Pharmacovigilance Officer at PM Clinical LTD by fax within 24 hours 
of learning of the event. The Pharmacovigilance Officer will forward this information to the 
Medical Monitor for review. The contact information for the Pharmacovigilance Officer is 
provided below. 
Pharmacovigilance Officer: Dr. Stefania De Santis 
Telephone: +39 0692919456 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 48 
CONFIDENTIAL 
Mobile: +39 3894547423 
Fax: +39 0656561998 
SAE Forms will be provided by the Sponsor or Sponsor designated CRO. If all information is not 
known at the time of initial reporting, an initial report should still be made. In the event there is a 
question as to whether the experience is serious, the information should be forwarded to the 
Pharmacovigilance Officer, who will then forward the information on to the Medical Monitor for 
review. The Investigator is responsible for following up on completion of the SAE Form. The 
Investigator will submit substantiating data in hard copy form, such as diagnostic test reports and 
progress notes, to the Pharmacovigilance Officer. In the case of fatality, autopsy reports will be 
furnished to the Pharmacovigilance Officer as soon as available. 
In the event of a medical emergency or a serious TEAE that is unexpected (as defined in Section 
8.1.4) and possibly related to the study drug(s) (i.e., an adverse reaction or suspected adverse 
reaction as defined in Section 8.1.3), the blind will be broken for the subject that experiences the 
event. An emergency code break envelope for each subject will be provided to each Investigational 
Site and also to the Pharmacovigilance Officer. In the event that the Investigational Site personnel 
need to unblind the study treatment and cannot access the relevant code break envelope at the site, 
they can contact the Pharmacovigilance Officer at any time. 
The following information about the subject and the reported SAE will be collected on the SAE 
Form: 
1. Subject identification including subject number, initials, and date of birth; 
2. Randomization number (only for serious TEAE); 
3. Date of first dose of study drugs and details of administration, including study drug names 
(including labeled strength and manufacturer), lot number, expiration date, and dose (only 
for serious TEAEs). If the serious TEAE does not require breaking of the blind, certain 
study drug specific details will not be available to enter in the initial SAE Form, but will 
be reported in the SAE Form updates; 
4. Date of last dose of study drugs (i.e., prior to onset of SAE) and details of administration, 
including study drug names (including labeled strength and manufacturer), lot number, 
expiration date, and dose (only for serious TEAEs). If the serious TEAE does not require 
breaking of the blind, certain study drug specific details will not be available to enter in the 
initial SAE Form, but will be reported in the SAE Form updates; 
5. Medical diagnosis of the event in standard medical terminology (if a medical diagnosis 
cannot be determined, a description of each sign or symptom characterizing the event); 
6. Date of onset of the event. For the days when the subject is in the clinic, the time (based 
on a 24-hour clock) of onset should be recorded if available; 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 49 
CONFIDENTIAL 
7. Date of resolution of the event (or confirmation ongoing). For the days when the subject is 
in the clinic, the time (based on a 24-hour clock) of resolution should be recorded if 
available; 
8. Severity of the event (see Section 8.1.2); 
9. Assessment of the attributability of the event to the study drug (see Section 8.1.3) (only for 
serious TEAE); 
10. Why event is considered serious (per definition in Section 8.1.1.2); 
11. Whether the event is expected (see Section 8.1.4); 
12. Action taken in treating the event and/or change in study drug administration or dose 
(including concomitant medications or therapies administered, whether hospitalization or 
prolongation of hospitalization was required, diagnostic procedures performed, whether 
the study drug was temporarily interrupted or discontinued, and whether the subject was 
discontinued from the study); 
13. Outcome of AE (recovered/resolved, recovered/resolved with sequelae, not recovered/not 
resolved, fatal, or unknown).  Fatal should only be used when death is possibly related to 
the AE. If an outcome is not available at the time of the initial report, follow-up will 
proceed until resolution or stabilization of the event and an updated SAE Form will be 
issued. 
14. All concomitant medications (including doses, routes, regimens, and indications) taken 
within 30 days prior to the initial screening visit through the point of onset of the event; 
15. Pertinent laboratory data; 
16. Medical history. 
The Investigator and the Medical Monitor will review each SAE report and evaluate the 
relationship of the adverse experience to study drug and to underlying disease. Based on the 
Investigator’s and Medical Monitor’s assessment of the adverse experience, a decision will be 
made concerning the need for further action. The primary consideration governing further action 
is whether new findings affect the safety of subjects participating in the clinical trial. If the 
discovery of a new adverse experience related to the study drug raises concern over the safety of 
continued administration of study drug, the Sponsor will take immediate steps to notify the 
regulatory authorities. 
Further action that may be required includes the following: 
1. Alteration of existing research by modification of the protocol; 
2. Discontinuation or suspension of the study; 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 50 
CONFIDENTIAL 
3. Alteration of the informed consent process by modification of the existing consent form 
and informing current study participants of new findings; 
4. Modification of previously identified expected adverse experiences to include adverse 
experiences newly identified as study medication-related. 
Any SAE that is determined by the Sponsor to be reportable to the Food and Drug Administration 
(FDA) as an Investigational New Drug application (IND) Safety Report [as defined in 21 Code of 
Federal Regulations (CFR) 312.32] will be reported to FDA by the Sponsor within the specified 
time frame. All IND Safety Reports will also be promptly provided to the Investigator for 
submission to his or her IRB/IEC. Similarly, any SAE that is determined by the Sponsor to require 
expedited reporting to other regulatory authorities will be reported to the appropriate authorities 
by the Sponsor designated CRO within the specified time frames, and will be provided to the 
Investigator for submission to his or her IRB/IEC. 
8.2 Physical Examination 
A comprehensive physical examination will be performed at the initial screening visit and on Day 
14. The comprehensive physical examination will include the following organ or body system 
assessments: skin; head, eyes, ears, nose, and throat; thyroid; lungs; cardiovascular; abdomen 
(liver, spleen); lymph nodes; and extremities, as well as an abbreviated neurological exam. 
A targeted physical examination will be performed at baseline (Day 0) and at the Day 7 and Day 28 
visit. This examination will specifically target the cardiovascular system and will include vital 
signs, plus an examination of the extremities to check for the presence of edema, as well as an 
examination to document any other evidence of a cardiovascular problem. Any areas of concern 
from the medical history or noted on the prior physical examination or indicated by subject 
symptoms or other findings as determined by the Investigator or designee may also be examined. 
8.3 Vital Signs 
Vital sign measurements (BP, pulse rate, respiration rate, and oral body temperature) will be 
collected on the days and times noted in the Schedule of Events (Appendix A). Vital signs will be 
taken with the subject in the sitting position after 5 minutes of rest, except for at the initial 
screening visit, where vital signs will be taken with the subject in the supine position after at least 
10 minutes of rest with minimal interaction.  
Measurements of BP made when subjects are at the Investigational Site as part of their clinic visits 
will be made using the standard American Heart Association criteria (Chobanian, 2003). This will 
require the following technique be utilized: 
1. Clinic visit BP measurements will be taken at the initial screening visit, in the morning on 
Days 0, 7, and 14, and at the follow-up visit (Day 28). On Day 0, the BP measurements 
will be taken in the morning prior to the first dose of study drugs. On Day 7, the subject 
will self-administer their study drugs at home prior to coming to the clinic, and therefore, 
the BP measurements will be taken after the subject has taken their daily dose of study 
drugs; 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 51 
CONFIDENTIAL 
2. A determination will be made as to which upper extremity has the greater BP; 
3. Prior to taking the subject’s BP, the subject will rest in the sitting position for a period of 
5 minutes, except for at the initial Screening visit, where BP measurements will be taken 
with the subject in the supine position after at least 10 minutes of rest with minimal 
interaction; 
4. At the completion of the rest period, three readings will be taken. There will be a one 
minute interval between each measurement; 
5. The subject’s recorded BP will be an average of the three recordings taken over 
approximately three minutes. 
6. At the initial screening visit (Day –10 to -14), three readings will be taken on each arm, as 
described. The averages for each arm will be calculated. The arm with the higher average 
systolic BP will be used for all further BP measurements including ABPM measurements. 
The continuous recording of BP by ABPM (Section 7.1) at Day -1 to Day 0, Day 6 to Day 7, and 
Day 13 to Day 14, will serve a dual function as both the official BP values for all efficacy 
determinations and calculations and an additional BP assessment for safety.  
8.4 Orthostatic Hypotension Evaluations 
Orthostatic hypotension will be evaluated at baseline (Day 0), Day 7, and Day 14.  
For this determination, the subject will be placed supine for 5 minutes. At the end of that time a 
manual BP will be assayed three times. The average of these three will be used as the baseline 
value. The subject will then be asked to stand vertically and two manual BPs will be obtained: the 
first will be one minute after standing and the second will be three minutes after standing. 
Orthostatic hypotension will be defined as a decrease in systolic BP of > 25 mmHg from baseline 
in either of the readings, or a decrease in diastolic BP of > 15 mmHg in either of the readings 
compared to the baseline average. 
In addition to these quantitative measurements, specific comparisons in reported AE rates for terms 
associated with hypotension will be made. These events will include dizziness, falls, 
light-headedness, and vertigo. 
8.5 ECG 
A 12-lead ECG will be obtained at the initial screening visit and at the Day 14 visit. The 12-lead 
ECGs will be performed with the subject in the recumbent position after 5 minutes of rest.  
8.6 Hematology, Serum Chemistry, and Urinalysis 
Blood and urine for clinical safety laboratory assessments will be collected at the initial screening 
visit, Day 0 (serum chemistry only), and on Day 14. The samples will be prepared using standard 
procedures. A detailed listing of the hematology, serum chemistry, and urinalysis tests that will be 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 52 
CONFIDENTIAL 
performed is provided in Appendix B. A regional laboratory will perform the clinical laboratory 
tests.  
In addition, at Day 7, blood will be collected for a subset of serum chemistry tests. Specifically, 
the testing will be limited to creatinine (and calculation of creatinine clearance) and electrolytes 
(sodium, bicarbonate, calcium, chloride, phosphorous, and potassium). 
Also, if the subject’s BP at Day 7 is too elevated for them to continue safely in the study (i.e., 
SBP24h > 169 mmHg and/or DBP24h > 110 mmHg), blood will be drawn for renal profile testing 
(non-fasting). The renal profile testing will include the following tests: creatinine, calcium, 
chloride, carbon dioxide, albumin, blood urea nitrogen (BUN), protein, phosphorus, glucose, and 
potassium. 
 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 53 
CONFIDENTIAL 
9. ASSESSMENT OF PHARMACOKINETICS 
9.1 Blood Collection 
Subjects will have a venous blood sample collected at 24 hours ± 1 hour post-dose on Day 14 to 
measure plasma concentrations of amlodipine. Only subjects enrolled at Investigational Sites that 
have UV-shielded lights will participate in the PK blood collection. Due to the design of the trial 
(randomized, double-blind, placebo-controlled), this blood sample will be collected and analyzed 
for all participating subjects, regardless of whether they are in a treatment arm that receives 
amlodipine. 
See PK procedures manual for specific information regarding the procedures for PK blood sample 
collection, processing, and shipment to bioanalytical laboratory. 
9.2 Bioanalytical Method 
Plasma samples will be assayed for amlodipine by a Sponsor designated laboratory using a 
validated LC-MS/MS method.  
9.3 Pharmacokinetic Analysis 
As blood will only be collected at a single time point in this trial, plasma concentration-time curves 
and noncompartmental analyses are not planned. See Section 10 for planned statistical analysis of 
plasma concentration data. 
 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 54 
CONFIDENTIAL 
10. STATISTICS 
10.1 Data Sets 
10.1.1 Intent-to-Treat (ITT) 
The ITT data set will be comprised of randomized subjects with at least a valid baseline (Day –1 
to Day 0) ABPM measurement and either 
a) A valid final (Day 13 to Day 14) ABPM measurement, where a subject completes the 
treatment program. 
or 
b) A valid Day 6 to Day 7 ABPM measurement, where a subject is withdrawn from the 
treatment program at that point because of an SBP24h > 169 mmHg and/or a 
DBP24h > 110 mmHg, or if they are withdrawn for any other reason. 
As noted in Section 6.4, if at the time of the Day 7 clinic visit subjects have too elevated a BP to 
be able to continue safely in the study (i.e., SBP24h > 169 mmHg or DBP24h > 110 mmHg), the 
study drug will be discontinued and the subjects will be instructed to resume taking their 
prescribed BP medication as directed by the study doctor or general practitioner. In this case, both 
mixed model for repeated measures (MMRM) and last observation carried forward (LOCF) 
techniques will be used with comparative sensitivity analysis. 
Subjects that do not have the two paired valid ABPM measurements, as required (baseline and 
final, for those who complete the treatment program, or baseline and Day 6 to Day 7, for those 
withdrawn from the study), will not be included. 
10.1.2 Per-protocol (PP) 
The PP data set will be comprised of randomized subjects with at least a valid baseline (Day –1 
to Day 0) ABPM measurement and also a valid final (Day 13 to Day 14) ABPM measurement. 
Dropouts and subjects who had major violations of the protocol will be excluded. Major protocol 
violations will include missing more than 25% of scheduled doses of study drugs, and taking 
prohibited medications including any NSAIDs or calcium channel blockers (other than the study 
drugs). 
All randomized subjects should receive their initial dose of study drugs in the clinic immediately 
following randomization. 
10.2 Statistical Analysis of Efficacy Data 
10.2.1 Primary Efficacy Endpoint 
The primary efficacy endpoint for this trial will be the difference in the mean reduction in SBPday 
from the baseline (Day –1 to Day 0) ABPM measurement to the final (Day 13 to Day 14) ABPM 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 55 
CONFIDENTIAL 
measurement, where a subject completes the 14-day treatment plan, or to the Day 6 to Day 7 
ABPM measurement, where a subject is withdrawn from treatment at Day 7, between subjects 
treated with amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together (arm 1) 
and amlodipine tablets (10 mg) given alone (i.e., with matched celecoxib placebo) (arm 2).  
The primary efficacy endpoint will be that the lower limits of the 95% confidence interval for 
SBPday reduction in treatment arm 1 will be at least 50% of the mean reduction in treatment arm 2. 
10.2.2 BP Change Comparisons 
Statistics are based on the reduction in BP from the baseline ABPM measurement (Day –1 to 
Day 0) to the post-dose ABPM measurement (Day 13 to Day 14 or if a LOCF is required Day 6 to 
Day 7), as this represents the efficacy of the treatment. Reductions will be, therefore, represented 
by positive numbers and increases by negative numbers. For this reason, the change in BP from 
baseline to final ABPM measurement will be a paired subtraction of the final ABPM measurement 
from the baseline ABPM measurement. Sensitivity analysis will compare these results with those 
of the PP dataset and an MMRM analysis. 
10.2.3 Primary Efficacy Endpoint Analysis 
A two-sample t-test will be used to test the one-sided hypothesis that treatment with amlodipine 
tablets (10 mg) and celecoxib capsules (200 mg) given together (arm 1) is non-inferior to half of 
the effect achieved with the control treatment with amlodipine tablets (10 mg) given alone (with 
matched celecoxib placebo) (arm 2). 
H0: ∆SBPday,1 – 0.5(∆SBPday,2) ≥ 0 mmHg 
H1: ∆SBPday,1 – 0.5(∆SBPday,2) < 0 mmHg 
Where 
∆SBPday,1 is the change, for subjects in arm 1, in the SBPday from the baseline ABPM 
measurement (SBPday,1,0) to the final ABPM measurement (SBPday,1,14). 
∆SBPday,1 = SBPday,1,0 – SBPday,1,14. 
∆SBPday,2 is the change, for subjects in arm 2, in SBPday from the baseline ABPM 
measurement (SBPday,2,0) to the final ABPM measurement (SBPday,2,14). 
∆SBPday,2 = SBPday,2,0 – SBPday,2,14.  
Refer to Appendix H for further details regarding the efficacy analysis, and in particular the 
non-inferiority margin. 
10.2.4 Secondary Efficacy Endpoints 
Recall that subjects will be randomized 3:3:1 to one of three treatment arms: 
1. OE Norvasc® tablet (10 mg amlodipine besylate) + OE Celebrex® capsule (200 mg 
celecoxib); 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 56 
CONFIDENTIAL 
2. OE Norvasc® tablet (10 mg amlodipine besylate) + matched placebo for OE Celebrex® 
capsule; 
3. Matched placebo for OE Norvasc® tablet + matched placebo for OE Celebrex® capsule. 
A serial gatekeeping strategy will be used to evaluate the effect of amlodipine tablets (10 mg) and 
celecoxib capsules (200 mg) given together on secondary efficacy endpoints. If and only if the 
statistical significance is achieved for the primary efficacy endpoint, a secondary hierarchical 
analysis will be used to evaluate the endpoints listed below, and will only proceed to the next 
endpoint in the list if the alpha is met for the prior analyses. 
1. Difference in mean change in body weight from baseline (Day 0) to Day 14 measurement 
(or if a LOCF is required, the Day 7 measurement) between treatment arms [amlodipine 
tablets (10 mg) and celecoxib capsules (200 mg) given together (arm 1), amlodipine 
tablets (10 mg) given alone (with matched celecoxib placebo) (arm 2), and placebo (arm 
3)]; 
2. Difference in the mean reduction in SBP24h from the baseline (Day -1 to Day 0) ABPM 
measurement to the Day 13 to Day 14 ABPM measurement (or if a LOCF is required, the 
Day 6 to Day 7 ABPM measurement) between subjects treated with amlodipine tablets 
(10 mg) and celecoxib capsules (200 mg) given together (arm 1) and amlodipine tablets 
(10 mg) given alone (with matched celecoxib placebo) (arm 2);  
3. Difference in the mean reductions in DBP24h from the baseline (Day –1 to Day 0) ABPM 
measurement to the Day 13 to Day 14 ABPM measurement (or if a LOCF is required, the 
Day 6 to Day 7 ABPM measurement) between subjects treated with amlodipine tablets 
(10 mg) and celecoxib capsules (200 mg) given together (arm 1) and amlodipine tablets 
(10 mg) given alone (with matched celecoxib placebo) (arm 2); 
4. Difference in the mean change in creatinine clearance from baseline (Day 0) to the Day 14 
measurement (or if a LOCF is required, the Day 7 measurement) between subjects treated 
with amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together (arm 1) 
and amlodipine tablets (10 mg) given alone (with matched celecoxib placebo) (arm 2). 
10.2.5 Secondary Efficacy Endpoints Analysis 
If the primary efficacy endpoint analysis fails to demonstrate statistical success, no further efficacy 
analyses will be performed. However, if it is successful, the following secondary hierarchical 
analysis to evaluate for the effect of amlodipine tablets (10 mg) and celecoxib capsules (200 mg) 
given together on secondary efficacy endpoints will be performed in the order listed.  The analysis 
will only proceed to the next endpoint in the list if the alpha is met for the prior analyses. 
1. Analysis of Variance (ANOVA) will be used to compare the changes in body weight 
among the three treatment arms.  The omni-bus test will conclude if any differences exist 
with post-hoc comparisons identifying specific differences between treatment arms.  Any 
statistically significant differences will be sufficient to pass this gate in the study-wide gate 
keeping strategy. 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 57 
CONFIDENTIAL 
H0: ∆BW1 = ∆BW2 = ∆BW3 
H1: At least one difference, ∆BWi - ∆BWj ≠ 0 
Where 
∆BW1 is the change, for subjects in arm 1, in body weight from the baseline 
measurement to the post-treatment measurement. 
∆BW2 is the change, for subjects in arm 2, in body weight from the baseline 
measurement to the post-treatment measurement.  
∆BW3 is the change, for subjects in arm 3, in body weight from the baseline 
measurement to the post-treatment measurement. 
2. A two-sample t-test for superiority will be used to test the one-sided hypothesis that 
treatment with amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together 
(arm 1) lowers SBP24h to a greater degree than amlodipine tablets (10 mg) given alone 
(with matched celecoxib placebo) (arm 2). 
H0: ∆SBP24h,1 – ∆SBP24h,2 = 0 
H1: ∆SBP24h,1– ∆SBP24h,2 > 0 
Where 
∆SBP24h,1 is the change, for subjects in arm 1, in SBP24h from the baseline ABPM 
measurement to the post-treatment ABPM measurement. 
∆SBP24h,2 is the change, for subjects in arm 2, in SBP24h from the baseline ABPM 
measurement to the post-treatment ABPM measurement. 
3. A two-sample t-test for superiority will be used to test the one-sided hypothesis that 
treatment with amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together 
(arm 1) lowers DBP24h to a greater degree than amlodipine tablets (10 mg) given alone 
(with matched celecoxib placebo) (arm 2). 
H0: ∆DBP24h,1 – ∆DBP24h,2 = 0 
H1: ∆DBP24h,1– ∆DBP24h,2 > 0 
Where 
∆DBP24h,1 is the change, for subjects in arm 1, in DBP24h from the baseline ABPM 
measurement to the post-treatment ABPM measurement. 
∆DBP24h,2 is the change, for subjects in arm 2, in DBP24h from the baseline ABPM 
measurement to the post-treatment ABPM measurement. 
4. A two-sample t-test for superiority will be used to test the one-sided hypothesis that 
treatment with amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together 
(arm 1) improves creatinine clearance to a greater degree than amlodipine tablets (10 mg) 
given alone (with matched celecoxib placebo) (arm 2). 
H0: ∆CC1 – ∆CC2 = 0 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 58 
CONFIDENTIAL 
H1: ∆CC1– ∆CC2 > 0 
Where 
∆CC1 is the change, for subjects in arm 1, in creatinine clearance from the 
baseline creatinine clearance to the post-treatment creatinine clearance. 
∆CC2 is the change, for subjects in arm 2, in creatinine clearance from the 
baseline creatinine clearance to the post-treatment creatinine clearance. 
10.3 Statistical Analysis of Pharmacokinetic Data 
Subjects will have a blood sample drawn on Day 14, approximately 24 hours after receiving the 
final dose of study drugs, for the measurement of amlodipine concentration. Only subjects 
enrolled at Investigational Sites that have UV-shielded lights will participate in the PK blood 
collection. Due to the design of the trial (randomized, double-blind, placebo-controlled), this 
blood sample will be collected and analyzed for all participating subjects, regardless of whether 
they are in a treatment arm that receives amlodipine. 
The plasma concentration of amlodipine will be determined by validated LC-MS/MS method. 
All plasma concentration values below the lower limit of quantification (LLOQ) will be reported 
as zero. Individual amlodipine plasma concentration data will be listed.  
A t-test will compare the plasma concentration of amlodipine in those subjects who receive 
amlodipine tablets (10 mg) given alone (with matched celecoxib placebo) (arm 2) with those who 
receive amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together (arm 1). 
10.4 Statistical Analysis of Safety Data 
Data from all subjects who receive at least one dose of study drug will be incorporated into the 
final safety analysis.  
Safety will be assessed primarily based on reported TEAEs. Clinically significant clinical 
laboratory abnormalities will be reported as AEs (i.e., either as PTAEs or TEAEs, depending on 
when they initiate or worsen). The incidence of TEAEs will be tabulated by Medical Dictionary 
for Regulatory Activities (MedDRA) system organ class and preferred term, and will be further 
categorized by treatment arm, severity, and assigned relationship to study drug. The incidence of 
PTAEs will be tabulated by MedDRA system organ class and preferred term, and will be further 
categorized by severity. 
The incidence for each PTAE and TEAE will be provided as the total number of subjects that 
experienced the PTAE or TEAE, as well as the percentage of the population that this represents. 
If a PTAE or TEAE is reported more than once for a given subject, the greatest severity and the 
worst-case attribution will be presented in the summary tables.  
TEAE rates across treatment arms will be analyzed using the chi square test or an exact binomial 
test (e.g., Suissa and Shuster, 1985).  
PTAEs and TEAEs will be separately listed for individual subjects, along with information 
regarding onset and end dates, onset time where available, severity, seriousness, relationship to 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 59 
CONFIDENTIAL 
study drug (only in the case of TEAEs), action taken, and outcome. Separate listings and tabular 
summaries of PTAEs and TEAEs that lead to withdrawal from the study will be generated. 
Separate listings and tabular summaries of serious PTAEs and serious TEAEs will also be 
generated.  
Secondary safety assessments, including physical examination, body weight, vital signs, 
orthostatic hypotension evaluations, ECG, hematology, serum chemistry, and urinalysis will be 
listed and summarized. Descriptive statistics will be generated as appropriate (i.e., mean, median, 
range, and standard deviation for continuous data and frequency for categorical data). The clinical 
laboratory results will also be summarized with respect to laboratory normal ranges and absolute 
changes from baseline. Comparisons among treatment arms will be performed using chi-square, 
binomial, and logistic analyses for dichotomous variables (e.g. normal/abnormal) and analysis of 
covariance (ANCOVA) for continuous variables. 
10.5 ABPM Measurement Weighting 
1) Each measurement shall be weighted according to half the duration to the preceding 
measurement and half the duration to the succeeding measurement up to maxima of half the 
expected intervals as follows: 
Time of Day (in minutes) 
Max Preceding Weight 
Max Succeeding Weight 
09:00 to 09:20 (540 to 560) 
15 min 
10 min 
09:21 to 21:39 (550 to 1299) 
10 min 
10 min 
21:40 to 21:59 (1300 to 1319) 
10 min 
15 min 
22:00 to 08:59 (0 to 539 and 1320 to 1439) 
15 min 
15 min 
2) All statistics shall be based on weighted measurements. For daytime and night-time statistics, 
weights for the first measurements within the respective periods shall be truncated at the start 
of the period and weights for the last measurements within the respective periods shall be 
truncated at the end of the period. 
3) Hourly mean pressures shall be based on the weights of measurements occurring within the 
hour. Each hour shall be defined by “m \ 60”, where m is the number of minutes from midnight 
on the day the monitor is fitted and \ represents the quotient of the Euclidian division. (m ≡ (m 
\ 60) × 60 + m mod 60) 
10.6 ABPM Study Measurements 
1) A measurement shall be regarded as valid if it contains values for systolic blood pressure 
(SBP), diastolic blood pressure (DBP) and heart rate (HR) and 
a. SBP is between 50 mmHg and 300 mmHg. 
b. DBP is between 40 mmHg and 150 mmHg. 
c. Pulse pressure is between 10 mmHg and 150 mmHg. 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 60 
CONFIDENTIAL 
d. HR is between 40 bpm and 150 bpm. 
2) The first study measurement shall be  
a. The nearest valid measurement to the drug intake time on the day the monitor is fitted 
that is both a) between 07:00 and 10:00 and b) within 15 minutes of the drug intake time. 
b. If there is no valid measurement within this period, a 1-hour grace period is permitted. It 
is, therefore, the nearest valid measurement to the drug intake time on the day the monitor 
is fitted that is both a) between 06:00 and 11:00 and b) within 75 minutes of the drug 
intake time.  
c. If there is no valid measurement within this period, or if no drug intake time is recorded 
(e.g., Day-1), the first valid measurement recorded between 07:00 and 10:00.  
d. If there is no valid measurement within this period, the first valid measurement recorded 
between 06:00 and 11:00. 
e. If there is no valid measurement within this period, the nearest valid measurement to the 
drug intake time on the day the monitor is fitted, if that is recorded, or first valid 
measurement otherwise. 
3) Measurements recorded during the first hour, from the first study measurement, shall be 
regarded as white-coat window measurements. The period covered by these measurements 
defines the white-coat window. 
4) The last study measurements shall be  
a. The earliest valid measurement that is a) at least 25 h after the first study measurement 
b) at least 25 h after the drug intake time on the day the monitor is fitted and c) less than 
25 h after the end of the white-coat window  
b. If there is no valid measurement within this period, a 1-hour grace period is permitted. It 
is, therefore, the earliest valid measurement that is a) at least 24 h after the first study 
measurement b) at least 24 h after the drug intake time on the day the monitor is fitted 
and c) less than 26 h after the end of the white-coat window 
c. If there is no valid measurement within this period, the latest measurement that is less 
than 26 h after the end of the white-coat window. 
5) Measurements before the first study measurement and measurements after the last study 
measurement shall be disregarded. 
6) Invalid measurements and measurements that result in an error shall not be regarded as study 
measurements. 
7) Measurements recorded during the white-coat window are not included in daytime, night-time 
and 24 h statistics. 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 61 
CONFIDENTIAL 
10.7 ABPM Validity 
1) An ABPM measurement shall be defined as valid if the data comply with the following criteria: 
a. The time of the first study measurement is between 07:00 and 10:00. 
b. The duration, from the first study measurement to the last study measurement, is at least 
25 h (1500 min). 
c. There are at least 21 study measurements recorded during the standard daytime period 
(09:00 to 21:00) 
d. There are at least 8 study measurements recorded during the standard night-time period 
(01:00 to 06:00) 
e. There are at least 35 study measurements recorded after the white-coat window 
f. There are no more than 3 hours with a total measurement weight of less than 20 min and 
no more than 2 consecutive hours with total measurement weights each of less than 
20 min. 
2) An ABPM measurement shall be defined as valid within tolerance if the data comply with the 
following criteria: 
a. The time, of the first study measurement is between 06:00 and 11:00. 
b. The duration, from the first study measurement to the last study measurement, is at least 
24 h (1440 min). 
c. There are at least 20 study measurements recorded during the standard daytime period 
(09:00 to 21:00) 
d. There are at least 7 study measurements recorded during the standard night-time period 
(01:00 to 06:00) 
e. There are at least 34 study measurements recorded after the white-coat window 
f. There are no more than 3 hours with a total measurement weight of less than 20 min and 
no more than 2 consecutive hours with total measurement weights each of less than 
20 min. 
3) An ABPM measurement shall be defined as invalid if it is not valid within tolerance. 
10.8 ABPM Statistics 
1) Average 24-hour, daytime and night-time pressures are calculated as 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 62 
CONFIDENTIAL 
,
,
,
,
LSM
r i
p i
i FSM
p r
LSM
p i
i FSM
v w
v
w
=
=
=
∑
∑
 
 
where 
r 
is SBP or DBP 
 
 
p 
is 24-hour, daytime or night-time 
 
 
vr,i 
is the SBP or DBP for measurement i 
 
 
wp,i 
is the weight of the measurement for period p, zero if the 
measurement does not belong to that period 
 
 
FSM 
is the first study measurement 
 
 
LSM 
is the last study measurement 
2) The standard deviations are calculated as 
2
2
,
,
,
,
,
,
1
LSM
LSM
r i
p i
p r
p i
i FSM
i FSM
p r
LSM
p
p i
p
i FSM
v w
v
w
s
M
w
M
=
=
=
−
=
−
∑
∑
∑
 
 
where 
Mp 
is the number of non-zero weighted measurements in period p 
10.9 Sample Size 
1) The sample size is to be based on the hypothesis that the mean reduction in SBPday from Day 0 
to Day 14 of subjects treated with amlodipine tablets (10 mg) and celecoxib capsules (200 mg) 
given together (arm 1) minus half the mean reduction in SBPday from Day 0 to Day 14 of 
subjects treated with amlodipine tablets (10 mg) given alone (with matched celecoxib placebo) 
(arm 2) is at least 0.  
2) Formula 
Sample size is based on the formula 
 
𝑛𝑛= ቜ2 ൬
𝑍𝑍1−𝛼𝛼+ 𝑍𝑍1−𝛽𝛽
𝑑𝑑
൰
2
𝑠𝑠2ቝ 
where 
s is the standard deviation (8.7) 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 63 
CONFIDENTIAL 
d is the anticipated mean difference (6.2) 
α is the one-sided level of significance (0.05) 
1-β is the power, one-sided (80%) 
 is the ceiling function 
3) Margin 
 
The margin is based on a mean reduction of 8.8 mmHg in SBPday for the 
Amlodipine+Placebo group and a mean reduction of 10.6 mmHg for the 
Amlodipine+Celecoxib group as seen in the previous study, KIT-302-03-01.  To ensure 
that at least half the effect is maintained, a value of 10.6 – 0.5(8.8) = 6.2 mmHg should 
be set for d.   
4) Standard Deviation 
 
The standard deviation is based on an 8.1 mmHg standard deviation for the 
Amlodipine+Placebo group and a 9.2 mmHg standard deviation for the 
Amlodipine+Celecoxib group in the previous study (KIT-302-03-01).  The pooled 
standard deviation for the power and sample size justification is 8.7 mmHg. 
5)  Loss to Follow-up Adjustment 
 
The final sample size is rounded up to allow for a loss to follow-up.  The study selected 
a round number at least 10% larger than the number necessary to protect against potential 
subjects not fully participating in the entire trial. 
Refer to Appendix H for further details regarding the determination of sample size. 
11. ACCESS TO SOURCE DOCUMENTS 
The Investigator will make the source documents for this trial available for monitoring by the 
Sponsor or its representatives, or by regulatory authorities or health authority inspectors. 
Subject medical information obtained as a result of this study is considered confidential and 
disclosure to third parties other than those noted below is prohibited. All reports and 
communications relating to subjects in this study will identify each subject only by their initials 
and number. Medical information resulting from a subject’s participation in this study may be 
given to the subject’s personal physician or to the appropriate medical personnel responsible for 
the subject’s welfare. Data generated as a result of this study are to be available for inspection on 
request by FDA or other government regulatory agency auditors, the Sponsor (or designee), and 
the IRB/IEC. 
The information developed in this clinical study will be used by the Sponsor in the clinical 
development of the study drug and therefore may be disclosed by the Sponsor as required for 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 64 
CONFIDENTIAL 
disclosure as a public company to other clinical investigators, to other pharmaceutical companies, 
to the FDA and to other government agencies. 
Any information, inventions, or discoveries (whether patentable or not), innovations, suggestions, 
ideas, and reports, made or developed by the Investigator(s) as a result of conducting this study 
shall be promptly disclosed to the Sponsor and shall be the sole property of the Sponsor. The 
Investigator agrees, upon the Sponsor’s request and at the Sponsor's expense, to execute such 
documents and to take such other actions, as the Sponsor deems necessary or appropriate to obtain 
patents in the Sponsor’s name covering any of the foregoing. 
The Investigator will retain all study documents for at least 2 years after the last approval of a 
marketing application in an ICH region (i.e., US, Europe, or Japan), and until there are no pending 
or contemplated marketing applications in an ICH region. If no application is filed or if the 
application is not approved for such indication, the Investigator will retain all study documents for 
at least 2 years after the Investigation is discontinued and regulatory authorities have been notified.  
The Investigator will notify the Sponsor prior to destroying any study records. Should the 
Investigator wish to assign the study records to another party or move them to another location, 
the Sponsor must be notified in writing in advance. 
If the Investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements will be made between the Investigator and the Sponsor for 
storage. If source documents are required for continued care of the subject, appropriate copies for 
storage off site will be made. 
 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 65 
CONFIDENTIAL 
12. QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 Data Collection 
All data required by the study protocol will be entered onto CRFs and must be verifiable against 
source documents. CRFs will be completed for every subject who signs an informed consent and 
has screening procedures performed.  
Only authorized Investigational Site personnel will enter data on the CRFs. Any corrections to 
data entered into the CRF will be made in such a way that the original entry is not obscured. The 
date of the correction and the initials of the person making the correction will be documented.  
The CRFs will be kept up-to-date by the Investigator and the research staff at the Investigational 
Site. The Investigator will be responsible for reviewing all data and CRF entries and will sign and 
date each subject’s CRF, verifying that the information is true and correct.  
12.2 Study Monitoring 
The study will be monitored to evaluate the progress of the study, to verify the accuracy and 
completeness of the CRFs, to assure that all protocol requirements, applicable laws and/or 
regulations, and Investigator’s obligations are being fulfilled, and to resolve any inconsistencies 
in the study records.  
The Investigator will allow the study monitor to periodically review, at mutually convenient times 
during the study and after the study has been completed, all CRFs and office, hospital, and 
laboratory records supporting the participation of each subject in the study.  
The study monitor will compare the CRF data against source documentation in order to verify its 
accuracy and completeness. The Investigator and research staff will collaborate with the study 
monitor to resolve any identified data discrepancies in a timely manner.  
The study monitor will record any protocol deviations identified, including, but not limited to, 
subjects that were enrolled even though they did not meet all eligibility criteria, subjects who took 
concomitant medications specifically prohibited by the protocol, subjects who received the wrong 
study drug or incorrect dose, and subjects who failed to comply with the protocol-defined dietary 
restrictions. The Investigator and research staff will collaborate with the study monitor to identify 
the reason for each protocol deviation.  
The study monitor will compare the Investigational Site study drug accountability record against 
the study drug inventory (unused and used) at the site. The Investigator and research staff will 
collaborate with the study monitor to resolve any identified discrepancies in a timely manner. 
Each issue identified during study monitoring visits will be documented and reported to both the 
Sponsor and the Investigator.  


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 66 
CONFIDENTIAL 
12.3 Data Management 
After the CRFs have been reviewed by the study monitor and all identified discrepancies have 
been identified, the Investigator signed copy of the CRF will be forwarded to Data Management. 
Queries generated by Data Management will be sent to the study site for resolution. The 
Investigator is responsible for the review and approval of all responses. 
All CRF data will be entered into a validated database and an electronic audit trial of edits 
maintained. Laboratory data may be imported to the database electronically. 
The database will be authorized for lock once no data queries are outstanding, all study data are 
considered clean, and all defined procedures completed. 
12.4 Sponsor Audits 
At some point during the study, individuals from the Sponsor’s Quality Assurance group or their 
authorized representative may visit the Investigator’s site to conduct an audit of the study. The 
purpose of this visit will be to determine the Investigator’s adherence to the protocol, applicable 
regulations, and the Sponsor’s procedures, in addition to assessing the accuracy of the study data. 
Prior to initiating this audit, the Investigator will be contacted by the Sponsor to arrange a 
convenient time for this visit. The Investigator and staff will cooperate with the auditors and allow 
access to all subject records supporting the CRFs and other study-related documents. 
12.5 Inspection by Regulatory Authorities 
At some point during the study, a regulatory authority may visit the Investigator to conduct an 
inspection of the study. The Investigator and staff will cooperate with the inspectors and allow 
access to all source documents supporting the CRFs and other study-related documents. The 
Investigator will immediately notify the Sponsor when contacted by any regulatory authority for 
purposes of conducting an inspection. 
 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 67 
CONFIDENTIAL 
13. ETHICS 
13.1 Declaration of Helsinki 
The study will be conducted in accordance with the Declaration of Helsinki (1964) including all 
amendments up to and including the October 2013 revision, as described in Appendix E. 
13.2 Good Clinical Practice and Regulatory Compliance 
This study will be conducted in accordance with the principles of GCP (current ICH guideline) 
and the requirements of all local regulatory authorities regarding the conduct of clinical trials and 
the protection of human subjects.  
13.3 Institutional Review Board/Independent Ethics Committee 
The protocol, ICF, Investigator’s Brochure, and any materials (such as advertisements, subject 
information sheets, or descriptions of the study used to obtain informed consent) for this study will 
be reviewed and approved by a duly constituted IRB/IEC. 
The Investigator will ensure that all aspects of the IRB/IEC review are conducted in accordance 
with current institutional, local, and national regulations. A letter documenting the IRB/IEC 
approval will be provided to the Sponsor prior to initiation of the study.  
Amendments to the protocol will be subject to the same requirements as the original protocol. A 
letter documenting the IRB/IEC approval will be provided to the Sponsor prior to implementation 
of the changes described in the protocol amendment. 
Revisions to the ICF will be reviewed and approved by the IRB/IEC prior to use in the study. The 
Investigator will inform the IRB/IEC of all reportable AEs. IND Safety Reports provided by the 
Sponsor to the Investigator will be promptly forwarded to the IRB/IEC by the Investigator. 
Updates to the Investigator’s Brochure provided by the Sponsor to the Investigator will be 
submitted to the IRB/IEC by the Investigator. 
The Investigator will submit all periodic reports and updates that the IRB/IEC may require. After 
completion or termination of the study, the Investigator will submit a final report to the IRB/IEC 
and to the Sponsor. The structure and content of the report will meet that described in Structure 
and Content of Clinical Study Reports E3 (ICH Harmonized Tripartite Guideline, dated November 
30, 1995). 
13.4 Informed Consent 
No study related procedures, including screening evaluations, will be performed until the subject 
has given written informed consent.  
The ICF will clearly describe the nature, scope, and potential risks and benefits of the study, in a 
language that the subject understands. Further, the ICF will identify the Sponsor, the Principal 
Investigators and institutional affiliations, potential conflicts of interest, provisions for treating 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 68 
CONFIDENTIAL 
subjects who are harmed as a consequence of participation in the study, and provisions for post-
trial access. 
The ICF will conform to all the requirements for informed consent according to ICH GCP and US 
FDA guidelines (21 CFR 50) and any additional elements required by the Investigator’s institution 
or local regulatory authorities. The Investigator will submit the ICF to the IRB/IEC for review, 
and will provide the Sponsor with a letter documenting the IRB/IEC approval prior to initiation of 
the study. 
The IRB/IEC approved ICF will be given to each prospective participant. The subjects will be 
given adequate time to discuss the study with the Investigator or site staff and to decide whether 
or not to participate. Each subject who agrees to participate in the trial and who signs the ICF will 
be given a copy of the signed, dated, and witnessed document. The original signed ICF will be 
retained by the Investigator in the study files. 
The Investigator will also obtain authorization from the subject to use and/or disclose PHI in 
compliance with HIPAA or equivalent. Written HIPAA authorization may be obtained as part of 
the informed consent process. 
If a protocol amendment substantially alters the study design or increases the potential risk to the 
subject, or the known risks of the study drug change over the course of the study, the ICF will be 
revised and submitted to the IRB/IEC for review and approval. The revised ICF must be used to 
obtain consent from subjects currently enrolled in the study if they are affected by the amendment 
and to obtain consent from new subjects prior to enrollment. 
13.5 Emergency Departure from Protocol 
When an emergency occurs that requires a departure from the protocol for an individual, a 
departure will be only for that subject. The Investigator or other physician in attendance in such 
an emergency will, if circumstances and time permit, contact the Sponsor’s Medical Monitor 
immediately by telephone. Such contacts will be made as soon as possible to permit a decision as 
to whether or not the subject (for whom the departure from protocol was effected) is to continue 
in the study. The CRF and source documents will completely describe the departure from the 
protocol and state the reasons for such departure. In addition, the IRB/IEC will be notified in 
writing of such departure from protocol. 
 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 69 
CONFIDENTIAL 
14. PUBLICATION POLICY 
All information and data obtained in the course of the study are the property of the Sponsor and 
are considered confidential. To avoid disclosures that could jeopardize proprietary rights, the 
institution and/or the Investigator agree to certain restrictions on publications (e.g., abstracts, 
speeches, posters, manuscripts, and electronic communications), as detailed in the clinical trial 
agreement. 
The publication or presentation of any study results shall comply with all applicable privacy laws, 
including, but not limited to, HIPAA or equivalent. 
This trial will be registered in a publicly accessible database (clinicaltrials.gov) not later than 21 
days after enrollment of the first subject. Results of this trial, including negative and inconclusive, 
as well as positive results, will be made publicly available. 
 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 70 
CONFIDENTIAL 
15. PROTOCOL AMENDMENTS AND MODIFICATIONS 
The Investigator will ensure that the study is conducted in accordance with the procedures and 
evaluations described in this protocol. The Investigator will not modify the protocol without first 
receiving Sponsor authorization to do so, except in those cases intended to reduce immediate risk 
of the subjects. The Sponsor is responsible for submitting protocol amendments to the appropriate 
government regulatory authorities. The Investigator is responsible for submitting protocol 
amendments to the appropriate IRB/IEC. Approval by the IRB/IEC will be obtained before 
protocol modifications are implemented, except in those cases intended to reduce immediate risk 
to subjects. 
 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 71 
CONFIDENTIAL 
16. REFERENCES 
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson 
BJ, Oparil S, Wright JT JR, Roccella EJ. National Heart, Lung, and Blood Institute; National High 
Blood Pressure Education Program Coordinating Committee. 2003. Seventh report of the Joint 
National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 
Hypertension. 42:1206-1252. 
Suissa S, Shuster JJ. 1985. Exact unconditional sample sizes for the 2 x 2 binomial trial. Journal 
of the Royal Statistical Society, Series A. 148:317-327. 
Wu MC, Bailey KR. 1989. Estimation and comparison of changes in the presence of informative 
censoring: conditional linear models. Biometrics. 45:939-955. 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 72 
CONFIDENTIAL 
APPENDIX A: SCHEDULE OF EVENTS 
 
Event  
Screening 
Baseline/
1st Dose 
Remainder of Treatment Period 
Follow-up 
Initial 
Screening Visit 
Final 
Screening
Visit 
Day 0 
Day 6 
Day 7 
Day 13 
Day 14 (a) 
Day 28 (a) 
Day –14 to -10 
Day -1 
Informed consent (b) 
X 
 
 
 
 
 
 
 
Record demographic data 
X 
 
 
 
 
 
 
 
Complete medical history 
X 
 
 
 
 
 
 
 
Monitor for pretreatment adverse events 
(PTAEs) (k) 
X 
X 
X 
 
 
 
 
 
Record prior medications 
X 
X 
X 
 
 
 
 
 
Record concomitant medications (CM) 
 
 
X 
X 
X 
X 
X 
X 
Height and BMI 
X 
 
 
 
 
 
 
 
Body weight while only wearing underwear 
and a light gown 
X 
 
X 
 
X 
 
X 
 
Comprehensive physical examination (c) 
X 
 
 
 
 
 
X 
 
Targeted physical examination (d) 
 
 
X 
 
X 
 
 
X 
Vital Signs (e) 
X (e) 
 
X 
 
X 
 
X 
X 
Provide ABPM and instruct on use 
 
X 
 
X 
 
X 
 
 
25-hour monitoring of BP via ABPM (f) 
 
X 
 
X 
 
X 
 
 
Orthostatic hypotension evaluation 
 
 
X 
 
X 
 
X 
 
12-lead ECG 
X 
 
 
 
 
 
X 
 
Hematology (g) 
X 
 
 
 
 
 
X 
 
Serum chemistry (g) 
X 
 
X 
 
X (g) 
 
X 
 
Serum pregnancy test (h) 
X 
 
 
 
 
 
 
 
Urine pregnancy test (h) 
 
 
 
 
 
 
X 
 
Urinalysis (g) 
X 
 
 
 
 
 
X 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 73 
CONFIDENTIAL 
Event  
Screening 
Baseline/
1st Dose 
Remainder of Treatment Period 
Follow-up 
Initial 
Screening Visit 
Final 
Screening
Visit 
Day 0 
Day 6 
Day 7 
Day 13 
Day 14 (a) 
Day 28 (a) 
Day –14 to -10 
Day -1 
Urine drug screen (g) 
X 
 
 
 
 
 
 
 
Review inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
Randomization (i) 
 
 
X 
 
 
 
 
 
Administer study drug in clinic (j) 
 
 
X 
X 
 
X 
 
 
Provide diary to record CMs and study drug 
details 
 
 
X 
 
 
 
 
 
Review diary 
 
 
 
X 
X 
X 
X 
X 
Collect study drug containers/capsule count 
 
 
 
X 
X 
X 
 
 
Monitor for treatment emergent adverse 
events (TEAEs) (k) 
 
 
X 
X 
X 
X 
X 
X 
Blood collection for PK (l) 
 
 
 
 
 
 
X 
 
a. 
If a subject is discontinued from study drug early, all study evaluations described for Day 14 and Day 28 will be performed if feasible. Study drug-related 
AEs (adverse reaction or suspected adverse reaction per the definitions in Section 8.1.3) will be followed until resolution or stabilization. 
b. ICF must be signed prior to performing any other screening evaluations 
c. 
Comprehensive physical examination will include the following organ or body system assessments: skin; head, eyes, ears, nose, and throat; thyroid; lungs; 
cardiovascular; abdomen (liver, spleen); lymph nodes; and extremities, as well as an abbreviated neurological exam 
d. Targeted physical examination will specifically target the cardiovascular system and will include vital signs, plus an examination of the extremities to check 
for the presence of edema, as well as an examination to document any other evidence of a cardiovascular problem. Any areas of concern from the medical 
history or noted on the prior physical examination or indicated by subject symptoms or other findings as determined by the Investigator or designee may also 
be examined. 
e. 
BP, pulse rate, respiration rate, and oral body temperature. At the Initial Screening Visit, the arm with the higher average clinical visit systolic BP will be 
determined and used for all further BP measurements including ABPM measurements (see Section 8.3). 
f. 
BP will be continually recorded with an ABPM on one to three 25-hour periods during the trial: Day -1 to Day 0, Day 6 to Day 7, and Day 13 to Day 14 (see 
Section 7.1 for further detail) 
g. See Appendix B for a list of the specific hematology, serum chemistry, urinalysis, and drug tests. The serum chemistry tests at Day 7 will be limited to 
creatinine (and calculation of creatinine clearance) and electrolytes (sodium, bicarbonate, calcium, chloride, phosphorous, and potassium), rather than the 
full panel listed in Appendix B. 
h. Only for WCBP 
i. 
Only after all other baseline procedures have been completed and the subject’s eligibility is confirmed. Subjects will be randomized 3:3:1 to one of three 
treatment arms (see Section 5.2)  


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 74 
CONFIDENTIAL 
j. 
Subjects will take study drug by mouth qd for 14 days (Days 0-13) for a total of 14 doses. With the exception of Days 0, 6 and 13, when study drug intake is 
at the time of clinic visit, the subjects shall be instructed to take the study drugs between 0700 and 1000 hours, and preferably at approximately the same 
time each day. At each dose, subjects will take one capsule from each of the two containers (OE Norvasc® tablet or matched placebo for the OE Norvasc® 
tablet and OE Celebrex® capsule or matched placebo for OE Celebrex® capsule). The first dose of study drug (morning dose on Day 0) and the Day 6 and 
Day 13 doses will be taken in the clinic, and all remaining doses will be self-administered at home. Subjects will be provided with a diary to record the 
details of study drug administration. 
k. Monitoring for PTAEs will begin upon completion of the initial screening visit procedures and will continue through the 9 to 13 days of washout, the final 
screening visit on Day -1, and the baseline procedures on Day 0 (i.e., prior to the administration of the first dose of study drugs). Monitoring for TEAEs will 
begin immediately following administration of the first dose of study drugs and will continue throughout the study. Subjects will be solicited for PTAE 
history at Day -1 and Day 0 (pre-dose).  Subjects will be solicited for TEAE history prior to leaving the clinic on Day 0 and on Days 6, 7, 13, 14, and 28. In 
order to avoid bias in eliciting AEs, subjects will be asked general, non-leading questions such as "How are you feeling?" 
l. 
For PK analysis, blood samples will be obtained at 24 hours ± 1 hour post-dose for measurement of amlodipine concentrations. Only subjects enrolled at 
Investigational Sites that have UV-shielded lights will participate in the PK blood collection. Due to the design of the trial (randomized, double-blind, 
placebo-controlled), this blood sample will be collected and analyzed for all participating subjects, regardless of whether they are in a treatment arm that 
receives amlodipine. 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 75 
CONFIDENTIAL 
APPENDIX B: CLINICAL LABORATORY TESTS 
 
Hematology 
Serum Chemistry (cont.) 
 
Hematocrit 
Phosphorus 
 
Hemoglobin 
Potassium 
 
Mean corpuscular hemoglobin 
Sodium 
 
Mean corpuscular hemoglobin conc. 
Total bilirubin 
 
Mean corpuscular volume 
Total protein 
 
Mean platelet volume 
Triglycerides 
 
Platelet count 
Uric acid 
 
Red blood cell distribution width 
 
WCBP Only 
Red blood cell count 
Urinalysis 
Serum pregnancy test (Screening)  
White blood cell count 
Color and appearance 
Urine pregnancy test (Day 14) 
White blood cell differential 
pH and specific gravity 
 
 (% & absolute): 
Bilirubin 
 
 Basophils 
Glucose 
 
 Eosinophils 
Ketones 
 
 Lymphocytes 
Leukocytes 
 
 Monocytes 
Nitrite 
 
 Neutrophils 
Occult blood 
 
 
Protein 
 
Serum Chemistry1 
Urobilinogen 
 
Albumin 
 
 
Alkaline phosphatase 
Urine Drug Screen:  
 
Alanine aminotransferase 
Amphetamines 
 
Aspartate aminotransferase 
Barbiturates 
 
Bicarbonate 
Benzodiazepines 
 
Blood urea nitrogen 
Cannabis and metabolites 
 
Calcium 
Cocaine and metabolites 
 
Chloride 
Methadone  
 
Cholesterol 
Methamphetamine  
 
Creatinine2 
Methylenedioxymethamphetamine  
 
Gamma glutamyl transferase 
Opiates  
 
Glucose 
Phencyclidine  
 
Iron 
 
 
Lactate dehydrogenase 
 
 
1 The serum chemistry tests at Day 7 will be limited to creatinine and electrolytes (sodium, bicarbonate, calcium, 
chloride, phosphorous, and potassium). 
2 Including calculation of creatinine clearance. 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 76 
CONFIDENTIAL 
APPENDIX C: WORLD HEALTH ORGANIZATION TOXICITY CRITERIA 
 
Category 
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hematology  
WBC (x103/l)  
4 
3.0 - 3.9 
2.0 - 2.9 
1.0 - 1.9 
< 1.0 
Platelets (x103/l)  
WNL 
75.0 - normal 
50.0 - 74.9 
25.0 - 49.9 
< 25.0 
Hemoglobin (g/dL)  
WNL 
10.0 - normal 
8.0 - 9.9 
6.5 - 7.9 
< 6.5 
Granulocytes/Bands 
(x103/l)  
2 
1.5 - 1.9 
1.0 - 1.4 
0.5 - 0.9 
< 0.5 
Lymphocytes (x103/l)  
2 
1.5 - 1.9 
1.0 - 1.4 
0.5 - 0.9 
< 0.5 
Hemorrhage  
None 
Mild, no 
Gross, 1 - 2 units 
transfusion per 
episode 
Gross, 3 - 4 units 
transfusion per 
episode 
Massive, > 4 units 
transfusion per 
episode 
Coagulation  
Fibrinogen  
WNL 
0.99 - 0.75 x N 
0.74 - 0.50 x N 
0.49 - 0.25 x N 
< 0.25 x N 
Prothrombin time 
(Quick)  
WNL 
1.01 - 1.25 x N 
1.26 - 1.50 x N 
1.51 - 2.00 x N 
> 2.00 x N 
Partial thromboplastin 
time  
WNL 
1.01 - 1.66 x N 
1.67 - 2.33 x N 
2.34 - 3.00 x N 
> 3.00 x N 
Metabolic  
Hyperglycemia (mg/dL)  
< 116 
116 - 160 
161 – 250 
251 - 500 
> 500 or 
ketoacidosis 
Hypoglycemia (mg/dL)  
> 64 
55 – 64 
40 – 54 
30 - 39 
< 30 
Amylase  
WNL 
< 1.5 x N 
1.5 - 2.0 x N 
2.1 - 5.0 N 
> 5.0 x N 
Hypercalcemia (mg/dL)  
< 10.6 
10.6 - 11.5 
11.6 - 12.5 
12.6 - 13.4 
13.5 
Hypocalcemias (mg/dL)  
> 8.4 
8.4 - 7.8 
7.7 - 7.0 
6.9 - 6.1 
6 
Hypomagnesemia 
(mg/dL)  
> 1.4 
1.4 - 1.2 
1.1 - 0.9 
0.8 - 0.6 
0.5 
 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 77 
CONFIDENTIAL 
Category 
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Gastrointestinal  
Nausea  
None 
Able to eat 
reasonable intake 
Intake significantly 
decreased but can eat 
No significant 
intake 
__ 
Vomiting  
None 
1 episode in 24 hr 
2 - 5 episodes in 24 hr 
6 - 10 episodes in 
24 hr 
> 10 episodes in 24 hr 
or requiring 
parenteral support 
Diarrhea  
None 
Increase of 2 - 3 
stools / day over 
pre-Rx 
Increase of 4 - 6 
stools / day, or 
nocturnal stools, or 
moderate cramping 
Increase of 7 - 9 
stools/day, or 
incontinence, or 
severe cramping 
Increase of > 10 
stools/day or grossly 
bloody diarrhea, or 
need for parenteral 
support 
Stomatitis  
None 
Painless ulcers, 
erythema, or mild 
soreness 
Painful erythema, 
edema, or ulcers but 
can eat solids 
Painful erythema, 
edema, or ulcers 
and cannot eat 
solids 
Requires parenteral or 
enteral support for 
alimentation 
Liver  
Bilirubin (N = 17 
µmol/L)  
WNL 
----- 
< 1.5 x N 
1.5 - 3.0 x N 
> 3.0 x N 
Transaminase (SGOT, 
SGPT)  
WNL 
2.5 x N 
2.6 - 5.0 x N 
5.1 - 20.0 x N 
> 20.0 x N 
ALK or 5 nucleotidase  
WNL 
< 2.5 x N 
2.6 - 5.0 x N 
5.1 - 20.0 x N 
> 20.0 x N 
Liver- clinical  
No change 
from 
baseline 
----- 
----- 
Precoma 
Hepatic coma 
Kidney, bladder  
Creatinine  
WNL 
< 1.5 x N 
1.5 - 3.0 x N 
3.1 - 6.0 x N 
> 6.0 x N 
Proteinuria  
No change 
1 (+) or < 0.3 g% or 
3 g/L 
2 - 3 (+) or 0.3 - 1.0 
g% or 3 - 10 g/L 
4 (+) or > 1.0 g% or 
> 10g/L 
Nephrotic syndrome 
Hematuria  
Negative 
Microscopic only 
Gross, no clots no Rx 
needed 
Gross and clots 
bladder irrigation 
Requires trans- fusion 
or cystectomy 
Weight gain/loss  
< 5.0 % 
5.0 - 9.9 % 
10.0 - 19.9 % 
20.00% 
----- 
Pulmonary  
Pulmonary  
None or no 
change 
Asymptomatic, 
with abnormality in 
PFTs 
Dyspnea on 
significant exertion 
Dyspnea at normal 
level of activity 
Dyspnea at rest 
 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 78 
CONFIDENTIAL 
Category 
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cardiac  
Cardiac arrhythmias  
None 
Asymptomatic, 
transient, requiring 
no therapy 
Recurrent or persistent, 
no therapy required 
Requires treatment 
Requires 
monitoring; or 
hypo- tension, or 
ventricular 
tachycardia or 
fibrillation 
Cardiac function  
None 
Asymptomatic, 
decline of resting 
ejection fraction by 
less than 20 % of 
baseline value 
Asymptomatic, decline 
of resting ejection 
fraction by more than 
20 % of baseline value 
Mild CHF, 
responsive to 
therapy 
Severe of 
refractory CHF 
Cardiac ischaemia  
None 
Non-specific T- 
wave flattening 
Asymptomatic, ST and 
T wave changes 
suggesting ischaemia 
Angina without 
evidence of 
infraction 
Acute myocardial 
infarction 
Cardiac- pericardial  
None 
Asymptomatic 
effusion, no 
intervention 
required 
Pericarditis (rub, chest 
pain, ECG changes) 
Symptomatic 
effusion; drainage 
required 
Tamponade; 
drainage urgently 
required 
Hypertension  
None or no 
change 
Asymptomatic, 
transient increase 
by greater than 
20 mmHg (D) or to 
> 150/100 if 
previously WNL. 
No treatment 
required. 
Recurrent or persistent 
increase by greater 
than 20 mmHg (D) or 
to > 150/100 if 
previously WNL. No 
treatment required. 
Requires therapy 
Hypertensive crisis 
Hypotension  
None or no 
change 
Changes requiring 
no therapy 
(including transient 
orthostatic hypo- 
tension) 
Requires fluid 
replacement or other 
therapy but not 
hospitalization 
Requires therapy 
and hospitalization; 
resolves within 48 
hours of stopping 
the agent 
Requires therapy 
and hospitalization 
for > 48 hr after 
stopping the agent 
 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 79 
CONFIDENTIAL 
Category 
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neurologic  
Neuro: sensory 
None or no 
change 
Mild paraesthesias; 
loss of deep tendon 
reflexes 
Mild or moderate 
objective sensory 
loss moderate 
paraesthesias 
Severe objective 
sensory loss or 
paraesthesias that 
interfere with 
function 
----- 
Neuro: motor 
None or no 
change 
Subjective 
weakness; no 
objective findings 
Mild objective 
weakness without 
significant 
impairment of 
function 
Objective weakness 
with impairment of 
function 
Paralysis 
Neuro: cortical 
None 
Mild somnolence or 
agitation 
Moderate 
somnolence or 
agitation 
Severe somnolence, 
(>50% waking hr), 
agitation, confusion, 
disorientation or 
hallucinations 
Coma, seizures, toxic 
psychosis 
Neuro: cerebellar 
None 
Slight 
incoordination, 
dysdiadochokinesia 
Intention tremor, 
dysmetria, slurred 
speech, nystagmus 
Locomotor ataxia 
Cerebellar necrosis 
Neuro: mood 
No change 
Mild anxiety or 
depression 
Moderate anxiety 
or depression 
Severe anxiety or 
depression 
Suicidal ideation 
Neuro: headache 
None 
Mild 
Moderate or severe 
but transient 
Unrelenting and 
severe 
----- 
Neuro: constipation 
None or no 
change 
Mild 
Moderate 
Severe 
Ileus > 96 hr 
Neuro: hearing 
None or no 
change 
Asymptomatic, 
hearing loss on 
audiometry only 
Tinnitus 
Hearing loss 
interfering with 
function but 
correctable with 
hearing aid 
Deafness not 
correctable 
Neuro: vision 
None or no 
change 
----- 
----- 
Symptomatic subtotal 
loss of vision 
Blindness 
 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 80 
CONFIDENTIAL 
Category 
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Pain  
Pain  
None 
Mild 
Moderate 
Severe 
Reg. narcotics 
Skin  
Skin  
None or no change 
Scattered macular 
ot papular eruption 
or erythema that is 
asymptomatic 
Scattered macular 
or papular eruption 
or erythema with 
pruritus or other 
associated 
symptoms 
Generalized 
symptomatic 
macular, papular 
or vesicular 
eruption 
Exfoliative 
dermatitis or 
ulcerating 
dermatitis 
Alopecia  
Alopecia  
No loss 
Mild hair loss 
Pronounced or 
total hair loss 
----- 
----- 
Allergy  
Allergy  
None 
Transient rash, 
drug fever < 38oC 
(100.4oF) 
Urticaria, drug 
fever 38oC 
(100.4oF), mild 
bronchospasm 
Serum sickness, 
bronchospasm 
requiring 
parenteral 
medication 
Anaphylaxis 
Local  
Local  
None 
Pain 
Pain and swelling 
with inflammation 
or phlebitis 
Ulceration 
plastic surgery 
indicated 
Fever of unknown origin  Fever of unknown 
origin  
None 
37.1 - 38.0ºC 
98.7º - 100.4ºF 
38.1º - 40.0ºC 
100.5º - 104ºF 
> 40.0ºC  
> 104.0ºF for less 
than 24 hr 
> 40.0ºC (>104ºF) 
for more than 24 hr 
or accompanied by 
hypotension 
Infection  
Infection  
None 
Mild 
Moderate 
Severe 
Life-threatening 
Additional events  
Asthenia  
Analogous to 
Karnofsky index 
(WHO grading) 
 
 
 
 
Chills  
Analogous to fever 
 
 
 
 
Peripheral edema  
Analogous to 
weight gain 
 
 
 
 
Anorexia  
Analogous to 
weight loss 
 
 
 
 
 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 81 
CONFIDENTIAL 
APPENDIX D: ABPM PROCEDURE 
D.1 ABPM Fitting Procedure 
D.1.1 
The ABPM measurements will be collected with the Spacelabs 90207 monitor (Spacelabs 
Healthcare, Issaqua, WA, USA). The blood pressure monitoring equipment, both 
hardware and software, will be consistent across all subjects. 
D.1.2 
The ABPM device shall be programmed to record measurements every 20 min between 
09:00 and 21:59 and every 30 min between 22:00 and 08:59. 
D.1.3 
The investigator shall ensure that a valid measurement is recorded manually upon fitting 
the monitor. This manual measurement shall take place between 07:00 and 10:00 on 
Day -1, Day 6, and Day 13. The date and time shall be noted in the subject diary. 
D.1.4 
With the exception of Day 0, when study drug intake is in the clinic after determination 
of eligibility (and at least 25 hours after the Day-1 ABPM was initiated), Days 6 and 13, 
when study drug intake is at the time of fitting the ABPM device (following fitting) and 
Day 7, when study drug intake is 24 h ± 1 h after the Day 6 dose, the subject shall be 
instructed to take the study drugs between 07:00 and 10:00, and preferably at 
approximately the same time each day. 
D.1.5 
The subject shall be instructed to record bed time, rising time and drug-intake times in 
the subject diary. 
D.1.6 
The ABPM shall be worn for a minimum of 25 h. This is the optimal duration, as it 
provides for a full 24 h after the white-coat window. 
D.2 ABPM Removal Procedure 
D.2.1 
The ABPM may be removed from the subject once 25 hours have elapsed since the 
recorded time of the first study measurement.  
D.2.2 
The ABPM measurements shall be uploaded. 
 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 82 
CONFIDENTIAL 
APPENDIX E: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
(OCTOBER 2013) 
 
 


Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964
and amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of
Clariﬁcation added)
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clariﬁcation added)
59th WMA General Assembly, Seoul, Republic of Korea, October 2008
64th WMA General Assembly, Fortaleza, Brazil, October 2013
Preamble
1.         The World Medical Association (WMA) has developed the Declaration of Helsinki
as a statement of ethical principles for medical research involving human subjects,
including research on identiﬁable human material and data.
            The Declaration is intended to be read as a whole and each of its constituent
paragraphs should be applied with consideration of all other relevant paragraphs.
2.         Consistent with the mandate of the WMA, the Declaration is addressed
primarily to physicians. The WMA encourages others who are involved in medical
research involving human subjects to adopt these principles. 
General Principles
3.         The Declaration of Geneva of the WMA binds the physician with the words,
WMA Declaration of Helsinki - Ethical
Principles for Medical Research Involving
Human Subjects
1/8


“The health of my patient will be my ﬁrst consideration,” and the International Code of
Medical Ethics declares that, “A physician shall act in the patient's best interest when
providing medical care.”
4.         It is the duty of the physician to promote and safeguard the health, well-being
and rights of patients, including those who are involved in medical research. The
physician's knowledge and conscience are dedicated to the fulﬁlment of this duty.
5.         Medical progress is based on research that ultimately must include studies
involving human subjects.
6.         The primary purpose of medical research involving human subjects is to
understand the causes, development and eﬀects of diseases and improve preventive,
diagnostic and therapeutic interventions (methods, procedures and treatments). Even
the best proven interventions must be evaluated continually through research for their
safety, eﬀectiveness, eﬃciency, accessibility and quality.
7.         Medical research is subject to ethical standards that promote and ensure
respect for all human subjects and protect their health and rights.
8.         While the primary purpose of medical research is to generate new knowledge,
this goal can never take precedence over the rights and interests of individual
research subjects.
9.         It is the duty of physicians who are involved in medical research to protect the
life, health, dignity, integrity, right to self-determination, privacy, and conﬁdentiality of
personal information of research subjects. The responsibility for the protection of
research subjects must always rest with the physician or other health care
professionals and never with the research subjects, even though they have given
consent.
10.       Physicians must consider the ethical, legal and regulatory norms and
standards for research involving human subjects in their own countries as well as
applicable international norms and standards. No national or international ethical, legal
or regulatory requirement should reduce or eliminate any of the protections for
research subjects set forth in this Declaration.
11.       Medical research should be conducted in a manner that minimises possible
harm to the environment.
12.       Medical research involving human subjects must be conducted only by
2/8


individuals with the appropriate ethics and scientiﬁc education, training and
qualiﬁcations. Research on patients or healthy volunteers requires the supervision of a
competent and appropriately qualiﬁed physician or other health care professional.
13.       Groups that are underrepresented in medical research should be provided
appropriate access to participation in research.
14.       Physicians who combine medical research with medical care should involve
their patients in research only to the extent that this is justiﬁed by its potential
preventive, diagnostic or therapeutic value and if the physician has good reason to
believe that participation in the research study will not adversely aﬀect the health of
the patients who serve as research subjects.
15.       Appropriate compensation and treatment for subjects who are harmed as a
result of participating in research must be ensured.
Risks, Burdens and Beneﬁts 
16.       In medical practice and in medical research, most interventions involve risks
and burdens.
           Medical research involving human subjects may only be conducted if the
importance of the objective outweighs the risks and burdens to the research subjects.
17.       All medical research involving human subjects must be preceded by careful
assessment of predictable risks and burdens to the individuals and groups involved in
the research in comparison with foreseeable beneﬁts to them and to other individuals
or groups aﬀected by the condition under investigation.
           Measures to minimise the risks must be implemented. The risks must be
continuously monitored, assessed and documented by the researcher. 
18.       Physicians may not be involved in a research study involving human subjects
unless they are conﬁdent that the risks have been adequately assessed and can be
satisfactorily managed.
           When the risks are found to outweigh the potential beneﬁts or when there is
conclusive proof of deﬁnitive outcomes, physicians must assess whether to continue,
modify or immediately stop the study.           
Vulnerable Groups and Individuals
3/8


19.       Some groups and individuals are particularly vulnerable and may have an
increased likelihood of being wronged or of incurring additional harm.
           All vulnerable groups and individuals should receive speciﬁcally considered
protection.
20.       Medical research with a vulnerable group is only justiﬁed if the research is
responsive to the health needs or priorities of this group and the research cannot be
carried out in a non-vulnerable group. In addition, this group should stand to beneﬁt
from the knowledge, practices or interventions that result from the research.
Scientiﬁc Requirements and Research Protocols 
21.       Medical research involving human subjects must conform to generally
accepted scientiﬁc principles, be based on a thorough knowledge of the scientiﬁc
literature, other relevant sources of information, and adequate laboratory and, as
appropriate, animal experimentation. The welfare of animals used for research must
be respected.
22.       The design and performance of each research study involving human subjects
must be clearly described and justiﬁed in a research protocol.
           The protocol should contain a statement of the ethical considerations involved
and should indicate how the principles in this Declaration have been addressed. The
protocol should include information regarding funding, sponsors, institutional
aﬃliations, potential conﬂicts of interest, incentives for subjects and information
regarding provisions for treating and/or compensating subjects who are harmed as a
consequence of participation in the research study.
           In clinical trials, the protocol must also describe appropriate arrangements for
post-trial provisions.
Research Ethics Committees
23.       The research protocol must be submitted for consideration, comment,
guidance and approval to the concerned research ethics committee before the study
begins. This committee must be transparent in its functioning, must be independent of
the researcher, the sponsor and any other undue inﬂuence and must be duly qualiﬁed.
It must take into consideration the laws and regulations of the country or countries in
which the research is to be performed as well as applicable international norms and
4/8


standards but these must not be allowed to reduce or eliminate any of the protections
for research subjects set forth in this Declaration. 
           The committee must have the right to monitor ongoing studies. The researcher
must provide monitoring information to the committee, especially information about
any serious adverse events. No amendment to the protocol may be made without
consideration and approval by the committee. After the end of the study, the
researchers must submit a ﬁnal report to the committee containing a summary of the
study’s ﬁndings and conclusions. 
Privacy and Conﬁdentiality 
24.       Every precaution must be taken to protect the privacy of research subjects
and the conﬁdentiality of their personal information.
Informed Consent 
25.       Participation by individuals capable of giving informed consent as subjects in
medical research must be voluntary. Although it may be appropriate to consult family
members or community leaders, no individual capable of giving informed consent may
be enrolled in a research study unless he or she freely agrees.
26.       In medical research involving human subjects capable of giving informed
consent, each potential subject must be adequately informed of the aims, methods,
sources of funding, any possible conﬂicts of interest, institutional aﬃliations of the
researcher, the anticipated beneﬁts and potential risks of the study and the
discomfort it may entail, post-study provisions and any other relevant aspects of the
study. The potential subject must be informed of the right to refuse to participate in
the study or to withdraw consent to participate at any time without reprisal. Special
attention should be given to the speciﬁc information needs of individual potential
subjects as well as to the methods used to deliver the information.
           After ensuring that the potential subject has understood the information, the
physician or another appropriately qualiﬁed individual must then seek the potential
subject’s freely-given informed consent, preferably in writing. If the consent cannot be
expressed in writing, the non-written consent must be formally documented and
witnessed.      
           All medical research subjects should be given the option of being informed
about the general outcome and results of the study.
5/8


27.       When seeking informed consent for participation in a research study the
physician must be particularly cautious if the potential subject is in a dependent
relationship with the physician or may consent under duress. In such situations the
informed consent must be sought by an appropriately qualiﬁed individual who is
completely independent of this relationship.
28.       For a potential research subject who is incapable of giving informed consent,
the physician must seek informed consent from the legally authorised representative.
These individuals must not be included in a research study that has no likelihood of
beneﬁt for them unless it is intended to promote the health of the group represented
by the potential subject, the research cannot instead be performed with persons
capable of providing informed consent, and the research entails only minimal risk and
minimal burden.
29.       When a potential research subject who is deemed incapable of giving informed
consent is able to give assent to decisions about participation in research, the
physician must seek that assent in addition to the consent of the legally authorised
representative. The potential subject’s dissent should be respected.
30.       Research involving subjects who are physically or mentally incapable of giving
consent, for example, unconscious patients, may be done only if the physical or
mental condition that prevents giving informed consent is a necessary characteristic
of the research  group. In such circumstances the physician must seek informed
consent from the legally authorised representative. If no such representative is
available and if the research cannot be delayed, the study may proceed without
informed consent provided that the speciﬁc reasons for involving subjects with a
condition that renders them unable to give informed consent have been stated in the
research protocol and the study has been approved by a research ethics committee.
Consent to remain in the research must be obtained as soon as possible from the
subject or a legally authorised representative.
31.       The physician must fully inform the patient which aspects of their care are
related to the research. The refusal of a patient to participate in a study or the
patient’s decision to withdraw from the study must never adversely aﬀect the patient-
physician relationship.
32.       For medical research using identiﬁable human material or data, such as
research on material or data contained in biobanks or similar repositories, physicians
must seek informed consent for its collection, storage and/or reuse. There may be
exceptional situations where consent would be impossible or impracticable to obtain
6/8


for such research. In such situations the research may be done only after
consideration and approval of a research ethics committee.
Use of Placebo
33.       The beneﬁts, risks, burdens and eﬀectiveness of a new intervention must be
tested against those of the best proven intervention(s), except in the following
circumstances:
           Where no proven intervention exists, the use of placebo, or no intervention, is
acceptable; or
           Where for compelling and scientiﬁcally sound methodological reasons the use
of any intervention less eﬀective than the best proven one, the use of placebo, or no
intervention is necessary to determine the eﬃcacy or safety of an intervention 
           and the patients who receive any intervention less eﬀective than the best
proven one, placebo, or no intervention will not be subject to additional risks of serious
or irreversible harm as a result of not receiving the best proven intervention. 
           Extreme care must be taken to avoid abuse of this option.
Post-Trial Provisions
34.       In advance of a clinical trial, sponsors, researchers and host country
governments should make provisions for post-trial access for all participants who still
need an intervention identiﬁed as beneﬁcial in the trial. This information must also be
disclosed to participants during the informed consent process.
Research Registration and Publication and Dissemination of
Results
35.       Every research study involving human subjects must be registered in a publicly
accessible database before recruitment of the ﬁrst subject.
36.       Researchers, authors, sponsors, editors and publishers all have ethical
obligations with regard to the publication and dissemination of the results of research.
Researchers have a duty to make publicly available the results of their research on
human subjects and are accountable for the completeness and accuracy of their
reports. All parties should adhere to accepted guidelines for ethical reporting. Negative
and inconclusive as well as positive results must be published or otherwise made
7/8


publicly available. Sources of funding, institutional aﬃliations and conﬂicts of interest
must be declared in the publication. Reports of research not in accordance with the
principles of this Declaration should not be accepted for publication.
Unproven Interventions in Clinical Practice
37.       In the treatment of an individual patient, where proven interventions do not
exist or other known interventions have been ineﬀective, the physician, after seeking
expert advice, with informed consent from the patient or a legally authorised
representative, may use an unproven intervention if in the physician's judgement it
oﬀers hope of saving life, re-establishing health or alleviating suﬀering. This
intervention should subsequently be made the object of research, designed to
evaluate its safety and eﬃcacy. In all cases, new information must be recorded and,
where appropriate, made publicly available.
© World Medical Association, Inc. - All Rights reserved.
© Asociación médica mundial - Todos los derechos reservados.
© L'Association Médicale Mondiale - Tous droits réservés.
8/8


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 91 
CONFIDENTIAL 
APPENDIX F: PACKAGE INSERT FOR NORVASC® (AMLODIPINE BESYLATE) 
TABLETS (MARCH 2015) 
 


 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
  
 
 
  
 
 
 
   
  
 
 
 
  
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
     
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
     
 
 
   
  
 
 
 
 
 
   
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
  
 
  
 
 
  
  
  
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
 
HI G H LI G H T S O F P R E S C RI BI N G I N F O R M A TI O N 
T hese hi g hli g hts d o n ot i ncl u de all t he i nf or m ati o n nee de d t o use 
N O R V A S C s afel y a n d eff ecti vel y. See f ull prescri bi n g i nf or m ati o n f or 
N O R V A S C . 
N O R V A S C ® ( aml o di pi ne bes yl ate ) t a blets, f or or al a d mi nistr ati o n 
I niti al U. S. A p pr o v al: 1 9 8 7 
---------------------------I N DI C A TI O N S A N D U S A G E---------------------------
N O R V A S C is a calci u m c h a n nel bl oc ker a n d ma y be use d al o ne or i n 
c o m bi n ati o n wit h ot h er a nti h y perte nsi ve a n d a ntia n gi nal a ge nts f or t he 
treat me nt of: 
•   
H y p ert e nsi o n ( 1. 1) 
o  N O R V A S C is i n dicate d f or t he treat me nt of h y perte nsi o n, t o 
l o wer bl o o d press ure. L o weri n g bl o o d press ure re d uces t he ris k 
of fatal a n d n o nfatal car di o vasc ular e ve nts, pri maril y str o kes 
a n d m y ocar dial i nfarcti o ns. 
•   
C or o n ar y Arter y Disease ( 1 .2) 
o  C hr o nic Sta ble A n gi na 
o  Vas os p astic A n gi na ( Pri nz metal’s or Varia nt A n gi na) 
o  A n gi o gra p hicall y D oc u me nte d C or o nar y Arter y Disease i n 
p atie nts wit h o ut heart fail ure or a n ejecti o n fracti o n < 4 0 % 
----------------------D O S A G E A N D A D MI NI S T R A TI O N -----------------------
•   
A d ult r ec o m me n d e d starti n g d ose: 5 m g o nce dail y wit h ma xi m u m d ose 
1 0 m g o nce d ail y . ( 2. 1) 
o   
S mall, fra gile, or el derl y patie nts , or patie nts wit h he patic 
i ns ufficie n c y ma y be starte d o n 2. 5 m g o nce dail y . (2. 1 ) 
•   
Pe diatric starti n g d ose: 2. 5 m g t o 5 m g o nce dail y . ( 2. 2) 
I m p o rt a nt Li mit ati o n: D oses i n e xcess of 5 m g dail y ha ve n ot bee n st u die d 
i n p e diatric patie nts. (2. 2 ) 
---------------------D O S A G E F O R M S A N D S T R E N G T H S ----------------------
•   
Ta blets: 2. 5 m g, 5 m g , a n d 1 0 m g ( 3) 
-------------------------------C O N T R AI N DI C A TI O N S ------------------------------
•   
K n o w n se nsiti vit y t o aml o di pi ne ( 4) 
-----------------------W A R NI N G S A N D P R E C A U TI O N S ------------------------
•   
S y m pt o matic h y p ote nsi o n is p ossi ble, partic ularl y i n patie nts wi t h se ver e 
a ortic sten osis . H o we ver, ac ute h y p ote nsi o n is u nli kel y. ( 5. 1) 
•   
W ors e ni n g a n gi na a n d ac ute m y ocar dial infarcti o n ca n de vel o p after 
starti n g or i ncreasi n g t he d ose of N O R V A S C, partic ularl y i n patie nts 
wit h se vere o bstr ucti ve c or o nar y arter y disease . ( 5. 2) 
•   
Titrate sl o wl y i n patie nts wit h se vere he patic i m pair me nt . (5. 3 ) 
------------------------------A D V E R S E R E A C TI O N S -------------------------------
M os t c o m m o n a d verse reactio n t o a ml o di pi ne is e de ma w hic h occ urre d i n a 
d ose relate d ma n ner. Ot her a d verse e x perie nces n ot d ose relate d b ut re p orte d 
wit h a n i nci de nce > 1. 0 % are fati g ue, na usea, a b d o mi nal pai n , a n d 
s o m n ole nce. ( 6) 
T o re p ort S U S P E C T E D A D V E R S E R E A C TI O N S, c o nt act Pfizer at 1 -
8 0 0 -4 3 8 -1 9 8 5 or w w w. pfizer.c o m or F D A at 1 -8 0 0- F D A -1 0 8 8 or 
w w w.f d a. g ov/ m e d w atc h . 
------------------------------D R U G I N T E R A C TI O N S -------------------------------
•   
D o n ot e xcee d d oses greater t ha n 2 0 m g dail y of si m vastati n. ( 7 . 2) 
-----------------------U S E I N S P E CI FI C P O P U L A TI O N S------------------------
•   
Pre g na nc y : Use o nl y if t he p ote ntial be nefit j ustifies t he ris k. ( 8. 1) 
•   
N ursi n g: Disc o nti n ue w he n a d mi nisteri n g N O R V A S C . ( 8.3) 
•   
Pe diatric : Effect o n patie nts less t ha n 6 years ol d is n ot k n o w n. ( 8.4) 
•   
Geriatr ic: Start d osi n g at t he l o w e n d of t he d ose ra n ge. ( 8.5 ) 
Re vise d : 0 3 / 2 0 15 
F U L L P R E S C RI BI N G I N F O R M A TI O N: C O N T E N T S * 
1 
I N DI C A TI O N S A N D U S A G E 
1. 1   H y p erte nsi o n 
1. 2   C or o n ar y Arter y Disease ( C A D) 
2 
D O S A G E A N D A D MI NI S T R A TI O N 
2. 1   A d ults 
2. 2   C hil dre n 
3 
D O S A G E F O R M S A N D S T R E N G T H S 
4 
C O N T R AI N DI C A TI O N S 
5 
W A R NI N G S A N D P R E C A U TI O N S 
5. 1   H y p ote nsi o n 
5. 2   I n crease d A n gi n a or M y ocar dial I nfar ctio n 
5. 3   Patie nts wit h He p atic Fail ure 
6 
A D V E R S E R E A C TI O N S 
6. 1   Cli nical Trials E x perie nce 
6. 2   P ost mar k eti n g E x perie nce 
7 
D R U G I N T E R A C TI O N S 
7. 1   I m p act of Ot h er Dr u gs o n A ml o di pi ne 
7. 2   I m p act of A ml o di pi ne o n Ot her Dr u gs 
8 
U S E I N S P E CI FI C P O P U L A TI O N S 
8. 1   Pre g n a n c y 
8. 3   N ursi n g M ot hers 
8. 4   Pe diatric Use 
8. 5   Geriatric Use 
1 0 O V E R D O S A G E 
1 1 D E S C RI P TI O N 
1 2 C LI NI C A L P H A R M A C O L O G Y 
1 2. 1 Mec ha nis m of Acti o n 
1 2. 2 P har mac o d y na mics 
1 2. 3 P har mac o ki netics 
1 2. 4 Pe diatric Patie nts 
1 3 N O N C LI NI C A L T O XI C O L O G Y 
1 3. 1 
Carci n o ge nesis, M uta ge nesis, I m pair me nt of Fertilit y 
1 4  C LI NI C A L S T U DI E S 
1 4. 1 
Effects i n H y perte nsi o n 
1 4. 2 
Effects i n C hr o nic Sta ble A n gi na 
1 4. 3 
Effects i n Vas os pastic A n gi na 
1 4. 4 
Effects i n D oc u me nte d C or o nar y Arter y Disease 
1 4. 5 
St u dies i n Patie nts wit h Heart Fail ure 
1 6 H O W S U P P LI E D/ S T O R A G E A N D H A N D LI N G 
* Secti o ns or s u bsecti o ns o mitte d fr o m t he f ull prescri bi n g i nf or mati o n are n ot 
liste d. 
R ef er e n c e I D: 3 7 1 9 9 6 1 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FULL PRESCRIBING INFORMATION 
1 INDICATIONS AND USAGE 
1.1 Hypertension 
NORVASC® is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the 
risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen 
in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including NORVASC. 
Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, 
lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many 
patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see 
published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on 
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). 
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have 
been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it 
is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those 
benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but 
reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. 
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is 
greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. 
Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute 
benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or 
hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure 
goal. 
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many 
antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney 
disease). These considerations may guide selection of therapy. 
NORVASC may be used alone or in combination with other antihypertensive agents. 
1.2 Coronary Artery Disease (CAD) 
Chronic Stable Angina 
NORVASC is indicated for the symptomatic treatment of chronic stable angina. NORVASC may be used alone or in 
combination with other antianginal agents. 
Vasospastic Angina (Prinzmetal’s or Variant Angina) 
NORVASC is indicated for the treatment of confirmed or suspected vasospastic angina. NORVASC may be used as 
monotherapy or in combination with other antianginal agents. 
Angiographically Documented CAD 
In patients with recently documented CAD by angiography and without heart failure or an ejection fraction <40%, 
NORVASC is indicated to reduce the risk of hospitalization for angina and to reduce the risk of a coronary revascularization 
procedure. 
2 DOSAGE AND ADMINISTRATION 
2.1 Adults 
The usual initial antihypertensive oral dose of NORVASC is 5 mg once daily, and the maximum dose is 10 mg once daily. 
Small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg once daily and this dose 
may be used when adding NORVASC to other antihypertensive therapy. 
Adjust dosage according to blood pressure goals. In general, wait 7 to 14 days between titration steps. Titrate more rapidly, 
however, if clinically warranted, provided the patient is assessed frequently. 
Angina: The recommended dose for chronic stable or vasospastic angina is 5–10 mg, with the lower dose suggested in the 
elderly and in patients with hepatic insufficiency. Most patients will require 10 mg for adequate effect. 
Reference ID: 3719961 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coronary artery disease: The recommended dose range for patients with coronary artery disease is 5–10 mg once daily. In 
clinical studies, the majority of patients required 10 mg [see Clinical Studies (14.4)]. 
2.2 Children 
The effective antihypertensive oral dose in pediatric patients ages 6–17 years is 2.5 mg to 5 mg once daily. Doses in excess of 
5 mg daily have not been studied in pediatric patients [see Clinical Pharmacology (12.4), Clinical Studies (14.1)]. 
3 DOSAGE FORMS AND STRENGTHS 
Tablets: 2.5 mg white, diamond, flat-faced, beveled edged, with “NORVASC” on one side and “2.5” on the other  
Tablets: 5 mg white, elongated octagon, flat-faced, beveled edged, with “NORVASC” on one side and “5” on the other  
Tablets: 10 mg white, round, flat-faced, beveled edge, with “NORVASC” on one side and “10” on the other  
4 CONTRAINDICATIONS 
NORVASC is contraindicated in patients with known sensitivity to amlodipine. 
5 WARNINGS AND PRECAUTIONS 
5.1 Hypotension 
Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of 
action, acute hypotension is unlikely. 
5.2 Increased Angina or Myocardial Infarction 
Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of NORVASC, 
particularly in patients with severe obstructive coronary artery disease. 
5.3 Patients with Hepatic Failure 
Because NORVASC is extensively metabolized by the liver and the plasma elimination half-life (t 1/2) is 56 hours in patients 
with impaired hepatic function, titrate slowly when administering NORVASC to patients with severe hepatic impairment. 
6 ADVERSE REACTIONS 
6.1 Clinical Trials Experience 
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 
a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in 
practice. 
NORVASC has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In general, treatment 
with NORVASC was well-tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with 
NORVASC were of mild or moderate severity. In controlled clinical trials directly comparing NORVASC (N=1730) at doses 
up to 10 mg to placebo (N=1250), discontinuation of NORVASC because of adverse reactions was required in only about 
1.5% of patients and was not significantly different from placebo (about 1%). The most commonly reported side effects more 
frequent than placebo are reflected in the table below. The incidence (%) of side effects that occurred in a dose related 
manner are as follows: 
Amlodipine 
Placebo 
2.5 mg 
5 mg 
10 mg 
N=275 
N=296 
N=268 
N=520 
Edema 
1.8 
3.0 
10.8 
0.6 
Dizziness 
1.1 
3.4 
3.4 
1.5 
Flushing 
0.7 
1.4 
2.6 
0.0 
Palpitation 
0.7 
1.4 
4.5 
0.6 
Reference ID: 3719961 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other adverse reactions that were not clearly dose related but were reported with an incidence greater than 1.0% in 
placebo-controlled clinical trials include the following: 
NORVASC (%) 
Placebo (%) 
(N=1730) 
(N=1250)  
Fatigue 
4.5 
2.8  
Nausea 
2.9 
1.9  
Abdominal Pain 
1.6 
0.3  
Somnolence 
1.4 
0.6  
For several adverse experiences that appear to be drug and dose related, there was a greater incidence in women than men 
associated with amlodipine treatment as shown in the following table: 
NORVASC 
Placebo 
Male=% 
Female=% 
Male=% 
Female=% 
(N=1218) 
(N=512) 
(N=914) 
(N=336) 
Edema 
5.6 
14.6 
1.4 
5.1  
Flushing 
1.5 
4.5 
0.3 
0.9  
Palpitations 
1.4 
3.3 
0.9 
0.9  
Somnolence 
1.3 
1.6 
0.8 
0.3  
The following events occurred in <1% but >0.1% of patients in controlled clinical trials or under conditions of open trials or 
marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship: 
Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral 
ischemia, syncope, tachycardia, vasculitis. 
Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo.  
Gastrointestinal: anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.  
General: allergic reaction, asthenia,1 back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.  
Musculoskeletal System: arthralgia, arthrosis, muscle cramps,1 myalgia.  
Psychiatric: sexual dysfunction (male1 and female), insomnia, nervousness, depression, abnormal dreams, anxiety,  
depersonalization.  
Respiratory System: dyspnea,1 epistaxis.  
Skin and Appendages: angioedema, erythema multiforme, pruritus,1 rash,1 rash erythematous, rash maculopapular.  
Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus.  
Urinary System: micturition frequency, micturition disorder, nocturia.  
Autonomic Nervous System: dry mouth, sweating increased.  
Metabolic and Nutritional: hyperglycemia, thirst.  
Reference ID: 3719961 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
Hemopoietic: leukopenia, purpura, thrombocytopenia. 
1 These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% 
and 2% in all multiple dose studies. 
NORVASC therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically 
relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric 
acid, blood urea nitrogen, or creatinine. 
In the CAMELOT and PREVENT studies [see Clinical Studies (14.4)], the adverse event profile was similar to that reported 
previously (see above), with the most common adverse event being peripheral edema. 
6.2 Postmarketing Experience 
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably 
estimate their frequency or establish a causal relationship to drug exposure. 
The following postmarketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In 
postmarketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some 
cases severe enough to require hospitalization, have been reported in association with use of amlodipine. 
Postmarketing reporting has also revealed a possible association between extrapyramidal disorder and amlodipine. 
NORVASC has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart 
failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles. 
7 DRUG INTERACTIONS 
7.1 Impact of Other Drugs on Amlodipine 
CYP3A Inhibitors 
Co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and 
may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with 
CYP3A inhibitors to determine the need for dose adjustment [see Clinical Pharmacology (12.3)]. 
CYP3A Inducers 
No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely  
monitored when amlodipine is co-administered with CYP3A inducers.  
Sildenafil  
Monitor for hypotension when sildenafil is co-administered with amlodipine [see Clinical Pharmacology (12.2)].  
7.2 Impact of Amlodipine on Other Drugs 
Simvastatin 
Co-administration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of 
simvastatin in patients on amlodipine to 20 mg daily [see Clinical Pharmacology (12.3)]. 
Immunosuppressants 
Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of 
trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see Clinical 
Pharmacology (12.3)]. 
8 USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy 
Pregnancy Category C 
There are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if 
the potential benefit justifies the risk to the fetus. 
Reference ID: 3719961 


 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally 
with amlodipine maleate at doses up to 10 mg amlodipine/kg/day (respectively, 8 times2 and 23 times2 the maximum 
recommended human dose of 10 mg on a mg/m2 basis) during their respective periods of major organogenesis. However, 
litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased 
(about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before 
mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and 
the duration of labor in rats at this dose. 
2 Based on patient weight of 50 kg. 
8.3 Nursing Mothers 
It is not known whether amlodipine is excreted in human milk. In the absence of this information, it is recommended that 
nursing be discontinued while NORVASC is administered. 
8.4 Pediatric Use 
NORVASC (2.5 to 5 mg daily) is effective in lowering blood pressure in patients 6 to 17 years [see Clinical Studies (14.1)]. 
Effect of NORVASC on blood pressure in patients less than 6 years of age is not known. 
8.5 Geriatric Use 
Clinical studies of NORVASC did not include sufficient numbers of subjects aged 65 and over to determine whether they 
respond differently from younger subjects. Other reported clinical experience has not identified differences in responses 
between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting 
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of 
concomitant disease or other drug therapy. Elderly patients have decreased clearance of amlodipine with a resulting increase 
of AUC of approximately 40–60%, and a lower initial dose may be required [see Dosage and Administration (2.1)]. 
10 OVERDOSAGE 
Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex 
tachycardia. In humans, experience with intentional overdosage of NORVASC is limited. 
Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, 
respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in 
dogs (11 or more times the maximum recommended human dose on a mg/m2 basis) caused a marked peripheral vasodilation 
and hypotension. 
If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements 
are essential. Should hypotension occur, provide cardiovascular support including elevation of the extremities and the 
judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider 
administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As NORVASC 
is highly protein bound, hemodialysis is not likely to be of benefit. 
11 DESCRIPTION 
NORVASC is the besylate salt of amlodipine, a long-acting calcium channel blocker. 
Amlodipine besylate is chemically described as 3-Ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-
4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate. Its empirical formula is 
C20H25CIN2O5•C6H6O3S, and its structural formula is: 
Reference ID: 3719961 


 
 
 
s
t
r
u
c
t u r
a
l
 f
o
r m u
l
a
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amlodipine besylate is a white crystalline powder with a molecular weight of 567.1. It is slightly soluble in water and 
sparingly soluble in ethanol. NORVASC (amlodipine besylate) Tablets are formulated as white tablets equivalent to 2.5, 5, 
and 10 mg of amlodipine for oral administration. In addition to the active ingredient, amlodipine besylate, each tablet 
contains the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch 
glycolate, and magnesium stearate. 
12 CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action 
Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the 
transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that 
amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. 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. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular 
smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not 
been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the 
physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel 
receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual 
onset of effect. 
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral 
vascular resistance and reduction in blood pressure. 
The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the 
following: 
Exertional Angina: In patients with exertional angina, NORVASC reduces the total peripheral resistance (afterload) against 
which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of 
exercise. 
Vasospastic Angina: NORVASC has been demonstrated to block constriction and restore blood flow in coronary arteries and 
arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal 
models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of 
NORVASC in vasospastic (Prinzmetal’s or variant) angina. 
12.2 Pharmacodynamics 
Hemodynamics: Following administration of therapeutic doses to patients with hypertension, NORVASC produces 
vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not 
accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute 
intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies 
Reference ID: 3719961 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically 
significant changes in heart rate or blood pressures in normotensive patients with angina. 
With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma 
concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with 
NORVASC is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension 
(diastolic pressure 105–114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic 
pressure 90–104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures 
(+1/–2 mmHg). 
In hypertensive patients with normal renal function, therapeutic doses of NORVASC resulted in a decrease in renal vascular 
resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or 
proteinuria. 
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or 
pacing) in patients with normal ventricular function treated with NORVASC have generally demonstrated a small increase in 
cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic 
studies, NORVASC has not been associated with a negative inotropic effect when administered in the therapeutic dose range 
to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been 
observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic 
effects. 
Electrophysiologic Effects: NORVASC does not change sinoatrial nodal function or atrioventricular conduction in intact 
animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H 
and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving 
NORVASC and concomitant beta-blockers. In clinical studies in which NORVASC was administered in combination with 
beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were 
observed. In clinical trials with angina patients alone, NORVASC therapy did not alter electrocardiographic intervals or 
produce higher degrees of AV blocks. 
Drug interactions 
Sildenafil: When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood 
pressure lowering effect [see Drug Interactions (7.1)]. 
12.3 Pharmacokinetics 
After oral administration of therapeutic doses of NORVASC, absorption produces peak plasma concentrations between 6 and 
12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of NORVASC is not 
altered by the presence of food. 
Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent 
compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that approximately 93% of the 
circulating drug is bound to plasma proteins in hypertensive patients. Elimination from the plasma is biphasic with a terminal 
elimination half-life of about 30–50 hours. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of 
consecutive daily dosing. 
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may 
therefore receive the usual initial dose. 
Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in 
AUC of approximately 40–60%, and a lower initial dose may be required. A similar increase in AUC was observed in 
patients with moderate to severe heart failure. 
Drug interactions 
In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and 
indomethacin. 
Impact of other drugs on amlodipine 
Co-administered cimetidine, magnesium-and aluminum hydroxide antacids, sildenafil, and grapefruit juice have no impact on 
the exposure to amlodipine. 
Reference ID: 3719961 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CYP3A inhibitors: Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive 
patients resulted in a 60% increase in amlodipine systemic exposure. Erythromycin co-administration in healthy volunteers 
did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A (e.g., itraconazole, 
clarithromycin) may increase the plasma concentrations of amlodipine to a greater extent [see Drug Interactions (7.1)]. 
Impact of amlodipine on other drugs 
Co-administered amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin 
response time. 
Simvastatin: Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase 
in exposure to simvastatin compared to simvastatin alone [see Drug Interactions (7.2)]. 
Cyclosporine: A prospective study in renal transplant patients (N=11) showed on an average of 40% increase in trough 
cyclosporine levels when concomitantly treated with amlodipine [see Drug Interactions (7.2)]. 
Tacrolimus: A prospective study in healthy Chinese volunteers (N=9) with CYP3A5 expressers showed a 2.5- to 4-fold 
increase in tacrolimus exposure when concomitantly administered with amlodipine compared to tacrolimus alone. This 
finding was not observed in CYP3A5 non-expressers (N= 6). However, a 3-fold increase in plasma exposure to tacrolimus in 
a renal transplant patient (CYP3A5 non-expresser) upon initiation of amlodipine for the treatment of post-transplant 
hypertension resulting in reduction of tacrolimus dose has been reported. Irrespective of the CYP3A5 genotype status, the 
possibility of an interaction cannot be excluded with these drugs [see Drug Interactions (7.2)]. 
12.4 Pediatric Patients 
Sixty-two hypertensive patients aged 6 to 17 years received doses of NORVASC between 1.25 mg and 20 mg. Weight-
adjusted clearance and volume of distribution were similar to values in adults. 
13 NONCLINICAL TOXICOLOGY 
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily 
dosage levels of 0.5, 1.25, and 2.5 amlodipine mg/kg/day, showed no evidence of a carcinogenic effect of the drug. For the 
mouse, the highest dose was, on a mg/m2 basis, similar to the maximum recommended human dose of 10 mg 
amlodipine/day.3 For the rat, the highest dose was, on a mg/m2 basis, about twice the maximum recommended human dose.3 
Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or chromosome 
level. 
There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days 
prior to mating) at doses up to 10 mg amlodipine/kg/day (8 times the maximum recommended human dose3 of 10 mg/day on 
a mg/m2 basis). 
3 Based on patient weight of 50 kg 
14 CLINICAL STUDIES 
14.1 Effects in Hypertension  
Adult Patients  
The antihypertensive efficacy of NORVASC has been demonstrated in a total of 15 double-blind, placebo-controlled, 
randomized studies involving 800 patients on NORVASC and 538 on placebo. Once daily administration produced 
statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours postdose, averaging 
about 12/6 mmHg in the standing position and 13/7 mmHg in the supine position in patients with mild to moderate 
hypertension. Maintenance of the blood pressure effect over the 24-hour dosing interval was observed, with little difference 
in peak and trough effect. Tolerance was not demonstrated in patients studied for up to 1 year. The 3 parallel, fixed dose, 
dose response studies showed that the reduction in supine and standing blood pressures was dose-related within the 
recommended dosing range. Effects on diastolic pressure were similar in young and older patients. The effect on systolic 
pressure was greater in older patients, perhaps because of greater baseline systolic pressure. Effects were similar in black 
patients and in white patients. 
Pediatric Patients 
Reference ID: 3719961 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
Two hundred sixty-eight hypertensive patients aged 6 to 17 years were randomized first to NORVASC 2.5 or 5 mg once 
daily for 4 weeks and then randomized again to the same dose or to placebo for another 4 weeks. Patients receiving 2.5 mg or 
5 mg at the end of 8 weeks had significantly lower systolic blood pressure than those secondarily randomized to placebo. The 
magnitude of the treatment effect is difficult to interpret, but it is probably less than 5 mmHg systolic on the 5 mg dose and 
3.3 mmHg systolic on the 2.5 mg dose. Adverse events were similar to those seen in adults. 
14.2 Effects in Chronic Stable Angina 
The effectiveness of 5–10 mg/day of NORVASC in exercise-induced angina has been evaluated in 8 placebo-controlled, 
double-blind clinical trials of up to 6 weeks duration involving 1038 patients (684 NORVASC, 354 placebo) with chronic 
stable angina. In 5 of the 8 studies, significant increases in exercise time (bicycle or treadmill) were seen with the 10 mg 
dose. Increases in symptom-limited exercise time averaged 12.8% (63 sec) for NORVASC 10 mg, and averaged 7.9% 
(38 sec) for NORVASC 5 mg. NORVASC 10 mg also increased time to 1 mm ST segment deviation in several studies and 
decreased angina attack rate. The sustained efficacy of NORVASC in angina patients has been demonstrated over long-term 
dosing. In patients with angina, there were no clinically significant reductions in blood pressures (4/1 mmHg) or changes in 
heart rate (+0.3 bpm). 
14.3 Effects in Vasospastic Angina 
In a double-blind, placebo-controlled clinical trial of 4 weeks duration in 50 patients, NORVASC therapy decreased attacks 
by approximately 4/week compared with a placebo decrease of approximately 1/week (p<0.01). Two of 23 NORVASC and 
7 of 27 placebo patients discontinued from the study due to lack of clinical improvement. 
14.4 Effects in Documented Coronary Artery Disease 
In PREVENT, 825 patients with angiographically documented coronary artery disease were randomized to NORVASC 
(5–10 mg once daily) or placebo and followed for 3 years. Although the study did not show significance on the primary 
objective of change in coronary luminal diameter as assessed by quantitative coronary angiography, the data suggested a 
favorable outcome with respect to fewer hospitalizations for angina and revascularization procedures in patients with CAD. 
CAMELOT enrolled 1318 patients with CAD recently documented by angiography, without left main coronary disease and 
without heart failure or an ejection fraction <40%. Patients (76% males, 89% Caucasian, 93% enrolled at US sites, 89% with 
a history of angina, 52% without PCI, 4% with PCI and no stent, and 44% with a stent) were randomized to double-blind 
treatment with either NORVASC (5–10 mg once daily) or placebo in addition to standard care that included aspirin (89%), 
statins (83%), beta-blockers (74%), nitroglycerin (50%), anti-coagulants (40%), and diuretics (32%), but excluded other 
calcium channel blockers. The mean duration of follow-up was 19 months. The primary endpoint was the time to first 
occurrence of one of the following events: hospitalization for angina pectoris, coronary revascularization, myocardial 
infarction, cardiovascular death, resuscitated cardiac arrest, hospitalization for heart failure, stroke/TIA, or peripheral 
vascular disease. A total of 110 (16.6%) and 151 (23.1%) first events occurred in the NORVASC and placebo groups, 
respectively, for a hazard ratio of 0.691 (95% CI: 0.540–0.884, p = 0.003). The primary endpoint is summarized in Figure 1 
below. The outcome of this study was largely derived from the prevention of hospitalizations for angina and the prevention of 
revascularization procedures (see Table 1). Effects in various subgroups are shown in Figure 2. 
In an angiographic substudy (n=274) conducted within CAMELOT, there was no significant difference 
between amlodipine and placebo on the change of atheroma volume in the coronary artery as assessed by intravascular 
ultrasound. 
Reference ID: 3719961 


  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
Figure 1 - Kaplan-Meier Analysis of Composite Clinical Outcomes for NORVASC versus Placebo 
1318 
1250 
1193 
1157 
1130 
1098 
1066 
1039 
594 # at risk 
graph
Time (Months) 
Figure 2 – Effects on Primary Endpoint of NORVASC versus Placebo across Sub-Groups graph
Table 1 below summarizes the significant composite endpoint and clinical outcomes from the composites of the primary 
endpoint. The other components of the primary endpoint including cardiovascular death, resuscitated cardiac arrest, 
myocardial infarction, hospitalization for heart failure, stroke/TIA, or peripheral vascular disease did not demonstrate a 
significant difference between NORVASC and placebo. 
Reference ID: 3719961 


      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1. 
Incidence of Significant Clinical Outcomes for CAMELOT 
Clinical Outcomes 
NORVASC 
Placebo 
Risk 
N (%) 
(N=663) 
(N=655) 
Reduction 
(p-value) 
Composite CV 
110 
151 
31% 
Endpoint 
(16.6) 
(23.1) 
(0.003) 
Hospitalization for 
51 
84 
42% 
Angina* 
(7.7) 
(12.8) 
(0.002) 
Coronary 
78 
103 
27% 
Revascularization* 
(11.8) 
(15.7) 
(0.033) 
* Total patients with these events 
14.5 Studies in Patients with Heart Failure 
NORVASC has been compared to placebo in four 8–12 week studies of patients with NYHA Class II/III heart failure, 
involving a total of 697 patients. In these studies, there was no evidence of worsened heart failure based on measures of 
exercise tolerance, NYHA classification, symptoms, or left ventricular ejection fraction. In a long-term (follow-up at least 
6 months, mean 13.8 months) placebo-controlled mortality/morbidity study of NORVASC 5–10 mg in 1153 patients with 
NYHA Classes III (n=931) or IV (n=222) heart failure on stable doses of diuretics, digoxin, and ACE inhibitors, NORVASC 
had no effect on the primary endpoint of the study which was the combined endpoint of all-cause mortality and cardiac 
morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart 
failure), or on NYHA classification, or symptoms of heart failure. Total combined all-cause mortality and cardiac morbidity 
events were 222/571 (39%) for patients on NORVASC and 246/583 (42%) for patients on placebo; the cardiac morbid events 
represented about 25% of the endpoints in the study. 
Another study (PRAISE-2) randomized patients with NYHA Class III (80%) or IV (20%) heart failure without clinical 
symptoms or objective evidence of underlying ischemic disease, on stable doses of ACE inhibitors (99%), digitalis (99%), 
and diuretics (99%), to placebo (n=827) or NORVASC (n=827) and followed them for a mean of 33 months. There was no 
statistically significant difference between NORVASC and placebo in the primary endpoint of all-cause mortality (95% 
confidence limits from 8% reduction to 29% increase on NORVASC). With NORVASC there were more reports of 
pulmonary edema. 
16 HOW SUPPLIED/STORAGE AND HANDLING 
2.5 mg Tablets 
NORVASC – 2.5 mg Tablets (amlodipine besylate equivalent to 2.5 mg of amlodipine per tablet) are supplied as white, 
diamond, flat-faced, beveled edged engraved with “NORVASC” on one side and “2.5” on the other side and supplied as 
follows: 
NDC 0069-1520-68 
Bottle of 90 
5 mg Tablets 
NORVASC – 5 mg Tablets (amlodipine besylate equivalent to 5 mg of amlodipine per tablet) are white, elongated octagon, 
flat-faced, beveled edged engraved with both “NORVASC” and “5” on one side and plain on the other side and supplied as 
follows: 
NDC 0069-1530-68 
NDC 0069-1530-41 
NDC 0069-1530-72 
Bottle of 90 
Unit Dose package of 100 
Bottle of 300 
10 mg Tablets 
NORVASC – 10 mg Tablets (amlodipine besylate equivalent to 10 mg of amlodipine per tablet) are white, round, flat-faced, 
beveled edged engraved with both “NORVASC” and “10” on one side and plain on the other side and supplied as follows: 
NDC 0069-1540-68 
Bottle of 90 
NDC 0069-1540-41 
Unit Dose package of 100 
Storage 
Store bottles at controlled room temperature, 59° to 86°F (15° to 30°C) and dispense in tight, light-resistant containers (USP). 
Reference ID: 3719961 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 company logo
LAB-0014-14.0 
Reference ID: 3719961  


 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
    
 
 
  
 
 
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rea d t his i nf or mati o n caref ull y bef ore y o u start ta ki n g N O R V A S C ( N O R E-vas k) a n d eac h ti me y o u refill y o ur prescri pti o n. T here 
ma y be ne w i nf or mati o n. T his i nf or mati o n d oes n ot re place t al ki n g wit h y o ur d oct or. If y o u ha ve a n y q uesti o ns a b o ut N O R V A S C , 
as k y o ur d oct or. Y o ur d oct or will k n o w if N O R V A S C is ri g ht f or y o u. 
W h at i s N O R V A S C ? 
N O R V A S C is a t y pe of me dici ne k n o w n as a calci u m c ha n nel bl oc ker ( C C B). It is use d t o treat hi g h bl o o d press ure ( h y perte nsi o n)  
a n d a t y pe of c hest pai n calle d a n gi na. It ca n be use d b y itself or wit h ot her me dici nes t o treat t hese c o n diti o ns.  
Hi g h Bl o o d Press ure ( h y perte nsi o n)   
Hi g h bl o o d press ure c o mes fr o m bl o o d p us hi n g t o o har d a gai nst y o ur bl o o d vessels. N O R V A S C rela xes y o ur bl o o d vessels, w hic h  
lets y o ur bl o o d fl o w m ore easil y a n d hel ps l o wer y o ur bl o o d press ure. Dr u gs t hat l o wer bl o o d press ure l o wer y o ur ris k of ha vi n g a  
str o ke or heart attac k.  
A n gi n a 
A n gi na is a pai n or disc o mf ort t hat kee ps c o mi n g bac k w he n part of y o ur heart d oes n ot get e n o u g h bl o o d. A n gi na feels li ke a pressi n g 
or s q ueezi n g pai n, us uall y i n y o ur c hest u n der t he breast b o ne. S o meti mes y o u ca n feel it i n y o ur s h o ul ders, ar ms, nec k, j a ws, or bac k. 
N O R V A S C ca n relie ve t his p ai n. 
W h o s h o ul d n ot u s e N O R V A S C ? 
D o n ot use N O R V A S C if y o u are aller gic t o a ml o di pi ne (t he acti ve i n gre die nt i n N O R V A S C) , or t o t he i nacti ve i n gre die nts. Y o ur 
d oct or or p har macist ca n gi ve y o u a list of t hese i n gre die nts. 
W h at s h o ul d I t ell m y d o ct or b ef or e t a ki n g N O R V A S C ? 
T ell y o ur d oct or a b o ut a n y prescri pti o n a n d n o n -prescri pti o n me dici nes y o u are ta ki n g, i ncl u di n g nat ural or her bal re me di es.  
T ell y o ur d oct or if y o u:  
•   e ver ha d heart disease 
•   e ver ha d li ver pr o ble ms 
•   are pre g na nt, or pla n t o bec o me pr e g na nt. Y o ur d oct or will deci de if N O R V A S C is t he best treat me nt f or y o u. 
•   are breast -fee di n g. D o n ot breast-fee d w hile ta ki n g N O R V A S C . Y o u ca n st o p breast-fee di n g or ta ke a differe nt me dici ne. 
H o w s h o ul d I t a k e N O R V A S C ? 
•   T a ke N O R V A S C o nce a da y, wit h or wit h o ut f o o d. 
•   It ma y be easier t o ta ke y o ur d ose if y o u d o it at t he sa me ti me e ver y da y, s uc h as wit h brea kfast or di n ner, or at be dti me. D o n ot 
ta ke m ore t ha n o ne d ose of N O R V A S C at a ti me. 
•   If y o u miss a d ose, ta ke it as s o o n as y o u re me m ber. D o n ot ta ke N O R V A S C if it has bee n m ore t ha n 1 2 h o urs si nce y o u misse d 
y o ur last d ose. W ait a n d ta ke t he ne xt d ose at y o ur re g ular ti me. 
•   Ot her me dici nes: Y o u ca n us e nitr o gl yceri n a n d N O R V A S C t o get her. If y o u ta ke nitr o gl yceri n f or a n gi na, d o n’t st o p t a ki n g it 
w hile y o u are ta ki n g N O R V A S C. 
•   W hile y o u are ta ki n g N O R V A S C , d o n ot st o p ta ki n g y o ur ot her prescri pti o n me dici nes, i ncl u di n g a n y ot her bl o o d press ure 
me dici nes, wit h o ut tal ki n g t o y o u r d oct or. 
•   If y o u t o o k t o o m uc h N O R V A S C , call y o ur d oct or or P ois o n C o ntr ol Ce nter, or g o t o t he nearest h os pital e mer ge nc y r o o m ri g ht 
a wa y. 
W h at s h o ul d I a v oi d w hil e t a ki n g N O R V A S C ? 
•   D o n ot breast -fee d. It is n ot k n o w n if N O R V A S C will pass t hr o u g h y o ur mil k. 
•   D o n ot start a n y ne w prescri pti o n or n o n-prescri pti o n me dici nes or s u p ple me nts, u nless y o u c hec k wit h y o ur d oct or first. 
W h at ar e t h e p o s si bl e si d e eff e ct s of N O R V A S C ? 
N O R V A S C ma y ca use t he f oll o wi n g si de effects. M ost si de effects are mil d or m o derate: 
•   s welli n g of y o ur le gs or a n kles 
•   tire d ness, e xtre me slee pi ness 
•   st o mac h pai n, na usea 
•   dizzi ness 
•   fl us hi n g ( h ot or war m feeli n g i n y o ur face) 
•   arr h yt h mia (irre g ular heart beat) 
•   heart pal pitati o ns ( ver y fast he art beat) 
•   m uscle ri gi dit y, tre m or a n d/ or a b n or mal m uscle m o ve me nt 
R ef er e n c e I D: 3 7 1 9 9 6 1 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
It is rare, but when you first start taking NORVASC or increase your dose, you may have a heart attack or your angina may get worse. 
If that happens, call your doctor right away or go directly to a hospital emergency room. 
Tell your doctor if you are concerned about any side effects you experience. These are not all the possible side effects of NORVASC. 
For a complete list, ask your doctor or pharmacist. 
How do I store NORVASC? 
Keep NORVASC away from children. Store NORVASC Tablets at room temperature (between 59° and 86°F). Keep NORVASC out 
of the light. Do not store in the bathroom. Keep NORVASC in a dry place. 
General advice about NORVASC 
Sometimes, doctors will prescribe a medicine for a condition that is not written in the patient information leaflets. Only use 
NORVASC the way your doctor told you to. Do not give NORVASC to other people, even if they have the same symptoms you 
have. It may harm them. 
You can ask your pharmacist or doctor for information about NORVASC, or you can visit the Pfizer website at www.pfizer.com or 
call 1-800-438-1985. company logo
LAB-0015-8.0 
Revised March 2015 
Reference ID: 3719961 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 107 
CONFIDENTIAL 
APPENDIX G: PACKAGE INSERT FOR CELEBREX® (CELECOXIB) CAPSULES 
(MAY 2016) 
 


 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
HI G H LI G H T S O F P R E S C RI BI N G I N F O R M A TI O N 
T h e s e hi g hli g ht s d o n ot i n cl u d e all t h e i nf or m ati o n n e e d e d t o u s e 
C E L E B R E X  s af el y a n d eff e cti v el y. S e e f ull pr e s cri bi n g i nf or m ati o n 
f or CE L E B R E X . 
C E L E B R E X
 ® ( c el e c o xi b) c a p s ul e s, f or or al u s e 
I niti al U. S. A p pr o v al: 1 9 9 8 
W A R NI N G: RI S K O F S E RI O U S C A R DI O V A S C U L A R A N D   
G A S T R OI N T E S TI N A L E V E N T S  
S e e f ull pr e s cri bi n g i nf or m ati o n f or c o m pl et e b o x e d w ar ni n g. 
•   N o n st er oi d al a nti-i nfl a m m at or y dr u g s ( N S AI D s) c a u s e a n 
i n cr e a s e d ri s k of s eri o u s c ar di o v a s c ul ar t hr o m b oti c e v e nt s, 
i n cl u di n g m y o c ar di al i nf ar cti o n a n d str o k e, w hi c h c a n b e f at al. 
T hi s ri s k m a y o c c ur e arl y i n t h e tr e at m e nt a n d m a y i n cr e a s e 
wit h d ur ati o n of u s e. ( 5. 1) 
•   C E L E B R E X  i s c o ntr ai n di c at e d i n t h e s etti n g of c or o n ar y art er y 
b y p a s s gr aft ( C A B G) s ur g er y. ( 4, 5. 1) 
•   N S AI D s c a u s e a n i n cr e a s e d ri s k of s eri o u s g a str oi nt e sti n al 
( GI) a d v er s e e v e nt s i n cl u di n g bl e e di n g, ul c er ati o n, a n d 
p erf or ati o n of t h e st o m a c h or i nt e sti n e s, w hi c h c a n b e f at al. 
T h e s e e v e nt s c a n o c c ur at a n y ti m e d uri n g u s e a n d wit h o ut 
w ar ni n g s y m pt o m s. El d erl y p ati e nt s a n d p ati e nt s wit h a pri or 
hi st or y of p e pti c ul c er di s e a s e a n d/ or GI bl e e di n g ar e at 
gr e at er ri s k f or s eri o u s GI e v e nt s. ( 5. 2) 
----------------------------- R E C E N T M A J O R C H A N G E S----------------------------
B o x e d W ar ni n g
 5/ 2 0 1 6 
W ar ni n g s a n d Pr e c a uti o n s, C ar di o v a s c ul ar T hr o m b oti c E v e nt s ( 5. 1) 
5/ 2 0 1 6 
W ar ni n g s a n d Pr e c a uti o n s, H e art F ail ur e a n d E d e m a ( 5. 5)  
5/ 2 0 1 6 
-----------------------------I N DI C A TI O N S A N D U S A G E-----------------------------
C E L E B R E X i s a n o n st er oi d al a nti-i nfl a m m at or y dr u g i n di c at e d f or:  
•  O st e o art hriti s ( O A) ( 1. 1)   
•  R h e u m at oi d Art hriti s ( R A) ( 1. 2)   
•  J u v e nil e R h e u m at oi d Art hriti s ( J R A ) i n p ati e nt s 2 y e ar s a n d ol d er ( 1. 3)  
•  A n k yl o si n g S p o n d yliti s ( A S) ( 1. 4)  
•  A c ut e P ai n ( A P) ( 1. 5)  
•  Pri m ar y D y s m e n orr h e a ( P D) ( 1. 6)   
-----------------------D O S A G E A N D A D MI NI S T R A TI O N ---------------------------
•  U s e t h e l o w e st eff e cti v e d o s a g e f o r s h ort e st d ur ati o n c o n si st e nt  
wit h i n di vi d u al p ati e nt tr e at m e nt g o al s ( 2. 1) 
•  O A: 2 0 0 m g o n c e d ail y or 1 0 0 m g t wi c e d ail y ( 2. 2, 1 4. 1) 
•  R A: 1 0 0 t o 2 0 0 m g t wi c e d ail y ( 2. 3, 1 4. 2) 
•  J R A: 5 0 m g t wi c e d ail y i n p ati e nt s 1 0- 2 5 k g. 1 0 0 m g t wi c e d ail y i n 
p ati e nt s m or e t h a n 2 5 k g ( 2. 4, 1 4. 3) 
•   A S: 2 0 0 m g o n c e d ail y si n gl e d o s e or 1 0 0 m g t wi c e d ail y. If n o eff e ct i s 
o b s er v e d aft er 6 w e e k s, a tri al of 4 0 0 m g ( si n gl e or di vi d e d d o s e s) m a y 
b e of b e n efit ( 2. 5, 1 4. 4) 
•   A P a n d P D: 4 0 0 m g i niti all y, f oll o w e d b y 2 0 0 m g d o s e if n e e d e d o n fir st 
d a y. O n s u b s e q u e nt d a y s, 2 0 0 m g t wi c e d ail y a s n e e d e d ( 2. 6, 1 4. 5) 
H e p ati c I m p air m e nt: R e d u c e d ail y d o s e b y 5 0 % i n p ati e nt s wit h 
m o d er at e h e p ati c i m p air m e nt ( C hil d- P u g h Cl a s s B). ( 2. 7, 8. 6, 1 2. 3) 
P o or M et a b oli z er s of C Y P 2 C 9 S u b str at e s: C o n si d er a d o s e r e d u cti o n b y 
5 0 % ( or alt er n ati v e m a n a g e m e nt f or J R A) i n p ati e nt s w h o ar e k n o w n or 
s u s p e ct e d t o b e C Y P 2 C 9 p o or m et a b oli z er s, ( 2. 7, 8. 8, 1 2. 3). 
---------------------- D O S A G E F O R M S A N D S T R E N G T H S----------------------
C E L E B R E X  ( c el e c o xi b) c a p s ul e s: 5 0 m g, 1 0 0 m g, 2 0 0 m g a n d 4 0 0 m g ( 3) 
------------------------------- C O N T R AI N DI C A TI O N S---------------------------------
•  K n o w n h y p er s e n siti vit y t o c el e c o xi b, or a n y c o m p o n e nt s of t h e dr u g 
pr o d u ct or s ulf o n a mi d e s ( 4) 
•  Hi st or y of a st h m a, urti c ari a, or ot h er all er gi c-t y p e r e a cti o n s aft er 
t a ki n g a s piri n or ot h er N S AI D s ( 4) 
•  I n t h e s etti n g of C A B G s ur g er y ( 4) 
------------------------ W A R NI N G S A N D P R E C A U TI O N S-------------------------
•   H e p at ot o xi cit y : I nf or m p ati e nt s of w ar ni n g si g n s a n d s y m pt o m s of 
h e p at ot o xi cit y. Di s c o nti n u e if a b n or m al li v er t e st s p er si st or w or s e n or if 
cli ni c al si g n s a n d s y m pt o m s of  li v er di s e a s e d e v el o p ( 5. 3) 
•   H y p ert e n si o n : P ati e nt s t a ki n g s o m e a nti h y p ert e n si v e m e di c ati o n s m a y 
h a v e i m p air e d r e s p o n s e t o t h e s e t h er a pi e s w h e n t a ki n g N S AI D s. 
M o nit or bl o o d pr e s s ur e ( 5. 4, 7) 
•   H e art F ail ur e a n d E d e m a : A v oi d u s e of CE L E B R E X i n p ati e nt s wit h 
s e v er e h e art f ail ur e u nl e s s b e n efit s ar e e x p e ct e d t o o ut w ei g h ri s k of 
w or s e ni n g h e art f ail ur e ( 5. 5) 
•   R e n al T o xi cit y : M o nit or r e n al f u n ctio n i n p ati e nt s wit h r e n al or h e p ati c 
i m p air m e nt, h e art f ail ur e, d e h y dr ati o n, or h y p o v ol e mi a. A v oi d u s e of 
C E L E B R E X i n p ati e nt s wit h a d v a n c e d r e n al di s e a s e u nl e s s b e n efit s ar e 
e x p e ct e d t o o ut w ei g h ri s k of w or s e ni n g r e n al f u n cti o n ( 5. 6) 
•   A n a p h yl a cti c R e a cti o n s : S e e k e m er g e n c y h el p if a n a n a p h yl a cti c 
r e a cti o n o c c ur s ( 5. 7) 
•   E x a c er b ati o n of A st h m a R el at e d t o A s piri n S e n siti vit y : CE L E B R E X i s 
c o ntr ai n di c at e d i n p ati e nt s wit h a s piri n- s e n siti v e a st h m a. M o nit or 
p ati e nt s wit h pr e e xi sti n g a st h m a ( w it h o ut a s piri n s e n siti vit y) ( 5. 8) 
•   S eri o u s S ki n R e a c ti o n s: Di s c o nti n u e CE L E B R E X at fir st a p p e ar a n c e of 
s ki n r a s h or ot h er si g n s of h y p er s e n siti vit y ( 5. 9) 
•   Pr e m at ur e Cl o s ur e of F et al D u ct u s  Art eri o s u s: A v oi d u s e i n pr e g n a nt 
w o m e n st arti n g at 3 0 w e e k s of g e st ati o n ( 5. 1 0, 8. 1) 
•   H e m at ol o gi c T o xi cit y : M o nit or h e m o glo bi n or h e m at o crit i n p ati e nt s wit h 
a n y si g n s or s y m pt o m s of a n e mi a ( 5. 1 1, 7) 
----------------------------- A D V E R S E R E A C TI O N S----------------------------
M o st c o m m o n a d v er s e r e a cti o n s i n art hriti s tri al s ( > 2 % a n d 
> pl a c e b o) ar e: a b d o mi n al p ai n, di arr h e a, d y s p e p si a, fl at ul e n c e, 
p eri p h er al e d e m a, a c ci d e nt al i nj ur y, di z zi n e s s, p h ar y n giti s, r hi niti s, 
si n u siti s, u p p er r e s pir at or y tr a ct i nf e cti o n, r a s h ( 6. 1).  
T o r e p ort S U S P E C T E D A D V E R S E R E A C TI O N S, c o nt a ct 
Pfi z er at 1- 8 0 0- 4 3 8- 1 9 8 5 or F D A at 1- 8 0 0- F D A- 1 0 8 8 or 
w w w.f d a. g o v/ m e d w at c h 
--------------------------- D R U G I N T E R A C TI O N S--------------------------
•   Dr u g s t h at I nt erf er e wit h H e m o st a si s ( e. g. w arf ari n, a s piri n, 
S S RI s/ S N RI s) : M o nit or p ati e nt s f or bl e e di n g w h o ar e c o n c o mit a ntl y 
t a ki n g C E L E B R E X wit h dr u g s t h at i nt erf er e wit h h e m o st a si s. C o n c o mit a nt 
u s e of C E L E B R E X a n d a n al g e si c d o s e s of a s piri n i s n ot g e n er all y 
r e c o m m e n d e d ( 7) 
•   A C E I n hi bit or s, A n gi ot e n si n R e c e pt or Bl o c k er s ( A R B), or B et a-
Bl o c k er s : C o n c o mit a nt u s e wit h CE L E B R E X m a y di mi ni s h t h e 
a nti h y p ert e n si v e eff e ct of t h e s e dr u g s. M o nit or bl o o d pr e s s ur e ( 7) 
•   A C E I n hi bit or s a n d A R B s : C o n c o mit a nt u s e wit h CE L E B R E X i n 
el d erl y, v ol u m e d e pl et e d, or t h o s e wit h r e n al i m p air m e nt m a y r e s ult i n 
d et eri or ati o n of r e n al f u n cti o n. I n s u c h hi g h ri s k p ati e nt s, m o nit or f or 
si g n s of w or s e ni n g r e n al f u n cti o n ( 7) 
•   Di ur eti c s : N S AI D s c a n r e d u c e n atri ur eti c eff e ct of f ur o s e mi d e a n d 
t hi a zi d e di ur eti c s. M o nit or p ati e nt s t o a s s ur e di ur eti c effi c a c y i n cl u di n g 
a nti h y p ert e n si v e eff e ct s ( 7) 
•   Di g o xi n : C o n c o mit a nt u s e wit h CE L E B R E X c a n i n cr e a s e s er u m 
c o n c e ntr ati o n a n d pr ol o n g h alf-lif e of  di g o xi n. M o nit or s er u m di g o xi n 
l e v el s ( 7) 
-------------------- U S E I N S P E CI FI C P O P U L A TI O N S------------------ 
•   Pr e g n a n c y : U s e of N S AI D s d uri n g t h e t hir d tri m e st er of pr e g n a n c y 
i n cr e a s e s t h e ri s k of pr e m at ur e cl o sur e of t h e f et al d u ct u s art eri o s u s. 
A v oi d u s e of N S AI D s i n pr e g n a nt w o m e n st arti n g at 3 0 w e e k s of 
g e st ati o n ( 5. 1 0, 8. 1) 
•   I nf ertilit y: N S AI D s ar e a s s o ci at e d wit h r e v er si bl e i nf ertilit y. C o n si d er 
wit h dr a w al of C E L E B R E X i n w o m e n w h o h a v e diffi c ulti e s c o n c ei vi n g ( 8. 3) 
S e e 1 7 f or P A TI E N T C O U N S E LI N G I N F O R M A TI O N a n d 
M e di c ati o n G ui d e.  
R e vi s e d: 5/ 2 0 1 6 
R ef er e n c e I D: 3 9 2 8 0 8 4 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F U L L P R E S C RI BI N G I N F O R M A TI O N: C O N T E N T S* 
W A R NI N G: RI S K O F S E RI O U S C A R DI O V A S C U L A R A N D 
G A S T R OI N T E S TI N A L E V E N T S 
1. 
 I N DI C A TI O N S A N D U S A G E 
1. 1   O st e o art hriti s  
1. 2   R h e u m at oi d Art hriti s  
1. 3  J u v e nil e R h e u m at oi d Art hriti s  
1. 4   A n k yl o si n g S p o n d yliti s  
1. 5   A c ut e P ai n  
1. 6   Pri m ar y D y s m e n orr h e a  
2.   
D O S A G E A N D A D MI NI S T R A TI O N 
2. 1  G e n er al D o si n g I n str u cti o n s  
2. 2   O st e o art hriti s  
2. 3   R h e u m at oi d Art hriti s  
2. 4  J u v e nil e R h e u m at oi d Art hriti s  
2. 5   A n k yl o si n g S p o n d yliti s  
2. 6  M a n a g e m e nt of A c ut e P ai n a n d Tr e at m e nt of Pri m ar y   
D y s m e n orr h e a   
2. 7   S p e ci al P o p ul ati o n s  
3.  
D O S A G E F O R M S A N D S T R E N G T H S 
4. 
 C O N T R AI N DI C A TI O N S 
5. 
 W A R NI N G S A N D P R E C A U TI O N S 
5. 1  C ar di o v a s c ul ar T hr o m b oti c E v e nt s   
5. 2  G a str oi nt e sti n al Bl e e di n g, Ul c er ati o n, a n d P erf or ati o n  
5. 3   H e p at ot o xi cit y  
5. 4   H y p ert e n si o n  
5. 5  H e art F ail ur e a n d E d e m a   
5. 6  R e n al T o xi cit y a n d H y p er k al e mi a  
5. 7   A n a p h yl a cti c R e a cti o n s  
5. 8  E x a c er b ati o n of A st h m a R e l at e d t o A s piri n S e n siti vit y  
5. 9  S eri o u s S ki n R e a cti o n s  
5. 1 0 Pr e m at ur e Cl o s ur e of F et al D u ct u s Art eri o s u s  
5. 1 1  H e m at ol o gi c T o xi cit y  
5. 1 2 M a s ki n g of I nfl a m m ati o n a n d F e v er  
5. 1 3  L a b or at or y M o nit ori n g  
5. 1 4  Di s s e mi n at e d I ntr a v a s c ul ar C o a g ul ati o n ( DI C)  
6.   
A D V E R S E R E A C TI O N S 
6. 1  Cli ni c al Tri al s E x p eri e n c e  
6. 2   P o st m ar k eti n g E x p eri e n c e  
7. 
 D R U G I N T E R A C TI O N S 
8.  
U S E I N S P E CI FI C P O P U L A TI O N S 
8. 1   Pr e g n a n c y  
8. 2   L a ct ati o n  
8. 3  F e m al e s a n d M al e s of R e pr o d u cti v e P ot e nti al  
8. 4   P e di atri c U s e  
8. 5   G eri atri c U s e  
8. 6   H e p ati c I n s uffi ci e n c y  
8. 7   R e n al I n s uffi ci e n c y  
8. 8  P o or M et a b oli z er s of C Y P 2 C 9 S u b str at e s  
1 0.   O V E R D O S A G E 
1 1.   D E S C RI P TI O N 
1 2.   C LI NI C A L P H A R M A C O L O G Y 
1 2. 1 M e c h a ni s m of A cti o n  
1 2. 2  P h ar m a c o d y n a mi c s  
1 2. 3  P h ar m a c o ki n eti c s  
1 2. 5  P h ar m a c o g e n o mi c s  
1 3.   N O N C LI NI C A L T O XI C O L O G Y 
1 3. 1  C ar ci n o g e n e si s, M ut a g e n e si s, I m p air m e nt of F ertilit y  
1 3. 2  A ni m al T o xi c ol o g y  
1 4.   C LI NI C A L S T U DI E S 
1 4. 1  O st e o art hriti s  
1 4. 2  R h e u m at oi d Art hriti s  
1 4. 3  J u v e nil e R h e u m at oi d Art hriti s  
1 4. 4  A n k yl o si n g S p o n d yliti s  
1 4. 5 A n al g e si a, I n cl u di n g Pri m ar y D y s m e n orr h e a   
1 4. 6  S p e ci al St u di e s  
1 6.  H O W S U P P LI E D/ S T O R A G E A N D H A N D LI N G 
1 7.   P A TI E N T C O U N S E LI N G I N F O R M A TI O N 
*  S e cti o n s or s u b s e cti o n s o mitt e d fr o m t h e f ull pr e s cri bi n g i nf or m ati o n 
ar e n ot li st e d. 
R ef er e n c e I D: 3 9 2 8 0 8 4 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
F U L L P R E S C RI BI N G I N F O R M A TI O N 
W A R NI N G: RI S K O F S E RI O U S C A R DI O V A S C U L A R A N D G A S T R OI N T E S TI N A L E V E N T S 
C ar di o v a s c ul ar T hr o m b oti c E v e nt s 
•   N o n st er oi d al a nti-i nfl a m m at or y dr u g s ( N S AI D s) c a u s e a n i n cr e a s e d ri s k of s eri o u s c ar di o v a s c ul ar t hr o m b oti c e v e nt s, 
i n cl u di n g m y o c ar di al i nf ar cti o n, a n d str o k e, w hi c h c a n b e f at al. T hi s ri s k m a y o c c ur e arl y i n t h e tr e at m e nt a n d m a y i n cr e a s e 
wit h d ur ati o n of u s e. [ s e e W ar ni n g s a n d Pr e c a uti o n s ( 5. 1) ] 
•   C E L E B R E X  i s c o ntr ai n di c at e d i n t h e s etti n g of c or o n ar y art er y b y p a s s gr aft ( C A B G) s ur g er y. [s e e C o ntr ai n di c ati o n s ( 4) a n d 
W ar ni n g s a n d Pr e c a uti o n s ( 5. 1) ] 
G a str oi nt e sti n al Bl e e di n g, Ul c er ati o n, a n d P erf or ati o n 
•   N S AI D s c a u s e a n i n cr e a s e d ri s k of s eri o u s g a str oi nt e sti n al ( GI) a d v er s e e v e nt s i n cl u di n g bl e e di n g, ul c er ati o n, a n d 
p erf or ati o n of t h e st o m a c h or i nt e sti n e s, w hi c h  ca n b e f at al. T h e s e e v e nt s c a n o c c ur at a n y ti m e d uri n g u s e a n d wit h o ut 
w ar ni n g s y m pt o m s. El d erl y p ati e nt s a n d p ati e nt s wit h a pri or hi st or y of p e pti c ul c er di s e a s e a n d/ or GI bl e e di n g ar e at 
gr e at er ri s k f or s eri o u s ( GI) e v e nt s. [ s e e W ar ni n g s a n d Pr e c a uti o n s ( 5. 2) ] 
1.   I N DI C A TI O N S A N D U S A G E 
C E L E B R E X i s i n di c at e d 
1. 1  O st e o art hriti s ( O A) 
F or t h e m a n a g e m e nt of t h e si g n s a n d s y m pt o m s of O A [ s e e Cli ni c al St u di e s ( 1 4. 1) ] 
1. 2  R h e u m at oi d Art hriti s ( R A) 
F or t h e m a n a g e m e nt of t h e si g n s a n d s y m pt o m s of R A [ s e e Cli ni c al St u di e s ( 1 4. 2) ] 
1. 3 J u v e nil e R h e u m at oi d Art hriti s ( J R A) 
F or t h e m a n a g e m e nt of t h e si g n s a n d s y m pt o m s of J R A i n p ati e nt s 2 y e ar s a n d ol d er [ s e e Cli ni c al St u di e s ( 1 4. 3) ] 
1. 4 A n k yl o si n g S p o n d yliti s ( A S) 
F or t h e m a n a g e m e nt of t h e si g n s a n d s y m pt o m s of A S [ s e e Cli ni c al St u di e s ( 1 4. 4) ] 
1. 5  A c ut e P ai n 
F or t h e m a n a g e m e nt of a c ut e p ai n i n a d ult s [ s e e Cli ni c al St u di e s ( 1 4. 5) ] 
1. 6  Pri m ar y D y s m e n orr h e a 
F or t h e m a n a g e m e nt of pri m ar y d y s m e n orr h e a [ s e e Cli ni c al St u di e s ( 1 4. 5) ] 
2.   D O S A G E A N D A D MI NI S T R A TI O N 
2. 1 G e n er al D o si n g I n str u cti o n s 
C ar ef ull y c o n si d er t h e p ot e nti al b e n efit s a n d ri s k s of C E L E B R E X  a n d ot h er tr e at m e nt o pti o n s b ef or e d e ci di n g t o u s e CE L E B R E X . U s e t h e 
l o w e st eff e cti v e d o s a g e f or t h e s h ort e st d ur ati o n co n si st e nt wit h i n di vi d u al p ati e nt tr e at m e nt g o al s [ s e e W ar ni n g s a n d Pr e c a uti o n s ( 5) ]. 
T h e s e d o s e s c a n b e gi v e n wit h o u t r e g ar d t o ti mi n g of m e al s. 
2. 2  O st e o art hriti s 
F or O A, t h e d o s a g e i s 2 0 0 m g p er d a y a d mi ni st er e d a s a si n gl e d o s e or a s 1 0 0 m g t wi c e d ail y. 
2. 3  R h e u m at oi d Art hriti s 
F or R A, t h e d o s a g e i s 1 0 0 t o 2 0 0 m g t wi c e d ail y. 
2. 4 J u v e nil e R h e u m at oi d Art hriti s 
F or J R A, t h e d o s a g e f or p e di atri c p ati e nt s ( a g e 2 y e ar s a n d ol d er) i s b a s e d o n w ei g ht. F or p ati e nt s > 1 0 k g t o < 2 5 k g t h e r e c o m m e n d e d d o s e 
i s 5 0 m g t wi c e d ail y. F or p ati e nt s > 2 5 k g t h e r e c o m m e n d e d d o s e i s 1 0 0 m g t wi c e d ail y. 
F or p ati e nt s w h o h a v e diffi c ult y s w all o wi n g c a p s ul e s, t h e c o nt e nt s of a C E L E B R E X c a p s ul e c a n b e a d d e d t o a p pl e s a u c e. T h e e ntir e  c a p s ul e 
c o nt e nt s ar e c ar ef ull y e m pti e d o nt o a l e v el t e a s p o o n of c o ol or r o o m t e m p er at ur e a p pl e s a u c e a n d in g e st e d i m m e di at el y wit h w at er . T h e 
s pri n kl e d c a p s ul e c o nt e nt s o n a p pl e s a u c e ar e st a bl e f or u p t o 6 h o ur s u n d er r e fri g er at e d c o n diti o n s ( 2- 8° C/ 3 5- 4 5° F).  
2. 5 A n k yl o si n g S p o n d yliti s 
F or A S, t h e d o s a g e of C E L E B R E X  i s 2 0 0 m g d ail y i n si n gl e ( o n c e p er d a y) or di vi d e d (twi c e p er d a y) d o s e s. If n o eff e ct i s o b s er v e d aft er 6 
w e e k s, a tri al of 4 0 0 m g d ail y m a y b e w ort h w hil e. If n o eff e ct i s o b s er v e d aft er 6 w e e k s o n 4 0 0 m g d ail y, a r e s p o n s e i s n ot li k el y a n d 
c o n si d er ati o n s h o ul d b e gi v e n t o alt er n at e tr e at m e nt o pti o n s. 
2. 6 M a n a g e m e nt of A c ut e P ai n a n d Tr e at m e nt of Pri m ar y D y s m e n orr h e a 
F or m a n a g e m e nt of A c ut e P ai n a n d Tr e at m e nt of Pri m ar y D y s m e n orr h e a,  t h e d o s a g e i s 4 0 0 m g i niti all y, f oll o w e d b y a n a d diti o n al 20 0 m g 
d o s e if n e e d e d o n t h e fir st d a y. O n s u b s e q u e nt d a y s, t h e r e c o m m e n d e d d o s e i s 2 0 0 m g t wi c e d ail y a s n e e d e d. 
2. 7  S p e ci al P o p ul ati o n s 
H e p ati c I m p air m e nt 
I n p ati e nt s wit h m o d er at e h e p ati c i m p air m e nt ( C hil d- P u g h Cl a s s B), r e d u c e t h e d o s e b y 5 0 %. T h e u s e of CE L E B R E X  i n p ati e nt s wit h s e v er e 
h e p ati c i m p air m e nt i s n ot r e c o m m e n d e d [ s e e W ar ni n g s a n d Pr e c a uti o n s ( 5. 5),  U s e i n S p e cifi c P o p ul ati o n s ( 8. 6) a n d Cli ni c al P h ar m a c ol o g y 
( 1 2. 3)]. 
R ef er e n c e I D: 3 9 2 8 0 8 4 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P o or M et a b oli z er s of C Y P 2 C 9 S u b str at e s 
I n a d ult p ati e nt s w h o ar e k n o w n or s u s p e ct e d t o b e p o or C Y P 2 C 9 m et a b oli z er s b a s e d o n g e n ot y p e or pr e vi o u s hi st or y/ e x p eri e n c e wi t h ot h er 
C Y P 2 C 9 s u b str at e s ( s u c h a s w arf ari n , p h e n yt oi n), i niti at e tr e at m e nt wit h h alf of t h e l o w e st r e c o m m e n d e d d o s e. 
I n p ati e nt s wit h J R A w h o ar e k n o w n or s u s p e ct e d t o b e p o or C YP 2 C 9 m et a b oli z er s, c o n si d er u s i n g alt er n ati v e tr e at m e nt s. [s e e U s e i n 
S p e cifi c p o p ul ati o n s ( 8. 8), a n d Cli ni c al P h ar m a c ol o g y ( 1 2. 5)] . 
3.  D O S A G E F O R M S A N D S T R E N G T H S
 CE L E B R E X  ( c el e c o xi b) c a p s ul e s:  
5 0 m g w hit e, wit h r e v er s e pri nt e d w hit e o n r e d b a n d of b o d y a n d c a p wit h m ar ki n g s of 7 7 6 7 o n t h e c a p a n d 5 0 o n t h e b o d y. 
1 0 0 m g w hit e, wit h r e v er s e pri nt e d w hit e o n bl u e b a n d of b o d y a n d c a p wit h m ar ki n g s of 7 7 6 7 o n t h e c a p a n d 1 0 0 o n t h e b o d y. 
2 0 0 m g w hit e, wit h r e v er s e pri nt e d w hit e o n g ol d b a n d wit h m ar ki n g s of 7 7 6 7 o n t h e c a p a n d 2 0 0 o n t h e b o d y. 
4 0 0 m g w hit e, wit h r e v er s e pri nt e d w hit e o n gr e e n b a n d wit h m ar ki n g s of 7 7 6 7 o n t h e c a p a n d 4 0 0 o n t h e b o d y. 
4.  C O N T R AI N DI C A TI O N S 
C E L E B R E X  i s c o ntr ai n di c at e d i n t h e f oll o wi n g p ati e nt s: 
•  K n o w n h y p er s e n siti vit y ( e. g., a n a p h yl a cti c r e a cti o n s a n d s eri o u s s ki n r e a cti o n s) t o c el e c o xi b, a n y c o m p o n e nt s of t h e dr u g pr o d u ct [ s e e 
W ar ni n g s a n d Pr e c a uti o n s ( 5. 7, 5. 9) ]. 
•  Hi st or y of a st h m a, urti c ari a, or ot h er a ll er gi c-t y p e r e a cti o n s aft er t aki n g a s piri n or ot h er N S AI D s. S e v er e, s o m eti m e s f at al, a n a p h yl a cti c 
r e a cti o n s t o N S AI D s, h a v e b e e n r e p ort e d i n s u c h p ati e nt s [s e e W ar ni n g s a n d Pr e c a uti o n s ( 5. 7, 5. 8) ]. 
•  I n t h e s etti n g of c or o n ar y art er y b y p a s s gr aft ( C A B G) s ur g er y [s e e W ar ni n g s a n d Pr e c a uti o n s ( 5. 1) ]. 
•  I n p ati e nt s w h o h a v e d e m o n str at e d all er gi c-t y p e r e a cti o n s t o s ulf o n a mi d e s. 
5.   W A R NI N G S A N D P R E C A U TI O N S 
5. 1  C ar di o v a s c ul ar T hr o m b oti c E v e nt s 
Cli ni c al tri al s of s e v er al C O X- 2 s el e ct i v e a n d n o n s el e cti v e N S AI D s of u p t o t hr e e y e ar s d ur ati o n h a v e s h o w n a n i n cr e a s e d ri s k of s eri o u s 
c ar di o v a s c ul ar ( C V) t hr o m b oti c e v e nt s, i n cl u di n g m y o c ar di al i nf a r cti o n ( MI) a n d str o k e, w hi c h c a n b e f at al. B a s e d o n a v ail a bl e d at a, it i s u n cl e ar 
t h at t h e ri s k f or C V t hr o m b oti c e v e nt s i s si mil ar f or all N S AI D s. T h e r el ati v e i n cr e a s e i n s eri o u s C V t hr o m b oti c e v e nt s o v er b as eli n e c o nf err e d b y 
N S AI D u s e a p p e ar s t o b e si mil ar i n t h o s e wit h a n d wit h o ut k n o w n C V  di s e a s e or ri s k f a ct or s f or C V di s e a s e. H o w e v er, p ati e nt s wit h k n o w n C V 
di s e a s e or ri s k f a ct or s h a d a hi g h er a b s ol ut e i n ci d e n c e of e x c e s s s eri o u s C V t hr o m b oti c e v e nt s, d u e t o t h eir i n cr e a s e d b a s eli n e  r at e. S o m e 
o b s er v ati o n al st u di e s f o u n d t h at t hi s i n cr e a s e d ri s k of s eri o u s C V t hr o m b oti c e v e nt s b e g a n a s e arl y a s t h e fir st w e e k s of tr e at m e nt. T h e i n cr e a s e 
i n C V t hr o m b oti c ri s k h a s b e e n o b s er v e d m o st c o n si st e ntl y at hi g h er d o s e s. 
I n t h e A P C ( A d e n o m a Pr e v e nti o n wit h C el e c o xi b) tri al, t h e h a zar d r ati o f or t h e c o m p o sit e e n d p oi nt of c ar di o v a s c ul ar d e at h, MI, or str o k e w a s 
3. 4  ( 9 5 % CI 1. 4 – 8. 5) f or CE L E B R E X  4 0 0 m g t wi c e d ail y a n d 2. 8 ( 9 5 % CI 1. 1 – 7. 2) wit h CE L E B R E X  2 0 0 m g t wi c e d ail y c o m p ar e d t o pl a c e b o. 
C u m ul ati v e r at e s f or t hi s c o m p o sit e e n d p oi nt o v er 3 y e ar s w er e 3. 0 % ( 2 0/ 6 7 1 s u bj e ct s) a n d 2. 5 % ( 1 7/ 6 8 5 s u bj e ct s), r e s p e cti v el y, c o m p ar e d 
t o 0. 9 % ( 6/ 6 7 9 s u bj e ct s) wit h pl a c e b o tr e at m e nt. T h e i n cr e a s e s i n b ot h c el e c o xi b d o s e gr o u p s v er s u s pl a c e b o-tr e at e d p ati e nt s w er e m ai nl y 
d u e t o a n i n cr e a s e d i n ci d e n c e of m y o c ar di al i nf ar cti o n [ s e e Cli ni c al St u di e s ( 1 4. 6) ]. 
T o mi ni mi z e t h e p ot e nti al ri s k f or a n a d v er s e C V e v e nt i n N S AI D- tr e at e d p ati e nt s, u s e t h e l o w e st eff e cti v e d o s e f or t h e s h ort e st d ur ati o n 
p o s si bl e. P h y si ci a n s a n d p ati e nt s s h o ul d r e m a i n al ert f or t h e d e v el o p m e nt of s u c h e v e nt s, t hr o u g h o ut t h e e ntir e tr e at m e nt c o ur se, e v e n i n t h e 
a b s e n c e of pr e vi o u s C V s y m pt o m s. P ati e nt s s h o ul d b e i nf or m e d a b o ut t h e s y m pt o m s of s eri o u s C V e v e nt s a n d t h e st e p s t o t a k e if t h e y 
o c c ur. 
T h er e i s n o c o n si st e nt e vi d e n c e t h at c o n c urr e nt u s e of a s piri n miti g at e s t h e i n cr e a s e d ri s k of s e ri o u s C V t hr o m b oti c e v e nt s a s so ci at e d wit h 
N S AI D u s e. T h e c o n c urr e nt u s e of a s piri n a n d a n N S AI D, s u c h a s c el e c o xi b, i n cr e a s e s t h e ri s k of s eri o u s g a str oi nt e sti n al ( GI) e v e nt s [ s e e 
W ar ni n g s a n d Pr e c a uti o n s ( 5. 2) ]. 
St at u s P o st C or o n ar y Art er y B y p a s s Gr aft ( C A B G) S ur g er y 
T w o l ar g e, c o ntr oll e d cli ni c al tri al s of a C O X- 2 s el e cti v e N S AI D f or t h e tr e at m e nt of p ai n i n t h e fir st 1 0- 1 4 d a y s f oll o wi n g C A B G s ur g er y f o u n d 
a n i n cr e a s e d i n ci d e n c e of m y o c ar di al i n f ar cti o n a n d str o k e. N S AI D s ar e c o ntr ai n di c at e d i n t h e s etti n g of C A B G [s e e C o ntr ai n di c ati o n s ( 4) ]. 
P o st- MI P ati e nt s 
O b s er v ati o n al st u di e s c o n d u ct e d i n t h e D a ni s h  N ati o n al R e gi str y h a v e d e m o n str at e d t h at p ati e nt s tr e at e d wit h N S AI D s i n t h e p o st- MI p eri o d 
w er e at i n cr e a s e d ri s k of r ei nf ar cti o n, C V-r el at e d d e at h, a n d a ll- c a u s e m ort alit y b e gi n ni n g i n t h e fir st w e e k of tr e at m e nt. I n t hi s s a m e c o h ort, t h e 
i n ci d e n c e of d e at h i n t h e fir st y e ar p o st- MI w a s 2 0 p er 1 0 0 p er so n y e ar s i n N S AI D-tr e at e d p ati e nt s c o m p ar e d t o 1 2 p er 1 0 0 p er s o n y e ar s i n n o n-
N S AI D e x p o s e d p ati e nt s. Alt h o u g h t h e a b s ol ut e r at e of d e at h d e cli n e d s o m e w h at aft er t h e fir st y e ar p o st- MI, t h e i n cr e a s e d r el at i v e ri s k of d e at h 
i n N S AI D u s er s p er si st e d o v er at l e a st t h e n e xt f o ur y e ar s of f oll o w- u p. 
A v oi d t h e u s e of C el e br e x i n p ati e nt s wit h a r e c e nt MI u nl e s s t h e b e n efit s ar e e x p e ct e d t o o ut w ei g h t h e ri s k of r e c urr e nt C V t h r o m b oti c e v e nt s. If 
C el e br e x i s u s e d i n p ati e nt s wit h a r e c e nt MI, m o nit or p ati e nt s f or si g n s of c ar di a c i s c h e mi a. 
5. 2 G a str oi nt e sti n al Bl e e di n g, Ul c er ati o n, a n d P erf or ati o n 
N S AI D s, i n cl u di n g c el e c o xi b c a u s e s eri o u s g a str oi nt e sti n al ( GI) a d v er s e e v e nt s i n cl u di n g i nfl a m m ati o n, bl e e di n g, ul c er ati o n, a n d p erf or ati o n of 
t h e e s o p h a g u s, st o m a c h, s m all i nt e sti n e, or l ar g e i nt e sti n e, w hi ch c a n b e f at al. T h e s e s eri o u s a d v er s e e v e nt s c a n o c c ur at a n y ti m e, wit h or 
wit h o ut w ar ni n g s y m pt o m s, i n p ati e nt s tr e at e d wit h C E L E B R E X . O nl y o n e i n fi v e p ati e nt s w h o d e v el o p a s eri o u s u p p er GI a d v er s e e v e nt o n N S AI D 
t h er a p y i s s y m pt o m ati c. U p p er GI ul c er s, gr o s s bl e e di n g, or p erfor ati o n c a u s e d b y N S AI D s o c c urr e d i n a p pr o xi m at el y 1 % of p ati e n t s tr e at e d f or 
3- 6 m o nt h s, a n d i n a b o ut 2 %- 4 % of p ati e nt s tr e at e d f or o n e y e ar. H o w e v er, e v e n s h ort-t er m N S AI D t h er a p y i s n ot wit h o ut ri s k.  
Ri s k F a ct or s f or GI Bl e e di n g, Ul c er ati o n, a n d P erf or ati o n 
P ati e nt s wit h a pri or hi st or y of p e pti c ul c er di s e a s e a n d/ or GI bl e e di n g w h o u s e d N S AI D s h a d a gr e at er t h a n 1 0-f ol d i n cr e a s e d r i s k f or d e v el o pi n g 
a GI bl e e d c o m p ar e d t o p ati e nt s wit h o ut t h e s e ri s k f a ct or s. Ot h er f a ct or s t h at i n cr e a s e t h e ri s k of GI bl e e di n g i n p ati e nt s tr eat e d wit h N S AI D s 
i n cl u d e l o n g er d ur ati o n of N S AI D t h er a p y; c o n c o mit a nt u s e of or al c orti c o st er oi d s, a s piri n, a nti c o a g ul a nt s; or s el e cti v e s er ot oni n r e u pt a k e 
i n hi bit or s ( S S RI s); s m o ki n g; u s e of al c o h ol; ol d er a g e; a n d p o or g e n er al h e alt h st at u s. M o st p o st m ar k eti n g r e p ort s of f at al GI e v e nt s o c c urr e d i n 
el d erl y or d e bilit at e d p ati e nt s. A d diti o n all y, p ati e nt s wit h a d v a n c e d li v er di s e a s e a n d/ or c o a g ul o p at h y ar e at i n cr e a s e d ri s k f or GI bl e e di n g. 
R ef er e n c e I D: 3 9 2 8 0 8 4 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complicated and symptomatic ulcer rates were 0.78% at nine months for all patients in the CLASS trial, and 2.19% for the subgroup on low-dose 
ASA. Patients 65 years of age and older had an incidence of 1.40% at nine months, 3.06% when also taking ASA [see Clinical Studies (14.6)]. 
Strategies to Minimize the GI Risks in NSAID-treated patients: 
• Use the lowest effective dosage for the shortest possible duration.  
• Avoid administration of more than one NSAID at a time.  
• Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as  
those with active GI bleeding, consider alternate therapies other than NSAIDs. 
• Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. 
• If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue CELEBREX until a serious GI 
adverse event is ruled out. 
• In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding 
[see Drug Interactions (7)]. 
5.3 Hepatotoxicity 
Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated 
patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic 
failure have been reported. 
Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including celecoxib.  
In controlled clinical trials of CELEBREX, the incidence of borderline elevations (greater than or equal to 1.2 times and less than 3 times the 
upper limit of normal) of liver associated enzymes was 6% for CELEBREX and 5% for placebo, and approximately 0.2% of patients taking 
CELEBREX and 0.3% of patients taking placebo had notable elevations of ALT and AST. 
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper 
quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations 
occur (e.g., eosinophilia, rash, etc.), discontinue CELEBREX immediately, and perform a clinical evaluation of the patient. 
5.4 Hypertension 
NSAIDs, including CELEBREX can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute 
to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics or loop diuretics 
may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. 
The rates of hypertension from the CLASS trial in the CELEBREX, ibuprofen and diclofenac-treated patients were 2.4%, 4.2% and 2.5%,  
respectively [see Clinical Studies (14.6)].  
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 
5.5 Heart Failure and Edema 
The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-
fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to 
placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, 
hospitalization for heart failure, and death. 
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of celecoxib may blunt the CV 
effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers 
[ARBs]) [see Drug Interactions (7)]. 
In the CLASS study [see Clinical Studies (14.6)], the Kaplan-Meier cumulative rates at 9 months of peripheral edema in patients on CELEBREX 
400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily and diclofenac 75 
mg twice daily were 4.5%, 6.9% and 4.7%, respectively. 
Avoid the use of CELEBREX in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart  
failure. If CELEBREX is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.  
5.6 Renal Toxicity and Hyperkalemia 
Renal Toxicity 
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. 
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In 
these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood 
flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, 
dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics, ACE-inhibitors or the ARBs, and the elderly. Discontinuation of 
NSAID therapy is usually followed by recovery to the pretreatment state. 
No information is available from controlled clinical studies regarding the use of CELEBREX in patients with advanced renal disease. The renal 
effects of CELEBREX may hasten the progression of renal dysfunction in patients with preexisting renal disease.  
Correct volume status in dehydrated or hypovolemic patients prior to initiating CELEBREX. Monitor renal function in patients with renal or hepatic 
impairment, heart failure, dehydration, or hypovolemia during use of CELEBREX [see Drug Interactions (7)]. Avoid the use of CELEBREX in patients 
with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If CELEBREX is used in patients 
with advanced renal disease, monitor patients for signs of worsening renal function. 
Reference ID: 3928084 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hyperkalemia 
Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without 
renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic- hypoadosteronism state.  
5.7 Anaphylactic Reactions 
Celecoxib has been associated with anaphylactic reactions in patients with and without known hypersensitivity to celecoxib and in patients with 
aspirin sensitive asthma. Celebrex is a sulfonamide and both NSAIDs and sulfonamides may cause allergic type reactions including 
anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people [see Contraindications (4) and 
Warnings and Precautions (5.8)]. 
Seek emergency help if any anaphylactic reaction occurs. 
5.8 Exacerbation of Asthma Related to Aspirin Sensitivity 
A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal 
polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and 
other NSAIDs has been reported in such aspirin-sensitive patients, CELEBREX is contraindicated in patients with this form of aspirin sensitivity 
[see Contraindications (4)]. When CELEBREX is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for 
changes in the signs and symptoms of asthma. 
5.9 Serious Skin Reactions 
Serious skin reactions have occurred following treatment with Celebrex, including erythema multiforme, exfoliative dermatitis, Stevens-Johnson 
Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized 
exanthematous pustulosis (AGEP). These serious events may occur without warning and can be fatal. 
Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of CELEBREX at the first appearance of skin 
rash or any other sign of hypersensitivity. CELEBREX is contraindicated in patients with previous serious skin reactions to NSAIDs [see 
Contraindications (4)]. 
5.10 Premature Closure of Fetal Ductus Arteriosus 
Celecoxib may cause premature closure of the ductus arteriosus. Avoid use of NSAIDs, including CELEBREX, in pregnant women starting at 30 
weeks of gestation (third trimester) [see Use in Specific Populations (8.1)]. 
5.11 Hematological Toxicity 
Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely 
described effect on erythropoiesis. If a patient treated with CELEBREX has any signs or symptoms of anemia, monitor hemoglobin or 
hematocrit. 
In controlled clinical trials the incidence of anemia was 0.6% with CELEBREX and 0.4% with placebo. Patients on long-term treatment with 
CELEBREX should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss. 
NSAIDs, including CELEBREX, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or 
concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin 
norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 
5.12 Masking of Inflammation and Fever 
The pharmacological activity of CELEBREX in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting 
infections. 
5.13 Laboratory Monitoring 
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients 
on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. 
In controlled clinical trials, elevated BUN occurred more frequently in patients receiving CELEBREX compared with patients on placebo. 
This laboratory abnormality was also seen in patients who received comparator NSAIDs in these studies. The clinical significance of this 
abnormality has not been established. 
5.14 Disseminated Intravascular Coagulation (DIC) 
Because of the risk of disseminated intravascular coagulation with use of CELEBREX in pediatric patients with systemic onset JRA, monitor 
patients for signs and symptoms of abnormal clotting or bleeding, and inform patients and their caregivers to report symptoms as soon as 
possible. 
6. ADVERSE REACTIONS 
The following adverse reactions are discussed in greater detail in other sections of the labeling: 
• Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] 
• GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] 
• Hepatotoxicity [see Warnings and Precautions (5.3)] 
• Hypertension [see Warnings and Precautions (5.4)] 
• Heart Failure and Edema [see Warnings and Precautions (5.5)] 
• Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] 
• Anaphylactic Reactions [see Warnings and Precautions (5.7)] 
• Serious Skin Reactions [see Warnings and Precautions (5.9)] 
• Hematologic Toxicity [see Warnings and Precautions (5.11)] 
Reference ID: 3928084 


 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6. 1  Cli ni c al Tri al s E x p eri e n c e 
B e c a u s e cli ni c al tri al s ar e c o n d u ct e d u n d er wi d el y v ar yi n g c o n diti o n s, a d v er s e r e a cti o n r at e s o b s er v e d i n t h e cli ni c al tri al s o f a dr u g 
c a n n ot b e dir e ctl y c o m p ar e d t o r at e s i n t h e cli ni c al tri al s of a n ot h er dr u g a n d m a y n ot r efl e ct t h e r at e s o b s er v e d i n pr a cti c e.  T h e a d v er s e 
r e a cti o n i nf or m ati o n fr o m cli ni c al tri al s d o e s, h o w e v er, pr o vi d e a b a si s f or i d e ntif yi n g t h e a d v er s e e v e nt s t h at a p p e ar t o b e r el at e d t o dr u g 
u s e a n d f or a p pr o xi m ati n g r at e s. 
Of t h e C E L E B R E X -tr e at e d p ati e nt s i n t h e pr e- m ar k eti n g co ntr oll e d cli ni c al tri al s, a p pr o xi m at el y 4, 2 5 0 w er e p ati e nt s wit h O A, a p pr o xi m at el y 
2, 1 0 0 w er e p ati e nt s wit h R A, a n d a p pr o xi m at el y 1, 0 5 0 w er e p ati e nt s wit h p o st- s ur gi c al p ai n. M or e t h a n 8, 5 0 0 p ati e nt s r e c ei v e d a  t ot al 
d ail y d o s e of C E L E B R E X  of 2 0 0 m g ( 1 0 0 m g t wi c e d ail y or 2 0 0 m g o n c e d ail y) or m or e, i n cl u di n g m or e t h a n 4 0 0 tr e at e d at 8 0 0 m g ( 4 0 0 m g 
t wi c e d ail y). A p pr o xi m at el y 3, 9 0 0 p ati e nt s r e c ei v e d CE L E B R E X  at t h e s e d o s e s f or 6 m o nt h s or m or e; a p pr o xi m at el y 2, 3 0 0 of t h e s e h a v e 
r e c ei v e d it f or 1 y e ar or m or e a n d 1 2 4 of t h e s e h a v e r e c ei v e d it f or 2 y e ar s or m or e. 
Pr e- m ar k eti n g C o ntr oll e d Art hriti s Tri al s 
T a bl e 1 li st s all a d v er s e e v e nt s, r e g ar dl e s s of c a u s alit y, o c c urri n g i n 2 % of p ati e nt s r e c ei vi n g C E L E B R E X  fr o m 1 2 c o ntr oll e d st u di e s 
c o n d u ct e d i n p ati e nt s wit h O A or R A t h at i n cl u d e d a pl a c e b o a n d/ or  a p o siti v e c o ntr ol gr o u p. Si n c e t h e s e 1 2 tri al s w er e of differ e nt d ur ati o n s, 
a n d p ati e nt s i n t h e tri al s m a y n ot h a v e b e e n e x p o s e d f or t h e s a m e d ur ati o n of ti m e, t h e s e p er c e nt a g e s d o n ot c a pt ur e c u m ul ati v e  r at e s of 
o c c urr e n c e. 
C B X 
N = 4 1 4 
6 
Pl a c e b o 
N = 1 8 6 4 
N A P 
N = 1 3 6 6 
D C F 
N = 3 8 7 
I B U 
N = 3 4 5 
G a str oi nt e sti n al 
A b d o mi n al P ai n 
Di arr h e a 
D y s p e p si a 
Fl at ul e n c e 
N a u s e a 
4. 1 % 
5. 6 % 
8. 8 % 
2. 2 % 
3. 5 % 
2. 8 % 
3. 8 % 
6. 2 % 
1. 0 % 
4. 2 % 
7. 7 % 
5. 3 % 
1 2. 2 % 
3. 6 % 
6. 0 % 
9. 0 % 
9. 3 % 
1 0. 9 % 
4. 1 % 
3. 4 % 
9. 0 % 
5. 8 % 
1 2. 8 % 
3. 5 % 
6. 7 % 
B o d y a s a w h ol e 
B a c k P ai n 
P eri p h er al E d e m a    
I nj ur y- A c ci d e nt al 
2. 8 % 
2. 1 % 
2. 9 % 
3. 6 % 
1. 1 % 
2. 3 % 
2. 2 % 
2. 1 % 
3. 0 % 
2. 6 % 
1. 0 % 
2. 6 % 
0. 9 % 
3. 5 % 
3. 2 % 
C e ntr al, P eri p h er al 
N er v o u s s y st e m 
Di z zi n e s s 
H e a d a c h e 
2. 0 % 
1 5. 8 % 
1. 7 % 
2 0. 2 % 
2. 6 % 
1 4. 5 % 
1. 3 % 
1 5. 5 % 
2. 3 % 
1 5. 4 % 
P s y c hi atri c 
I n s o m ni a 
2. 3 % 
2. 3 % 
2. 9 % 
1. 3 % 
1. 4 % 
R e s pir at or y 
P h ar y n giti s 
R hi niti s 
Si n u siti s 
U p p er R e s pir at or y 
I nf e cti o n 
2. 3 % 
2. 0 % 
5. 0 % 
8. 1 % 
1. 1 % 
1. 3 % 
4. 3 % 
6. 7 % 
1. 7 % 
2. 4 % 
4. 0 % 
9. 9 % 
1. 6 % 
2. 3 % 
5. 4 % 
9. 8 % 
2. 6 % 
0. 6 % 
5. 8 % 
9. 9 % 
S ki n 
R a s h 
2. 2 % 
2. 1 % 
2. 1 % 
1. 3 % 
1. 2 % 
T a bl e 1: A d v er s e E v e nt s O c c urri n g i n > 2 % of C E L E B R E X P ati e nt s fr o m Pr e- m ar k eti n g C o ntr oll e d Art hriti s Tri al s 
C B X = C E L E B R E X  1 0 0 – 2 0 0 m g t wi c e d ail y or 2 0 0 m g o n c e d ail y; N A P = 
N a pr o x e n 5 0 0 m g t wi c e d ail y; 
D C F = Di cl of e n a c 7 5 m g t wi c e d ail y; 
I B U = I b u pr of e n 8 0 0 m g t hr e e ti m e s d ail y. 
I n pl a c e b o- or a cti v e- c o ntr oll e d cli ni c al tri al s, t h e di s c o nti n u ati o n r at e d u e t o 
a d v er s e e v e nt s w a s 7. 1 % f or p ati e nt s r e c ei vi n g C E L E B R E X  a n d 6. 1 % f or 
p ati e nt s r e c ei vi n g pl a c e b o. A m o n g t h e m o st c o m m o n r e a s o n s f or 
di s c o nti n u ati o n d u e t o a d v er s e e v e nt s i n t h e C E L E B R E X  tr e at m e nt gr o u p s 
w er e d y s p e p si a a n d a b d o mi n al p ai n ( cit e d a s r e a s o n s f or di s c o nti n u ati o n i n 
0. 8 % a n d 0. 7 % of C E L E B R E X  p ati e nt s, r e s p e cti v el y). A m o n g p ati e nt s 
r e c ei vi n g pl a c e b o, 0. 6 % di s c o nti n u e d d u e t o d y s p e p si a a n d 0. 6 % wit h dr e w 
d u e t o a b d o mi n al p ai n. 
T h e f oll o wi n g a d v er s e r e a cti o n s o c c urr e d i n 0. 1 - 1. 9 % of p ati e nt s 
tr e at e d wit h CE L E B R E X ( 1 0 0 - 2 0 0 m g t wi c e d ail y or 2 0 0 m g o n c e d ail y): 
G a str oi nt e sti n al : 
C o n sti p ati o n, di v erti c uliti s , d y s p h a gi a, er u ct ati o n, 
e s o p h a giti s, g a striti s, g a str o e nt eriti s , g a str o e s o p h a g e al r efl u x, h e m orr h oi d s, 
hi at al h er ni a, m el e n a, dr y m o ut h, st o m atiti s, t e n e s m u s, v o miti n g 
C ar di o v a s c ul ar: 
A g gr a v at e d h y p ert e n si o n, a n gi n a p e ct ori s, 
c or o n ar y art er y di s or d er, m y o c ar di al i nf ar cti o n 
G e n er al :  H y p er s e n siti vit y, all er gi c re a cti o n, c h e st p ai n, c y st N O S, 
e d e m a g e n er ali z e d, f a c e e d e m a, f ati g u e,  f e v er, h ot fl u s h e s, i nfl u e n z a-
li k e s y m pt o m s, p ai n, p eri p h er al p ai n 
C e ntr al, p eri p h er al L e g cr a m p s, h y p ert o ni a, h y p o e st h e si a,  
n er v o u s s y st e m: 
mi gr ai n e, p ar e st h e si a, v erti g o 
H e ari n g a n d v e sti b ul ar : 
D e af n e s s, ti n nit u s 
H e art r at e a n d r h yt h m :  P al pit ati o n, t a c h y c ar di a 
Li v er a n d bili ar y :  
H e p ati c e n z y m e i n cr e a s e d (i n cl u di n g S G O T i n cr e a s e d, S G P T i n cr e a s e d) 
M et a b oli c a n d   
B U N i n cr e a s e d, C P K i n cr e a s e d, 
n utriti o n al :  
h y p er c h ol e st er ol e mi a, h y p er gl y c e mi a, h y p o k al e mi a, N P N i n cr e a s e d, cr e ati ni n e i n cr e a s e d, al k ali n e p h o s p h at a s e 
i n cr e a s e d, w ei g ht i n cr e a s e d 
M u s c ul o s k el et al :  
Art hr al gi a, art hr o si s, m y al gi a, s y n o viti s, t e n di niti s 
Pl at el et s ( bl e e di n g 
E c c h y m o si s, e pi st a xi s, t hr o m b o c yt h e mi a, 
or cl otti n g) : 
P s y c hi atri c : 
A n or e xi a, a n xi et y, a p p etit e i n cr e a s e d,  d e pr e s si o n, n er v o u s n e s s, s o m n ol e n c e 
H e mi c : 
A n e mi a 
R e s pir at or y : 
Br o n c hiti s, br o n c h o s p a s m, br o n c h o s p a s m a g gr a v at e d, c o u g h, d y s p n e a, l ar y n giti s, p n e u m o ni a 
S ki n a n d 
Al o p e ci a, d er m atiti s, p h ot o s e n siti vit y 
a p p e n d a g e s : 
r e a cti o n, pr urit u s, r a s h er yt h e m at o u s, r a s h m a c ul o p a p ul ar, s ki n di s or d er, s ki n dr y, s w e ati n g i n cr e a s e d, urti c ari a 
A p pli c ati o n sit e C ell uliti s, d er m atiti s c o nt a ct 
di s or d er s : 
Uri n ar y : 
Al b u mi n uri a, c y stiti s, d y s uri a, h e m at ur i a, mi ct uriti o n fr e q u e n c y, r e n al c al c ul u s 
T h e f oll o wi n g s eri o u s a d v er s e e v e nt s ( c a u s alit y n ot e v al u at e d) o c c urr e d i n < 0. 1 % of p ati e nt s: 
C ar di o v a s c ul ar :  S y n c o p e, c o n g e sti v e h e art f ail ur e, v e ntri c u l ar fi brill ati o n, p ul m o n ar y e m b oli s m, c ere br o v a s c ul ar a c ci d e nt, p eri p h er al g a n gr e n e, 
t hr o m b o p hl e biti s 
R ef er e n c e I D: 3 9 2 8 0 8 4 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Gastrointestinal: Intestinal obstruction, intestinal perforation, gastrointestinal bleeding, colitis with bleeding, esophageal perforation, 
pancreatitis, ileus 
General: 
Sepsis, sudden death 
Liver and biliary: Cholelithiasis 
Hemic and 
Thrombocytopenia 
lymphatic: 
Nervous: Ataxia, suicide [see Drug Interactions (7.1)] 
Renal: 
Acute renal failure 
The Celecoxib Long-Term Arthritis Safety Study [see Special Studies (14.6)]  
Hematological Events: The incidence of clinically significant decreases in hemoglobin (>2 g/dL) was lower in patients on CELEBREX 400 mg  
twice daily (0.5%) compared to patients on either diclofenac 75 mg twice daily (1.3%) or ibuprofen 800 mg three times daily 1.9%. The lower  
incidence of events with CELEBREX was maintained with or without aspirin use [see Clinical Pharmacology (12.2)].  
Withdrawals/Serious Adverse Events: Kaplan-Meier cumulative rates at 9 months for withdrawals due to adverse events for CELEBREX,  
diclofenac and ibuprofen were 24%, 29%, and 26%, respectively. Rates for serious adverse events (i.e., causing hospitalization or felt to be  
life-threatening or otherwise medically significant), regardless of causality, were not different across treatment groups (8%, 7%, and 8%,  
respectively).  
Juvenile Rheumatoid Arthritis Study 
In a 12-week, double-blind, active-controlled study, 242 JRA patients 2 years to 17 years of age were treated with celecoxib or 
naproxen; 77 JRA patients were treated with celecoxib 3 mg/kg twice daily, 82 patients were treated with celecoxib 6 mg/kg twice daily, 
and 83 patients were treated with naproxen 7.5 mg/kg twice daily. The most commonly occurring (5%) adverse events in celecoxib 
treated patients were headache, fever (pyrexia), upper abdominal pain, cough, nasopharyngitis, abdominal pain, nausea, arthralgia, 
diarrhea and vomiting. The most commonly occurring (5%) adverse experiences for naproxen-treated patients were headache, nausea, 
vomiting, fever, upper abdominal pain, diarrhea, cough, abdominal pain, and dizziness (Table 2). Compared with naproxen, celecoxib at 
doses of 3 and 6 mg/kg twice daily had no observable deleterious effect on growth and development during the course of the 12-week 
double-blind study. There was no substantial difference in the number of clinical exacerbations of uveitis or systemic features of JRA 
among treatment groups. 
In a 12-week, open-label extension of the double-blind study described above, 202 JRA patients were treated with celecoxib 6 mg/kg 
twice daily. The incidence of adverse events was similar to that observed during the double-blind study; no unexpected adverse events 
of clinical importance emerged. 
Table 2: Adverse Events Occurring in 5% of JRA Patients in Any Treatment Group, by System Organ Class (% of patients with 
events) 
All Doses Twice Daily 
Celecoxib Celecoxib Naproxen 
System Organ Class
 
Preferred Term 
3 mg/kg 
N=77 
6 mg/kg 
N=82 
7.5 mg/kg 
N=83 
Any Event 
64 
70 
72 
Eye Disorders 
5 
5 
5 
Gastrointestinal 
26 
24 
36 
Abdominal pain NOS 
4 
7 
7 
Abdominal pain upper 
 
Vomiting NOS 
8 
3 
6 
6 
10 
11 
Diarrhea NOS 
5 
4 
8 
Nausea 
7 
4 
11 
General 
13 
11 
18 
 
Pyrexia 
8 
9 
11 
Infections 
25 
20 
27 
Nasopharyngitis 
5 
6 
5 
Injury and Poisoning 
4 
6 
5 
Investigations* 
3 
11 
7 
Musculoskeletal 
8 
10 
17 
Arthralgia 
3 
7 
4 
Nervous System 
17 
11 
21 
Headache NOS 
13 
10 
16 
Dizziness (excl vertigo) 
1 
1 
7 
Respiratory 
8 
15 
15 
Cough 
7 
7 
8 
Skin & Subcutaneous 
10 
7 
18 
* Abnormal laboratory tests, which include: Prolonged activated partial thromboplastin time, Bacteriuria NOS present, Blood creatine 
phosphokinase increased, Blood culture positive, Blood glucose increased, Blood pressure increased, Blood uric acid increased, Hematocrit 
decreased, Hematuria present, Hemoglobin decreased, Liver function tests NOS abnormal, Proteinuria present, Transaminase NOS 
increased, Urine analysis abnormal NOS 
Reference ID: 3928084 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
 
 
   
     
 
 
 
   
 
              
  
                
 
 
Other Pre-Approval Studies 
Adverse Events from Ankylosing Spondylitis Studies: A total of 378 patients were treated with CELEBREX in placebo- and active-controlled 
AS studies. Doses up to 400 mg once daily were studied. The types of adverse events reported in the AS studies were similar to those reported 
in the OA/RA studies. 
Adverse Events from Analgesia and Dysmenorrhea Studies: Approximately 1,700 patients were treated with CELEBREX in analgesia and 
dysmenorrhea studies. All patients in post-oral surgery pain studies received a single dose of study medication. Doses up to 600 mg/day of 
CELEBREX were studied in primary dysmenorrhea and post-orthopedic surgery pain studies. The types of adverse events in the analgesia 
and dysmenorrhea studies were similar to those reported in arthritis studies. The only additional adverse event reported was post-dental 
extraction alveolar osteitis (dry socket) in the post-oral surgery pain studies. 
The APC and PreSAP Trials 
Adverse reactions from long-term, placebo-controlled polyp prevention studies: Exposure to CELEBREX in the APC and PreSAP 
trials was 400 to 800 mg daily for up to 3 years [see Special Studies Adenomatous Polyp Prevention Studies (14.6)]. 
Some adverse reactions occurred in higher percentages of patients than in the arthritis pre-marketing trials (treatment durations up to  
12 weeks; see Adverse events from CELEBREX pre-marketing controlled arthritis trials, above). The adverse reactions for which these  
differences in patients treated with CELEBREX were greater as compared to the arthritis pre-marketing trials were as follows: 
 
CELEBREX  
(400 to 800 mg daily)  Placebo  
N = 2285 
N=1303  
Diarrhea 
10.5% 
7.0%  
Gastroesophageal reflux disease 
4.7% 
3.1%  
Nausea 
6.8% 
5.3%  
Vomiting 
3.2% 
2.1%  
Dyspnea 
2.8% 
1.6%  
Hypertension 
12.5% 
9.8%  
Nephrolithiasis 
2.1% 
0.8%  
The following additional adverse reactions occurred in ≥0.1% and <1% of patients taking CELEBREX, at an incidence greater than placebo in 
the long-term polyp prevention studies, and were either not reported during the controlled arthritis pre-marketing trials or occurred with greater 
frequency in the long-term, placebo-controlled polyp prevention studies: 
Nervous system disorders: Cerebral infarction 
Eye disorders: 
Vitreous floaters, conjunctival hemorrhage 
Ear and labyrinth: 
Labyrinthitis 
Cardiac disorders: Angina unstable, aortic valve incompetence, coronary artery atherosclerosis, sinus bradycardia, ventricular hypertrophy 
Vascular disorders: Deep vein thrombosis 
Reproductive system and breast disorders: Ovarian cyst 
Investigations: 
Blood potassium increased, blood sodium increased, blood testosterone decreased 
Injury, poisoning 
Epicondylitis, tendon rupture  
and procedural  
complications:  
6.2 Postmarketing Experience 
The following adverse reactions have been identified during post approval use of CELEBREX. Because these reactions are reported 
voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship 
to drug exposure 
Cardiovascular: Vasculitis, deep venous thrombosis 
General:             
Anaphylactoid reaction, angioedema 
Liver and biliary: Liver necrosis, hepatitis, jaundice, hepatic failure 
Hemic and 
Agranulocytosis, aplastic 
lymphatic:
     anemia, pancytopenia, leucopenia 
Metabolic: 
Hypoglycemia, hyponatremia 
Nervous: 
Aseptic meningitis, ageusia, anosmia, fatal intracranial hemorrhage 
Renal:
 Interstitial nephritis 
Reference ID: 3928084 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
7. DRUG INTERACTIONS 
See Table 3 for clinically significant drug interactions with celecoxib. 
Table 3: Clinically Significant Drug Interactions with Celecoxib 
Drugs That Interfere with Hemostasis 
Clinical Impact: 
• Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use 
of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either 
drug alone. 
• Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort 
epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an 
NSAID may potentiate the risk of bleeding more than an NSAID alone.  
Intervention: 
Monitor patients with concomitant use of CELEBREX with anticoagulants (e.g., warfarin), antiplatelet agents 
(e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake 
inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)]. 
Aspirin 
Clinical Impact: 
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does 
not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant 
use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions 
as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. 
In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease 
respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective 
antiplatelet effect of aspirin (100-325 mg). 
Intervention: 
Concomitant use of CELEBREX and analgesic doses of aspirin is not generally recommended because of the 
increased risk of bleeding [see Warnings and Precautions (5.11)]. 
CELEBREX is not a substitute for low dose aspirin for cardiovascular protection. 
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers 
Clinical Impact: 
• 
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, 
angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).   
• 
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal 
impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal 
function, including possible acute renal failure. These effects are usually reversible.  
Intervention: 
• 
During concomitant use of CELEBREX and ACE-inhibitors, ARBs, or beta-blockers, monitor blood 
pressure to ensure that the desired blood pressure is obtained.  
• 
During concomitant use of CELEBREX and ACE-inhibitors or ARBs in patients who are elderly, volume-
depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and 
Precautions (5.6)]. 
• 
When these drugs are administered concomitantly, , patients should be adequately hydrated. Assess renal 
function at the beginning of the concomitant treatment and periodically thereafter. 
Diuretics 
Clinical Impact: 
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of 
loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the 
NSAID inhibition of renal prostaglandin synthesis.   
Intervention: 
During concomitant use of CELEBREX with diuretics, observe patients for signs of worsening renal function, 
in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions 
(5.6)]. 
Digoxin 
Clinical Impact: 
The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and 
prolong the half-life of digoxin.  
Intervention: 
During concomitant use of CELEBREX and digoxin, monitor serum digoxin levels. 
Lithium 
Clinical Impact: 
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The 
mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 
20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.  
Intervention: 
During concomitant use of CELEBREX and lithium, monitor patients for signs of lithium toxicity. 
Methotrexate 
Clinical Impact: 
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., 
neutropenia, thrombocytopenia, renal dysfunction). 
Celebrex has no effect on methotrexate pharmacokinetics. 
Intervention: 
During concomitant use of CELEBREX and methotrexate, monitor patients for methotrexate toxicity. 
Cyclosporine 
Clinical Impact: 
Concomitant use of CELEBREX and cyclosporine may increase cyclosporine’s nephrotoxicity. 
Intervention: 
During concomitant use of CELEBREX and cyclosporine, monitor patients for signs of worsening renal 
function. 
Reference ID: 3928084 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NSAIDs and Salicylates 
Clinical Impact: 
Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of 
GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. 
Intervention: 
The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.  
Pemetrexed 
Clinical Impact: 
Concomitant use of CELEBREX and pemetrexed may increase the risk of pemetrexed-associated 
myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). 
Intervention: 
During concomitant use of CELEBREX and pemetrexed, in patients with renal impairment whose creatinine 
clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. 
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two 
days before, the day of, and two days following administration of pemetrexed.  
In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives 
(e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days 
before, the day of, and two days following pemetrexed administration. 
CYP2C9 Inhibitors or inducers 
Clinical Impact: 
Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-
administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance 
the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) 
may lead to compromised efficacy of celecoxib. 
Intervention 
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage 
adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. 
[see Clinical Pharmacology (12.3)]. 
CYP2D6 substrates 
Clinical Impact: 
In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, 
there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. 
atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs. 
Intervention 
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage 
adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. 
[see Clinical Pharmacology (12.3)]. 
Corticosteroids 
Clinical Impact: 
Concomitant use of corticosteroids with CELEBREX may increase the risk of GI ulceration or bleeding. 
Intervention 
Monitor patients with concomitant use of CELEBREX with corticosteroids for signs of bleeding [see 
Warnings and Precautions (5.2)]. 
8. USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy 
Pregnancy Category C. Pregnancy category D from 30 weeks of gestation onward. 
Risk Summary 
Use of NSAIDs, including CELEBREX, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus  
arteriosus. Avoid use of NSAIDs, including CELEBREX, in pregnant women starting at 30 weeks of gestation.   
There are no adequate and well-controlled studies of CELEBREX in pregnant women. Data from observational studies regarding potential 
embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all 
clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for 
pregnancy loss. In animal reproduction studies, embryo-fetal deaths and an increase in diaphragmatic hernias were observed in rats 
administered celecoxib daily during the period of organogenesis at oral doses approximately 6 times the maximum recommended human dose 
of 200 mg twice daily. In addition, structural abnormalities (e.g., septal defects, ribs fused, sternebrae fused and sternebrae misshapen) were 
observed in rabbits given daily oral doses of celecoxib during the period of organogenesis at approximately 2 times the MRHD [see Data]. Based 
on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and 
decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as celecoxib, resulted in increased pre- and post-
implantation loss. 
Clinical Considerations 
Labor or Delivery 
There are no studies on the effects of CELEBREX during labor or delivery. In animal studies, NSAIDs, including celecoxib, inhibit prostaglandin 
synthesis, cause delayed parturition, and increase the incidence of stillbirth. 
Data 
Human Data 
The available data do not establish the presence or absence of developmental toxicity related to the use of Celebrex. 
Animal data 
Celecoxib at oral doses 150 mg/kg/day (approximately 2 times the human exposure at 200 mg twice daily as measured by AUC0-24), 
caused an increased incidence of ventricular septal defects, a rare event, and fetal alterations, such as ribs fused, sternebrae fused and 
sternebrae misshapen when rabbits were treated throughout organogenesis. A dose-dependent increase in diaphragmatic hernias was 
observed when rats were given celecoxib at oral doses 30 mg/kg/day (approximately 6 times human exposure based on the AUC0-24 at 
200 mg twice daily for RA) throughout organogenesis. In rats, exposure to celecoxib during early embryonic development resulted in 
Reference ID: 3928084 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
pre-implantation and post-implantation losses at oral doses 50 mg/kg/day (approximately 6 times human exposure based on the AUC0-24 at 
200 mg twice daily for RA). 
Celecoxib produced no evidence of delayed labor or parturition at oral doses up to 100 mg/kg in rats (approximately 7-fold human exposure 
as measured by the AUC0-24 at 200 mg twice daily). The effects of CELEBREX on labor and delivery in pregnant women are unknown. 
8.2 Lactation 
Risk Summary 
Limited data from 3 published reports that included a total of 12 breastfeeding women showed low levels of CELEBREX in breast milk. The 
calculated average daily infant dose was 10-40 mcg/kg/day, less than 1% of the weight-based therapeutic dose for a two-year old-child. A report 
of two breastfed infants 17 and 22 months of age did not show any adverse events. Caution should be exercised when CELEBREX is 
administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical 
need for CELEBREX and any potential adverse effects on the breastfed infant from the CELEBREX or from the underlying maternal condition.  
8.3 Females and Males of Reproductive Potential 
Infertility 
Females 
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including CELEBREX, may delay or prevent rupture of ovarian 
follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of 
prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin mediated follicular rupture required for ovulation. Small studies in 
women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including CELEBREX, in women 
who have difficulties conceiving or who are undergoing investigation of infertility. 
8.4 Pediatric Use 
CELEBREX is approved for relief of the signs and symptoms of Juvenile Rheumatoid Arthritis in patients 2 years and older. Safety and efficacy 
have not been studied beyond six months in children. The long-term cardiovascular toxicity in children exposed to CELEBREX has not been 
evaluated and it is unknown if long-term risks may be similar to that seen in adults exposed to CELEBREX or other COX-2 selective and non-
selective NSAIDs [(see Boxed Warning, Warnings and Precautions (5.12), and Clinical Studies (14.3)]. 
The use of celecoxib in patients 2 years to 17 years of age with pauciarticular, polyarticular course JRA or in patients with systemic onset JRA 
was studied in a 12-week, double-blind, active controlled, pharmacokinetic, safety and efficacy study, with a 12-week open-label extension. 
Celecoxib has not been studied in patients under the age of 2 years, in patients with body weight less than 10 kg (22 lbs), and in patients with 
active systemic features. Patients with systemic onset JRA (without active systemic features) appear to be at risk for the development of 
abnormal coagulation laboratory tests. In some patients with systemic onset JRA, both celecoxib and naproxen were associated with mild 
prolongation of activated partial thromboplastin time (APTT) but not prothrombin time (PT). When NSAIDs including celecoxib are used in 
patients with systemic onset JRA, monitor patients for signs and symptoms of abnormal clotting or bleeding, due to the risk of disseminated 
intravascular coagulation. Patients with systemic onset JRA should be monitored for the development of abnormal coagulation tests [see 
Dosage and Administration (2.4), Warnings and Precautions (5.12), Adverse Reactions (6.3), Animal Toxicology (13.2), Clinical Studies (14.3)]. 
Alternative therapies for treatment of JRA should be considered in pediatric patients identified to be CYP2C9 poor metabolizers [see Poor 
Metabolizers of CYP2C9 substrates (8.8)]. 
8.5 Geriatric Use 
Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal 
adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, 
and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.13)]. 
Of the total number of patients who received CELEBREX in pre-approval clinical trials, more than 3,300 were 65-74 years of age, while 
approximately 1,300 additional patients were 75 years and over. No substantial differences in effectiveness were observed between these 
subjects and younger subjects. In clinical studies comparing renal function as measured by the GFR, BUN and creatinine, and platelet 
function as measured by bleeding time and platelet aggregation, the results were not different between elderly and young volunteers. 
However, as with other NSAIDs, including those that selectively inhibit COX-2, there have been more spontaneous post-marketing reports of 
fatal GI events and acute renal failure in the elderly than in younger patients [see Warnings and Precautions (5.4, 5.6)]. 
8.6 Hepatic Impairment 
The daily recommended dose of CELEBREX capsules in patients with moderate hepatic impairment (Child-Pugh Class B) should be 
reduced by 50%. The use of CELEBREX in patients with severe hepatic impairment is not recommended [see Dosage and Administration 
(2.6) and Clinical Pharmacology (12.3)]. 
8.7 Renal Impairment 
CELEBREX is not recommended in patients with severe renal insufficiency [see Warnings and Precautions (5.6) and Clinical Pharmacology 
(12.3)]. 
8.8 Poor Metabolizers of CYP2C9 Substrates 
In patients who are known or suspected to be poor CYP2C9 metabolizers (i.e., CYP2C9*3/*3), based on genotype or previous 
history/experience with other CYP2C9 substrates (such as warfarin, phenytoin) administer CELEBREX starting with half the lowest 
recommended dose. Alternative management should be considered in JRA patients identified to be CYP2C9 poor metabolizers. [see Dosage 
and Administration (2.6) and Clinical Pharmacology (12.5)]. 
Reference ID: 3928084 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10. OVERDOSAGE 
Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which 
have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory 
depression, and coma have occured, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6)]. 
No overdoses of CELEBREX were reported during clinical trials. Doses up to 2400 mg/day for up to 10 days in 12 patients did not result in serious 
toxicity. No information is available regarding the removal of celecoxib by hemodialysis, but based on its high degree of plasma protein binding 
(>97%) dialysis is unlikely to be useful in overdose. 
Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or 
activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic 
patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, 
alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. 
For additional information about overdosage treatment contact a poison control center (1-800-222-1222). 
11. DESCRIPTION 
CELEBREX (celecoxib) capsule is a nonsteroidal anti-inflammatory drug, available as capsules containing 50 mg, 100 mg, 200 mg and 400 mg 
celecoxib for oral administration. The chemical name is 4-[5-(4-methylphenyl)- 3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide and is a 
diaryl-substituted pyrazole. The molecular weight is 381.38. Its molecular formula is C17H14F3N3O2S, and it has the following chemical structure: 
stru
c
tu
ral 
fo
rmul
a
Celecoxib is a white to off-white powder with a pKa of 11.1 (sulfonamide moiety). Celecoxib is hydrophobic (log P is 3.5) and is practically insoluble 
in aqueous media at physiological pH range. 
The inactive ingredients in CELEBREX include: croscarmellose sodium, edible inks, gelatin, lactose monohydrate, magnesium stearate, povidone 
and sodium lauryl sulfate. 
12. CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action 
CELECOXIB has analgesic, anti-inflammatory, and antipyretic properties. 
The mechanism of action of CELEBREX is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of 
cyclooxygenase-2 (COX-2). 
Celecoxib is a potent inhibitor of prostaglandin synthesis in vitro. Celecoxib concentrations reached during therapy have produced in vivo 
effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are 
mediators of inflammation. Since celecoxib is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of 
prostaglandins in peripheral tissues. 
12.2 Pharmacodynamics 
Platelets 
In clinical trials using normal volunteers, CELEBREX at single doses up to 800 mg and multiple doses of 600 mg twice daily for up to 7 days 
duration (higher than recommended therapeutic doses) had no effect on reduction of platelet aggregation or increase in bleeding time. 
Because of its lack of platelet effects, CELEBREX is not a substitute for aspirin for cardiovascular prophylaxis. It is not known if there are any 
effects of CELEBREX on platelets that may contribute to the increased risk of serious cardiovascular thrombotic adverse events associated 
with the use of CELEBREX. 
Fluid Retention 
Inhibition of PGE2 synthesis may lead to sodium and water retention through increased reabsorption in the renal medullary thick ascending 
loop of Henle and perhaps other segments of the distal nephron. In the collecting ducts, PGE2 appears to inhibit water reabsorption by 
counteracting the action of antidiuretic hormone. 
Reference ID: 3928084 


 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12.3 Pharmacokinetics 
Celecoxib exhibits dose-proportional increase in exposure after oral administration up to 200 mg twice daily and less than proportional increase 
at hgher doses. It has extensive distribution and high protein binding. It is primarily metabolized by CYP2C9 with a half-life of approximately 
11 hours. 
Absorption 
Peak plasma levels of celecoxib occur approximately 3 hrs after an oral dose. Under fasting conditions, both peak plasma levels (Cmax) and 
area under the curve (AUC) are roughly dose-proportional up to 200 mg twice daily; at higher doses there are less than proportional increases 
in Cmax and AUC [see Food Effects]. Absolute bioavailability studies have not been conducted. With multiple dosing, steady-state conditions 
are reached on or before Day 5. The pharmacokinetic parameters of celecoxib in a group of healthy subjects are shown in Table 4. 
Table 4 
Summary of Single Dose (200 mg) Disposition 
Kinetics of Celecoxib in Healthy Subjects
1 
Mean (%CV) PK Parameter Values 
Cmax, ng/mL 
Tmax, hr Effective t1/2, hr Vss/F, L 
CL/F, L/hr 
705 (38) 
2.8 (37) 
11.2 (31) 
429 (34) 
27.7 (28) 
1 Subjects under fasting conditions (n=36, 19-52 yrs.) 
Food Effects 
When CELEBREX capsules were taken with a high fat meal, peak plasma levels were delayed for about 1 to 2 hours with an increase in total 
absorption (AUC) of 10% to 20%. Under fasting conditions, at doses above 200 mg, there is less than a proportional increase in Cmax and AUC, 
which is thought to be due to the low solubility of the drug in aqueous media.  
Coadministration of CELEBREX with an aluminum- and magnesium-containing antacids resulted in a reduction in plasma celecoxib 
concentrations with a decrease of 37% in Cmax and 10% in AUC. CELEBREX, at doses up to 200 mg twice daily, can be administered without 
regard to timing of meals. Higher doses (400 mg twice daily) should be administered with food to improve absorption. 
In healthy adult volunteers, the overall systemic exposure (AUC) of celecoxib was equivalent when celecoxib was administered as intact 
capsule or capsule contents sprinkled on applesauce. There were no significant alterations in Cmax, Tmax or t1/2 after administration of 
capsule contents on applesauce [see Dosage and Administration (2)]. 
Distribution 
In healthy subjects, celecoxib is highly protein bound (~97%) within the clinical dose range. In vitro studies indicate that celecoxib binds 
primarily to albumin and, to a lesser extent, α1-acid glycoprotein. The apparent volume of distribution at steady state (Vss/F) is approximately 
400 L, suggesting extensive distribution into the tissues. Celecoxib is not preferentially bound to red blood cells. 
Elimination 
Metabolism 
Celecoxib metabolism is primarily mediated via CYP2C9. Three metabolites, a primary alcohol, the corresponding carboxylic acid and its 
glucuronide conjugate, have been identified in human plasma. These metabolites are inactive as COX-1 or COX-2 inhibitors.   
Excretion 
Celecoxib is eliminated predominantly by hepatic metabolism with little (<3%) unchanged drug recovered in the urine and feces. Following a 
single oral dose of radiolabeled drug, approximately 57% of the dose was excreted in the feces and 27% was excreted into the urine. The 
primary metabolite in both urine and feces was the carboxylic acid metabolite (73% of dose) with low amounts of the glucuronide also 
appearing in the urine. It appears that the low solubility of the drug prolongs the absorption process making terminal half-life (t1/2) 
determinations more variable. The effective half-life is approximately 11 hours under fasted conditions. The apparent plasma clearance 
(CL/F) is about 500 mL/min. 
Specific Populations 
Geriatric 
At steady state, elderly subjects (over 65 years old) had a 40% higher Cmax and a 50% higher AUC compared to the young subjects. In elderly 
females, celecoxib Cmax and AUC are higher than those for elderly males, but these increases are predominantly due to lower body weight in 
elderly females. Dose adjustment in the elderly is not generally necessary. However, for patients of less than 50 kg in body weight, initiate 
therapy at the lowest recommended dose [see Dosage and Administration (2.7) and Use in Specific Populations (8.5)]. 
Pediatric 
The steady state pharmacokinetics of celecoxib administered as an investigational oral suspension was evaluated in 152 JRA patients 2 
years to 17 years of age weighing ≥10 kg with pauciarticular or polyarticular course JRA and in patients with systemic onset JRA. Population 
pharmacokinetic analysis indicated that the oral clearance (unadjusted for body weight) of celecoxib increases less than proportionally to 
increasing weight, with 10 kg and 25 kg patients predicted to have 40% and 24% lower clearance, respectively, compared with a 70 kg adult 
RA patient. 
Twice-daily administration of 50 mg capsules to JRA patients weighing ≥12 to ≤25 kg and 100 mg capsules to JRA patients weighing >25 kg 
should achieve plasma concentrations similar to those observed in a clinical trial that demonstrated the non-inferiority of celecoxib to 
naproxen 7.5 mg/kg twice daily (see Dosage and Administration (2.4). Celecoxib has not been studied in JRA patients under the age of 
2 years, in patients with body weight less than 10 kg (22 lbs), or beyond 24 weeks. 
Reference ID: 3928084 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Race 
Meta-analysis of pharmacokinetic studies has suggested an approximately 40% higher AUC of celecoxib in Blacks compared to  
Caucasians. The cause and clinical significance of this finding is unknown.  
Hepatic Impairment 
A pharmacokinetic study in subjects with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment has shown that 
steady-state celecoxib AUC is increased about 40% and 180%, respectively, above that seen in healthy control subjects. Therefore, the 
daily recommended dose of CELEBREX capsules should be reduced by approximately 50% in patients with moderate (Child-Pugh Class B) 
hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied. The use of CELEBREX in patients 
with severe hepatic impairment is not recommended [see Dosage and Administration (2.6) and Use in Specific Populations (8.6)]. 
Renal Impairment 
In a cross-study comparison, celecoxib AUC was approximately 40% lower in patients with chronic renal insufficiency (GFR 35-60 mL/min) 
than that seen in subjects with normal renal function. No significant relationship was found between GFR and celecoxib clearance. Patients 
with severe renal insufficiency have not been studied. Similar to other NSAIDs, CELEBREX is not recommended in patients with severe renal 
insufficiency [see Warnings and Precautions (5.6)]. 
Drug Interaction Studies 
In vitro studies indicate that celecoxib is not an inhibitor of cytochrome P450 2C9, 2C19 or 3A4. 
In vivo studies have shown the following:  
Aspirin 
When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not 
altered. The clinical significance of this interaction is not known. See Table 3 for clinically significant drug interactions of NSAIDs with aspirin 
[see Drug Interactions (7)]. 
Lithium 
In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 
450 mg twice daily with CELEBREX 200 mg twice daily as compared to subjects receiving lithium alone [see Drug Interactions (7)]. 
Fluconazole 
Concomitant administration of fluconazole at 200 mg once daily resulted in a two-fold increase in celecoxib plasma concentration. This increase 
is due to the inhibition of celecoxib metabolism via P450 2C9 by fluconazole [see Drug Interactions (7)]. 
Other Drugs 
The effects of celecoxib on the pharmacokinetics and/or pharmacodynamics of glyburide, ketoconazole, [see Drug Interactions (7)], phenytoin, and 
tolbutamide have been studied in vivo and clinically important interactions have not been found. 
12.5 Pharmacogenomics 
CYP2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as those homozygous  
for the CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from 4 published reports that included a total of 8 subjects with the  
homozygous CYP2C9*3/*3 genotype showed celecoxib systemic levels that were 3- to 7-fold higher in these subjects compared to  
subjects with CYP2C9*1/*1 or *I/*3 genotypes. The pharmacokinetics of celecoxib have not been evaluated in subjects with other  
CYP2C9 polymorphisms, such as *2, *5, *6, *9 and *11. It is estimated that the frequency of the homozygous *3/*3 genotype is 0.3% to  
1.0% in various ethnic groups. [see Dosage and Administration (2.6), Use in Specific Populations (8.8)].  
13. NONCLINICAL TOXICOLOGY 
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
Carcinogenesis 
Celecoxib was not carcinogenic in Sprague-Dawley rats given oral doses up to 200 mg/kg for males and 10 mg/kg for females (approximately 
2-to 4-times the human exposure as measured by the AUC0-24 at 200 mg twice daily) or in mice given oral doses up to 25 mg/kg for males and 
50 mg/kg for females (approximately equal to human exposure as measured by the AUC0-24 at 200 mg twice daily) for two years. 
Mutagenesis 
Celecoxib was not mutagenic in an Ames test and a mutation assay in Chinese hamster ovary (CHO) cells, nor clastogenic in a chromosome 
aberration assay in CHO cells and an in vivo micronucleus test in rat bone marrow. 
Impairment of Fertility 
Celecoxib had no effect on male or female fertility or male reproductive function in rats at oral doses up to 600 mg/kg/day (approximately 11-
times human exposure at 200 mg twice daily based on the AUC0-24). At 50 mg/kg/day (approximately 6-times human exposure based on the 
AUC0-24 at 200 mg twice daily) there was increased preimplantation loss. 
13.2 Animal Toxicology 
An increase in the incidence of background findings of spermatocele with or without secondary changes such as epididymal hypospermia as 
well as minimal to slight dilation of the seminiferous tubules was seen in the juvenile rat. These reproductive findings while apparently 
treatment-related did not increase in incidence or severity with dose and may indicate an exacerbation of a spontaneous condition. Similar 
reproductive findings were not observed in studies of juvenile or adult dogs or in adult rats treated with celecoxib. The clinical significance of 
this observation is unknown. 
Reference ID: 3928084 


 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 4.   C LI NI C A L S T U DI E S 
1 4. 1 O st e o art hriti s 
C E L E B R E X  h a s d e m o n str at e d si g nifi c a nt r e d u cti o n i n j oi nt p ai n c o m p ar e d t o pl a c e b o. CE L E B R E X w a s e v al u at e d f or tr e at m e nt of t h e si g n s a n d 
t h e s y m pt o m s of O A of t h e k n e e a n d hi p i n pl a c e b o- a n d a cti v e- c o ntr oll e d cli ni c al tri al s of u p t o 1 2 w e e k s d ur ati o n. I n p ati e nts wit h O A, 
tr e at m e nt wit h CE L E B R E X  1 0 0 m g t wi c e d ail y or 2 0 0 m g o n c e d ail y r e s ult e d i n i m pr o v e m e nt i n W O M A C ( W e st er n O nt ari o a n d M c M a st er 
U ni v er siti e s) o st e o art hriti s i n d e x, a c o m p o sit e of p ai n, stiff n e s s, a n d f u n cti o n al m e a s ur e s i n O A. I n t hr e e 1 2- w e e k st u di e s of p ai n 
a c c o m p a n yi n g O A fl ar e, C E L E B R E X  d o s e s of 1 0 0 m g t wi c e d ail y a n d 2 0 0 m g t wi c e d ail y pr o vi d e d si g nifi c a nt r e d u ctio n of p ai n wit hi n 2 4- 4 8 
h o ur s of i niti ati o n of d o si n g. At d o s e s of 1 0 0 m g t wi c e d ail y or 2 0 0 m g t wi c e d ail y t h e eff e cti v e n e s s of C E L E B R E X w a s s h o w n t o b e si mil ar t o 
t h at of n a pr o x e n 5 0 0 m g t wi c e d ail y. D o s e s of 2 0 0 m g t wi c e d ail y pr o vi d e d n o a d diti o n al b e n efit a b o v e t h at s e e n wit h 1 0 0 m g t wic e d ail y. A 
t ot al d ail y d o s e of 2 0 0 m g h a s b e e n s h o w n t o b e e q u all y eff e cti ve w h et h er a d mi ni st er e d a s 1 0 0 m g t wi c e d ail y or 2 0 0 m g o n c e d ai l y. 
1 4. 2 R h e u m at oi d Art hriti s 
C E L E B R E X  h a s d e m o n str at e d si g nifi c a nt r e d u cti o n i n j oi nt te n d er n e s s/ p ai n a n d j oi nt s w elli n g c o m p ar e d t o pl a c e b o. C E L E B R E X  w a s e v al u at e d 
f or tr e at m e nt of t h e si g n s a n d s y m pt o m s of R A i n pl a c e b o- a n d a cti v e- c o ntr oll e d cli ni c al tri al s of u p t o 2 4 w e e k s i n d ur ati o n. C E L E B R E X  w a s 
s h o w n t o b e s u p eri or t o pl a c e b o i n t h e s e st u di e s, u si n g t h e A C R 2 0 R e s p o n d er I n d e x, a c o m p o sit e of cli ni c al, l a b or at or y, a n d f u n cti o n al 
m e a s ur e s i n R A. C E L E B R E X  d o s e s of 1 0 0 m g t wi c e d ail y a n d 2 0 0 m g t wi c e d ail y w er e si mil ar i n eff e cti v e n e s s a n d b ot h w er e c o m p ar a bl e t o 
n a pr o x e n 5 0 0 m g t wi c e d ail y. 
Alt h o u g h C E L E B R E X  1 0 0 m g t wi c e d ail y a n d 2 0 0 m g t wi c e d ail y pr o vi d e d si mil ar o v er all eff e cti v e n e s s, s o m e p ati e nt s d eri v e d a d diti o n al 
b e n efit fr o m t h e 2 0 0 m g t wi c e d ail y d o s e. D o s e s of 4 0 0 m g t wi c e d ail y pr o vi d e d n o a d diti o n al b e n efit a b o v e t h at s e e n wit h 1 0 0- 2 0 0 m g t wi c e 
d ail y . 
1 4. 3 J u v e nil e R h e u m at oi d Art hriti s 
I n a 1 2- w e e k, r a n d o mi z e d, d o u bl e- bli n d a cti v e- c o ntr oll e d, p ar all el- gr o u p, m ulti c e nt er, n o n-i nf eri orit y st u d y, p ati e nt s fr o m 2 ye ar s t o 1 7 y e ar s 
of a g e wit h p a u ci arti c ul ar, p ol y arti c ul ar c o ur s e J R A or s y st e mi c o n s et J R A ( wit h c urr e ntl y i n a cti v e s y st e mi c f e at ur e s), r e c ei v e d o n e of t h e 
f oll o wi n g tr e at m e nt s: c el e c o xi b 3 m g/ k g (t o a m a xi m u m of 1 5 0 m g) t wi c e d ail y; c el e c o xi b 6 m g/ k g (t o a m a xi m u m of 3 0 0 m g) t wi c e d ail y; or 
n a pr o x e n 7. 5 m g/ k g (t o a m a xi m u m of 5 0 0 m g) t wi c e d ail y. T h e r e s p o n s e r at e s w er e b a s e d u p o n t h e J R A D efi niti o n of I m pr o v e m e nt g r e at er 
t h a n or e q u al t o 3 0 % ( J R A D OI 3 0) crit eri o n, w hi c h i s a c o m p o site of cli ni c al, l a b or at or y, a n d f u n cti o n al m e a s ur e s of J R A. T h e J R A D OI 3 0 
r e s p o n s e r at e s at w e e k 1 2 w er e 6 9 %, 8 0 % a n d 6 7 % i n t h e c el e c oxi b 3 m g/ k g t wi c e d ail y, c el e c o xi b 6 m g/ k g t wi c e d ail y, a n d n a pr o x e n 7. 5 
m g/ k g t wi c e d ail y tr e at m e nt gr o u p s, r e s p e cti v el y. 
T h e effi c a c y a n d s af et y of C E L E B R E X f or J R A h a v e n ot b e e n st u di e d b e y o n d si x m o nt h s. T h e l o n g-t er m c ar di o v a s c ul ar t o xi cit y i n c hil dr e n 
e x p o s e d t o C E L E B R E X  h a s n ot b e e n e v al u at e d a n d it i s u n k n o w n if t h e l o n g-t er m ri s k m a y b e si mil ar t o t h at s e e n i n a d ult s e x p o s e d t o 
C E L E B R E X  or ot h er C O X- 2 s el e cti v e a n d n o n- s el e cti v e N S AI D s [(s e e B o x e d W ar ni n g, W ar ni n g s a n d Pr e c a uti o n s ( 5. 1 2) ]. 
1 4. 4 A n k yl o si n g S p o n d yliti s 
C E L E B R E X w a s e v al u at e d i n A S p ati e nt s i n t w o pl a c e b o- a n d a cti v e- c o nt r oll e d cli ni c al tri al s of 6 a n d 1 2 w e e k s d ur ati o n. CE L E B R E X  at d o s e s of 
1 0 0 m g t wi c e d ail y, 2 0 0 m g o n c e d ail y a n d 4 0 0 m g o n c e d ail y w a s s h o w n t o b e st ati sti c all y s u p eri or t o pl a c e b o i n t h e s e st u di e s f or all t hr e e 
c o- pri m ar y effi c a c y m e a s ur e s a s s e s si n g gl o b al p ai n i nt e n sit y ( Vi s u al A n al o g u e S c al e), gl o b al dis e a s e a cti vit y ( Vi s u al A n al o g u e S c al e) a n d 
f u n cti o n al i m p air m e nt ( B at h A n k yl o si n g S p o n d yliti s F u n cti o n al I n d e x). I n t h e 1 2- w e e k stu d y, t h er e w a s n o diff er e n c e i n t h e e xt e nt of 
i m pr o v e m e nt b et w e e n t h e 2 0 0 m g a n d 4 0 0 m g CE L E B R E X  d o s e s i n a c o m p ari s o n of m e a n c h a n g e fr o m b a s eli n e, b ut t h er e w a s a gr e at er 
p er c e nt a g e of p ati e nt s w h o r e s p o n d e d t o C E L E B R E X  4 0 0 m g, 5 3 %, t h a n t o CE L E B R E X  2 0 0 m g, 4 4 %, u si n g t h e A s s e s s m e nt i n A n k yl o si n g 
S p o n d yliti s r e s p o n s e crit eri a ( A S A S 2 0). T h e A S A S 2 0 d efi n e s a r e s p o n d er a s i m pr o v e m e nt fr o m b a s eli n e of at l e a st 2 0 % a n d a n a b s ol ut e 
i m pr o v e m e nt of at l e a st 1 0 m m, o n a 0 t o 1 0 0 m m s c al e, i n at le a st t hr e e of t h e f o ur f oll o wi n g d o m ai n s: p ati e nt gl o b al p ai n, B a t h A n k yl o si n g 
S p o n d yliti s F u n cti o n al I n d e x, a n d i nfl a m m ati o n. T h e r e s p o n d er a n al y si s al s o d e m o n str at e d n o c h a n g e i n t h e r e s p o n d er r at e s b e y o n d 6 
w e e k s . 
1 4. 5 A n al g e si a, i n cl u di n g Pri m ar y D y s m e n orr h e a 
I n a c ut e a n al g e si c m o d el s of p o st- or al s ur g er y p ai n, p o st- ort h o p e di c s ur gi cal p ai n, a n d pri m ar y d y s m e n orr h e a, C E L E B R E X  r eli e v e d p ai n t h at 
w a s r at e d b y p ati e nt s a s m o d er at e t o s e v er e. Si n gl e d o s e s [ s e e D o s a g e a n d A d mi ni str ati o n ( 2. 6) ] of CE L E B R E X  pr o vi d e d p ai n r eli ef wit hi n 
6 0 mi n ut e s. 
1 4. 6  S p e ci al St u di e s 
A d e n o m at o u s P ol y p Pr e v e nti o n St u di e s 
C ar di o v a s c ul ar s af et y w a s e v al u at e d i n t w o r a n d o mi z e d, d o u bl e- bli n d, pl a c e b o- c o ntr oll e d, t hr e e y e ar st u di e s i n v ol vi n g p ati e nt s wit h 
S p or a di c A d e n o m at o u s P ol y p s tr e at e d wit h C E L E B R E X : t h e A P C tri al ( A d e n o m a Pr e v e nti o n wit h C el e c o xi b) a n d t h e Pr e S A P tri al 
( Pr e v e nti o n of S p o nt a n e o u s A d e n o m at o u s P ol y p s). I n t h e A P C tri al, t h er e w a s a d o s e-r el at e d i n cr e a s e i n t h e c o m p o sit e e n d p oi nt 
( a dj u di c at e d) of c ar di o v a s c ul ar d e at h, m y o c ar di al i nf ar cti o n, or str o k e wit h c el e c o xi b c o m p ar e d t o pl a c e b o o v er 3 y e ar s of tr e a t m e nt. T h e 
Pr e S A P tri al di d n ot d e m o n str at e a st ati sti c all y si g nifi c a nt i n cr e a s e d ri s k f or t h e s a m e c o m p o sit e e n d p oi nt ( a dj u di c at e d): 
•  I n t h e A P C tri al, t h e h a z ar d r ati o s c o m p ar e d t o pl a c e b o f or a c o m p o sit e e n d p oi nt ( a dj u di c at e d) of c ar di o v a s c ul ar d e at h, m y o c a r di al 
i nf ar cti o n, or str o k e w er e 3. 4 ( 9 5 % CI 1. 4 - 8. 5) wit h c el e c o xi b 4 0 0 m g t wi c e d ail y a n d 2. 8 ( 9 5 % CI 1. 1 - 7. 2) wit h c el e c o xi b 2 0 0 m g 
t wi c e d ail y. C u m ul ati v e r at e s f or t hi s c o m p o sit e e n d p oi nt o v er 3 y e ar s w er e 3. 0 % ( 2 0/ 6 7 1 s u bj e c t s) a n d 2. 5 % ( 1 7/ 6 8 5 s u bj e ct s), 
r e s p e cti v el y, c o m p ar e d t o 0. 9 % ( 6/ 6 7 9 s u bj e ct s) wit h pl a c e b o tr e at m e nt. T h e i n cr e a s e s i n b ot h c el e c o xi b d o s e gr o u p s v er s u s pl a ce b o-
tr e at e d p ati e nt s w er e m ai nl y d u e t o a n i n cre a s e d i n ci d e n c e of m y o c ar di al i nf ar cti o n. 
•  I n t h e Pr e S A P tri al, t h e h a z ar d r ati o f or t hi s s a m e c o m p o sit e e n d p oi nt ( a dj u di c at e d) w a s 1. 2 ( 9 5 % CI 0. 6 - 2. 4) wit h c el e c o xi b 4 0 0 m g 
o n c e d ail y c o m p ar e d t o pl a c e b o. C u m ul ati v e r at e s f or t hi s c o m p o s it e e n d p oi nt o v er 3 y e ar s w er e 2. 3 % ( 2 1/ 9 3 3 s u bj e ct s) a n d 1. 9 % 
( 1 2/ 6 2 8 s u bj e ct s), r e s p e cti v el y. 
Cli ni c al tri al s of ot h er C O X- 2 s el e cti v e a n d n o n- s el e cti v e N S AI D s of u p t o t hr e e- y e ar s d ur ati o n h a v e s h o w n a n i n cr e a s e d ri s k of  s eri o u s 
c ar di o v a s c ul ar t hr o m b oti c e v e nt s, m y o c ar di al i nf ar cti o n, a n d str o k e, w hi c h c a n b e f at al. A s a r e s ult, all N S AI D s ar e c o n si d er e d  p ot e nti all y 
a s s o ci at e d wit h t hi s ri s k. 
R ef er e n c e I D: 3 9 2 8 0 8 4 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Celecoxib Long-Term Arthritis Safety Study (CLASS) 
This was a prospective, long-term, safety outcome study conducted post-marketing in approximately 5,800 OA patients and 2,200 RA patients. 
Patients received CELEBREX 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three 
times daily or diclofenac 75 mg twice daily (common therapeutic doses). Median exposures for CELEBREX (n = 3,987) and diclofenac (n = 
1,996) were 9 months while ibuprofen (n = 1,985) was 6 months. The primary endpoint of this outcome study was the incidence of complicated 
ulcers (gastrointestinal bleeding, perforation or obstruction). Patients were allowed to take concomitant low-dose ( 325 mg/day) aspirin (ASA) 
for cardiovascular prophylaxis (ASA subgroups: CELEBREX, n = 882; diclofenac, n = 445; ibuprofen, n = 412). Differences in the incidence of 
complicated ulcers between CELEBREX and the combined group of ibuprofen and diclofenac were not statistically significant.  
Patients on CELEBREX and concomitant low-dose ASA (N=882) experienced 4-fold higher rates of complicated ulcers compared to those not on 
ASA (N=3105). The Kaplan-Meier rate for complicated ulcers at 9 months was 1.12% versus 0.32% for those on low-dose ASA and those not 
on ASA, respectively [see Warnings and Precautions (5.4)]. 
The estimated cumulative rates at 9 months of complicated and symptomatic ulcers for patients treated with CELEBREX 400 mg twice daily 
are described in Table 4. Table 4 also displays results for patients less than or greater than 65 years of age. The difference in rates 
between CELEBREX alone and CELEBREX with ASA groups may be due to the higher risk for GI events in ASA users. 
Table 5: Complicated and Symptomatic Ulcer Rates in Patients Taking CELEBREX 400 mg Twice Daily (Kaplan-Meier Rates at  
9 months [%]) Based on Risk Factors  
All Patients 
CELEBREX alone (n=3105) 
0.78  
CELEBREX with ASA (n=882) 
2.19  
Patients <65 Years 
CELEBREX alone (n=2025) 
0.47  
CELEBREX with ASA (n=403) 
1.26  
Patients 65 Years 
CELEBREX alone (n=1080) 
1.40  
CELEBREX with ASA (n=479) 
3.06  
In a small number of patients with a history of ulcer disease, the complicated and symptomatic ulcer rates in patients taking CELEBREX alone or 
CELEBREX with ASA were, respectively, 2.56% (n=243) and 6.85% (n=91) at 48 weeks. These results are to be expected in patients with a prior 
history of ulcer disease [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]. 
Cardiovascular safety outcomes were also evaluated in the CLASS trial. Kaplan-Meier cumulative rates for investigator-reported serious 
cardiovascular thromboembolic adverse events (including MI, pulmonary embolism, deep venous thrombosis, unstable angina, transient ischemic 
attacks, and ischemic cerebrovascular accidents) demonstrated no differences between the CELEBREX, diclofenac, or ibuprofen treatment groups. 
The cumulative rates in all patients at nine months for CELEBREX, diclofenac, and ibuprofen were 1.2%, 1.4%, and 1.1%, respectively. The 
cumulative rates in non-ASA users at nine months in each of the three treatment groups were less than 1%. The cumulative rates for myocardial 
infarction in non-ASA users at nine months in each of the three treatment groups were less than 0.2%. There was no placebo group in the CLASS 
trial, which limits the ability to determine whether the three drugs tested had no increased risk of CV events or if they all increased the risk to a 
similar degree. 
Endoscopic Studies 
The correlation between findings of short-term endoscopic studies with CELEBREX and the relative incidence of clinically significant serious upper GI 
events with long-term use has not been established. Serious clinically significant upper GI bleeding has been observed in patients receiving 
CELEBREX in controlled and open-labeled trials [see Warnings and Precautions (5.4) and Clinical Studies (14.6)] 
A randomized, double-blind study in 430 RA patients was conducted in which an endoscopic examination was performed at 6 months. The 
incidence of endoscopic ulcers in patients taking CELEBREX 200 mg twice daily was 4% vs. 15% for patients taking diclofenac SR 75 mg twice daily. 
However, CELEBREX was not statistically different than diclofenac for clinically relevant GI outcomes in the CLASS trial [see Clinical Studies (14.6)]. 
The incidence of endoscopic ulcers was studied in two 12-week, placebo-controlled studies in 2157 OA and RA patients in whom baseline 
endoscopies revealed no ulcers. There was no dose relationship for the incidence of gastroduodenal ulcers and the dose of CELEBREX (50 mg to 
400 mg twice daily). The incidence for naproxen 500 mg twice daily was 16.2 and 17.6% in the two studies, for placebo was 2.0 and 2.3%, and for 
all doses of CELEBREX the incidence ranged between 2.7%-5.9%. There have been no large, clinical outcome studies to compare clinically relevant 
GI outcomes with CELEBREX and naproxen. 
In the endoscopic studies, approximately 11% of patients were taking aspirin ( 325 mg/day). In the CELEBREX groups, the endoscopic ulcer rate 
appeared to be higher in aspirin users than in non-users. However, the increased rate of ulcers in these aspirin users was less than the endoscopic 
ulcer rates observed in the active comparator groups, with or without aspirin. 
Reference ID: 3928084 


 
 
 
 
  
 
  
 
 
 
 
 
  
 
  
 
  
 
  
 
 
 
  
 
  
 
  
 
  
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16. HOW SUPPLIED/STORAGE AND HANDLING 
CELEBREX (celecoxib) 50 mg capsules are white, with reverse printed white on red band of body and cap with markings of 7767 on the cap 
and 50 on the body, supplied as: 
NDC Number 
Size 
0025-1515-01 
bottle of 60 
CELEBREX (celecoxib) 100 mg capsules are white, with reverse printed white on blue band of body and cap with markings of 7767 on the cap 
and 100 on the body, supplied as: 
NDC Number 
Size 
0025-1520-31 
bottle of 100 
0025-1520-51 
bottle of 500 
0025-1520-34 
carton of 100 unit dose 
CELEBREX (celecoxib) 200 mg capsules are white, with reverse printed white on gold band with markings of 7767 on the cap and 200 on the 
body, supplied as: 
NDC Number 
Size 
0025-1525-31 
bottle of 100 
0025-1525-51 
bottle of 500 
0025-1525-34 
carton of 100 unit dose 
CELEBREX (celecoxib) 400 mg capsules are white, with reverse printed white on green band with markings of 7767 on the cap and 400 on the 
body, supplied as: 
NDC Number 
Size 
0025-1530-02 
bottle of 60 
0025-1530-01 
carton of 100 unit dose 
Storage 
Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room 
Temperature] 
17. PATIENT COUNSELING INFORMATION 
Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform 
patients, families, or their caregivers of the following information before initiating therapy with CELEBREX and periodically during the course of 
ongoing therapy. 
Cardiovascular Thrombotic Events 
Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of 
speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)]. 
Gastrointestinal Bleeding, Ulceration, and Perforation 
Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health 
care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs 
and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. 
Hepatotoxicity 
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea jaundice, right upper 
quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop CELEBREX and seek immediate medical therapy [see 
Warnings and Precautions (5.3), Use in Specific Populations (8.6)]. 
Heart Failure and Edema 
Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to 
contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5)]. 
Anaphylactic Reactions 
Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate 
emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. 
Serious Skin Reactions 
Advise patients to stop CELEBREX immediately if they develop any type of rash and to contact their healthcare provider as soon as possible [see 
Warnings and Precautions (5.9)]. 
Female Fertility 
Advise females of reproductive potential who desire pregnancy that NSAIDs, including CELEBREX, may be associated with a reversible delay in 
ovulation [see Use in Specific Populations (8.3)]. 
Fetal Toxicity 
Inform pregnant women to avoid use of CELEBREX and other NSAIDs starting at 30 weeks of gestation because of the risk of the premature closing 
of the fetal ductus arteriosus [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1)]. 
Reference ID: 3928084 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
Avoid Concomitant Use of NSAIDs 
Inform patients that the concomitant use of CELEBREX with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the 
increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert 
patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. 
Use of NSAIDS and Low-Dose Aspirin 
Inform patients not to use low-dose aspirin concomitantly with CELEBREX until they talk to their healthcare provider [see Drug Interactions (7)]. company logo
Issued: May 2016 
LAB-0036-16.x 
Reference ID: 3928084 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) 
What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? 
NSAIDs can cause serious side effects, including: 
• Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: 
o 
with increasing doses of NSAIDs 
o 
with longer use of NSAIDs 
Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." 
Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of 
another heart attack if you take NSAIDs after a recent heart attack. 
• Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), 
stomach and intestines: 
o 
anytime during use 
o 
without warning symptoms 
o 
that may cause death 
The risk of getting an ulcer or bleeding increases with: 
o 
past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs 
o 
taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs” or “SNRIs” 
o 
increasing doses of NSAIDs 
o 
longer use of NSAIDs 
o 
smoking 
o 
drinking alcohol 
o 
older age 
o 
poor health 
o 
advanced liver disease 
o 
bleeding problems 
NSAIDs should only be used: 
o 
exactly as prescribed  
o 
at the lowest dose possible for your treatment 
o 
for the shortest time needed 
What are NSAIDs? 
NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of 
arthritis, menstrual cramps, and other types of short-term pain. 
Who should not take NSAIDs? 
Do not take NSAIDs: 
• 
if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. 
• 
right before or after heart bypass surgery. 
Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you: 
• 
have liver or kidney problems 
• 
have high blood pressure 
• 
have asthma 
• 
are pregnant or plan to become pregnant. Talk to your healthcare provider if you are considering taking NSAIDs during pregnancy. 
You should not take NSAIDs after 29 weeks of pregnancy 
• 
are breastfeeding or plan to breast feed. 
Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or 
herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking 
any new medicine without talking to your healthcare provider first. 
Reference ID: 3928084 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                               
What are the possible side effects of NSAIDs? 
NSAIDs can cause serious side effects, including: 
See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs 
(NSAIDs)? 
• 
new or worse high blood pressure 
• 
heart failure 
• 
liver problems including liver failure 
• 
kidney problems including kidney failure 
• 
low red blood cells (anemia) 
• 
life-threatening skin reactions 
• 
life-threatening allergic reactions 
• 
Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. 
Get emergency help right away if you get any of the following symptoms: 
• 
shortness of breath or trouble breathing  
• 
chest pain 
• 
weakness in one part or side of your body 
• 
slurred speech 
• 
swelling of the face or throat 
Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: 
• 
nausea 
• 
more tired or weaker than usual 
• 
diarrhea 
• 
itching 
• 
your skin or eyes look yellow 
• 
indigestion or stomach pain 
• 
flu-like symptoms 
• 
vomit blood 
• 
there is blood in your bowel movement or it is black 
and sticky like tar 
• 
unusual weight gain 
• 
skin rash or blisters with fever 
• 
swelling of the arms, legs, hands and feet 
If you take too much of your NSAID, call your healthcare provider or get medical help right away. 
These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs.  
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. 
Other information about NSAIDs 
• 
Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and 
intestines. Aspirin can also cause ulcers in the stomach and intestines. 
• 
Some NSAIDs are sold in lower doses without a prescription (over-the counter). Talk to your healthcare provider before using over-
the-counter NSAIDs for more than 10 days. 
General information about the safe and effective use of NSAIDs 
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which 
it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. 
If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for 
information about NSAIDs that is written for health professionals. 
Manufactured for: Pfizer Inc., 235 East 42nd Street, New York, NY, 10017 
Distributed by: G. D. Searle LLC, Division of Pfizer Inc., 235 East 42
nd Street, New York, NY, 10017 
For more information, go to www.pfizer.com or call 1-800-438-1985 
This Medication Guide has been approved by the U.S. Food and Drug Administration. 
Issued: May 2016 
LAB number: LAB-0609-1.x 
Reference ID: 3928084 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 129 
CONFIDENTIAL 
APPENDIX H: SAMPLE SIZE AND EFFICACY ANALYSIS 
 
H.1 Results from Study No. KIT-302-03-01 
H.1.1 
Study No. KIT-302-03-01 documented that while celecoxib had only minor effects on 
BP, and amlodipine reduced BP significantly, adding celecoxib to the amlodipine 
increased the BP reduction.  The mean changes in SBPday, DBPday, SBPnight, and DBPnight 
from baseline to end of therapy are listed below. 
Changes in Blood Pressure from Baseline to End of Therapy  
(Mean ± Standard Deviation mmHg) 
 
SBPday 
DBPday 
SBPnight 
DBPnight 
Placebo 
-2.1 ± 8.2 
-0.3 ± 5.4 
-1.4 ± 9.2 
0.0 ± 6.2 
Celecoxib 
-0.5 ± 8.8 
-1.5 ± 5.1 
-1.7 ± 12.3 
0.3 ± 7.1 
Amlodipine 
-8.8 ± 8.1 
-5.5 ± 5.1 
-6.4 ± 11.4 
-3.2 ± 7.8 
Amlodipine + Celecoxib 
-10.6 ± 9.2 
-7.5 ± 6.4 
-10.5 ± 10.6 
-7.0 ± 8.6 
 
H.2 Margin 
H.2.1 
The sample size is to be based on the hypothesis that the mean reduction in SBPday from 
Day 0 to Day 14 of subjects in the Amlodipine+Celecoxib group (arm 1) minus half the 
mean reduction in SBPday from Day 0 to Day 14 of subjects in the Amlodipine+Placebo 
group (arm 2) is at least 0.  
H.2.2 
The margin is based on a mean reduction of 8.8 mmHg in SBPday for the 
Amlodipine+Placebo group and a mean reduction of 10.6 mmHg for the 
Amlodipine+Celecoxib group as seen in the previous study, KIT-302-03-01.   
H.2.3 
To ensure that at least half the effect is maintained, a value of 10.6 – 0.5(8.8) = 6.2 mmHg 
should be set for d (anticipated mean difference) in the sample size formula (see Section 
10.9 for formula). 
H.3 Standard Deviation 
H.3.1 
The standard deviation for SBPday with Amlodipine+Placebo was observed to be 
8.1 mmHg in the previous study (Study No. KIT-302-03-01). 
H.3.2 
The standard deviation for SBPday with Amlodipine+Celecoxib was observed to be 
9.2 mmHg in the previous study (Study No. KIT-302-03-01).  
H.3.3 
The pooled standard deviation for the power and sample size justification is 8.7 mm Hg. 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 130 
CONFIDENTIAL 
H.4 Preliminary Estimate 
H.4.1 
It is suggested that a preliminary analysis is carried out at n = 27 per group. This is based 
on α = 0.025, β = 0.2 and a conservative estimate of s = 8.7.  To further optimize the 
probability of success the actual number is to be increased to 45 per group. 
 
 
 


Protocol No. KIT-302-03-02 
Version 4: December 16, 2016 
Page 131 
CONFIDENTIAL 
APPENDIX I: CHILD-PUGH CLASSIFICATION OF LIVER CIRRHOSIS 
 
The Child-Pugh score is based on five clinical measures of liver disease. Each measure is scored 
1-3 as outlined in the table below. 
 
Measure 
1 Point 
2 Points 
3 Points 
Bilirubin (μmol/L) 
<34 
34-50 
>50 
Serum albumin (g/L) 
>35 
28-35 
<28 
Prothrombin time (s prolonged) 
<4 
4-6 
>6 
Ascites 
None 
Mild 
Marked 
Encephalopathy 
None 
Mild 
Marked 
 
 
Chronic liver disease is classified into Child-Pugh Classes A to C based on the added score from 
above. Subjects with Child-Pugh Class B or C cirrhosis will be excluded from this trial. 
 
Points 
Class 
5-6 
A 
7-9 
B 
10-15 
C 
 
 
References 
 
Child CG, Turcotte JG. 1964. Surgery and portal hypertension. In: The liver and portal 
hypertension. Edited by CG Child. Philadelphia: Saunders. 50-64. 
 
Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. 1973. Transection of the 
oesophagus for bleeding oesophageal varices. Br J Surg. 60(8):646–649. 
 
 

SAP_001.pdf: 
Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 1 of 190
 
 
 Statistical Analysis Plan 
 
 
A Prospective Randomized Placebo Controlled Study to Evaluate 
the Effect of Celecoxib on the Efficacy and Safety of Amlodipine 
on Renal and Vascular Function in Subjects with Existing 
Hypertension Requiring Antihypertensive Therapy 
 
 
Protocol No.: 
KIT-302-03-02 
 
 
 
Original SAP: 
Final version pre-unblinding 3.0, 12th October 2017 
 
 
Current Version: 
Final version post-unblinding 4.0, 20th April 2018 
 
 
Prepared by: 
Dr. Gloria Crispino 
 
 
StatisticaMedica 
 
Dublin 
 
Ireland 
 
 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 2 of 190
 
 
APPROVAL SIGNATURE(S) 
 
A Prospective Randomized Placebo Controlled Study to Evaluate 
the Effect of Celecoxib on the Efficacy and Safety of Amlodipine 
on Renal and Vascular Function in Subjects with Existing 
Hypertension Requiring Antihypertensive Therapy 
 
 
 
Protocol No. KIT-302-03-02 
I have read this SAP and confirm that to the best of my knowledge it accurately describes the 
statistical analyses for this study. 
 
Sponsor Signatory: 
 
................................................................................................ 
.................................... 
 
Date 
 
 
 
 
 
Statistician Signatory: 
 
................................................................................................ 
.................................... 
 
Date 
 
 
 
20 April 2018
20/APR/2018


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 3 of 190
 
 
ABBREVIATIONS 
ABPM  
ambulatory blood pressure monitor 
ADR 
 
Adverse Drug Reaction 
AE 
 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
ATC 
 
Anatomical Therapeutic Chemical 
BE 
 
bioequivalence 
BLQ 
 
below limit of quantification 
BMI 
 
Body Mass Index 
BP 
 
blood pressure 
BUN   
Blood urea nitrogen 
Ca 
 
calcium 
CI 
 
Confidence Interval 
CRF 
 
Case Report Form 
CRO 
 
Contract Research Organization 
CS 
 
Clinically Significant 
DBP 
 
diastolic blood pressure 
DBP24h  
average 24-hour ambulatory diastolic blood pressure 
DBPday  
average daytime (9:00 to 21:00) ambulatory diastolic blood pressure 
DBPnight 
average night-time (01:00 to 06:00) ambulatory diastolic blood pressure 
DDI 
 
drug-drug interaction 
ECG 
 
electrocardiogram 
FCDP  
fixed combination drug product 
IB 
 
Investigator’s Brochure 
ITT 
 
Intent-To-Treat 
LLOQ  
Lower Limit of Quantification 
LOCF  
last observation carried forward 
MedDRA 
Medical Dictionary for regulatory activities 
mITT  
modified intent-to-treat 
NCS 
 
Not clinically significant 
NSAID  
non-steroidal anti-inflammatory drug 
OE 
 
over-encapsulated 
PI 
 
Principal Investigator 
PK 
 
Pharmacokinetic 
PP  
 
Per-Protocol 
PT 
 
Preferred Term 
PTAE  
pre-treatment adverse event 
qd 
 
once a day 
SAE 
 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 
SAS 
 
Statistical Analysis System 
SBP 
 
systolic blood pressure 
SBP24h  
average 24-hour ambulatory systolic blood pressure 
SBPday  
average daytime (9:00 to 21:00) ambulatory systolic blood pressure 
SBPnight  
average night-time (01:00 to 06:00) ambulatory systolic blood pressure 
SD 
 
Standard Deviation 
SOC 
 
System Organ Class 
TEAE  
Treatment Emergent Adverse Event 
UAE   
Unexpected adverse event 
UV 
 
ultraviolet 
WHO-DD 
World Health Organization-Drug Dictionary 
 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 4 of 190
 
 
TABLE OF CONTENTS 
APPROVAL SIGNATURE(S) ............................................................................................................... 2 
ABBREVIATIONS ................................................................................................................................ 3 
TABLE OF CONTENTS ........................................................................................................................ 4 
1. 
Introduction ..................................................................................................................................... 7 
1.1. 
Background ............................................................................................................................. 7 
1.2. 
Statistical Analysis Plan Summary ......................................................................................... 8 
1.3. 
Changes from Protocol............................................................................................................ 8 
1.3.1. 
Validity of ABPM measurements ................................................................................... 8 
1.3.2. 
Definition of Intent-to-Treat (ITT) and Modified Intent-to-Treat (mITT) populations .. 9 
1.3.3. 
Sensitivity analyses ......................................................................................................... 9 
1.3.3.1. 
Sensitivity analysis for the validity of ABPM measurements ................................. 9 
1.3.3.2. 
Sensitivity analysis of ITT versus mITT population ............................................... 9 
1.3.3.3. 
Sensitivity analysis of baseline effect ................................................................... 10 
1.3.4. 
Exploratory efficacy analyses ....................................................................................... 10 
1.3.5. 
Definition of one-sided confidence interval (CI) .......................................................... 10 
1.3.6. 
Analysis populations ..................................................................................................... 10 
1.3.7. 
Definition of change from baseline ............................................................................... 11 
1.3.8. 
Peak and trough analyses .............................................................................................. 11 
1.3.9. 
Safety analyses .............................................................................................................. 11 
1.3.10. 
BLQ computation for plasma concentration ................................................................. 14 
1.3.11. 
Sample size formula ...................................................................................................... 14 
1.3.12. 
Demographic and baseline characteristics .................................................................... 14 
1.3.13. 
Investigational site-specific analyses ............................................................................ 15 
1.3.14. 
Past and concomitant diseases ...................................................................................... 15 
1.3.15. 
Previous medications .................................................................................................... 16 
1.3.16. 
Concomitant, posterior, and unclassified medications .................................................. 16 
1.3.17. 
Treatment compliance and extent of exposure .............................................................. 16 
1.3.18. 
Hierarchical analysis of secondary efficacy endpoints ................................................. 17 
1.4. 
Study Summary ..................................................................................................................... 17 
1.5. 
Version History ..................................................................................................................... 17 
2. 
Study Objectives and Endpoints ................................................................................................... 17 
2.1. 
Primary Objective(s) ............................................................................................................. 17 
2.2. 
Secondary Objective(s) ......................................................................................................... 17 
2.3. 
Primary Endpoint(s) .............................................................................................................. 18 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 5 of 190
 
 
2.4. 
Secondary Endpoint(s) .......................................................................................................... 18 
3. 
Study Design ................................................................................................................................. 19 
3.1. 
Sample Size ........................................................................................................................... 26 
3.2. 
Randomization ...................................................................................................................... 26 
4. 
Analysis Sets ................................................................................................................................. 28 
4.1. 
Study Populations ................................................................................................................. 28 
4.2. 
Misallocations ....................................................................................................................... 29 
4.3. 
Protocol Deviations ............................................................................................................... 29 
5. 
Definitions and Data Conventions ................................................................................................ 30 
6. 
Efficacy Variables ......................................................................................................................... 34 
6.1. 
Primary Efficacy Variable .................................................................................................... 34 
6.2. 
Secondary Efficacy Variables ............................................................................................... 34 
6.3. 
Exploratory and Other Efficacy Variables ............................................................................ 35 
6.4. 
Safety Variables .................................................................................................................... 35 
6.5. 
Other Variables ..................................................................................................................... 38 
7. 
Statistical Methodology ................................................................................................................ 39 
7.1. 
Handling of Missing Data ..................................................................................................... 39 
7.2. 
Covariates and Subgroups ..................................................................................................... 40 
7.3. 
General Methodology ........................................................................................................... 40 
7.4. 
Patients Disposition .............................................................................................................. 40 
7.5. 
Demographic and Screening/Baseline Characteristics .......................................................... 40 
7.6. 
Treatment Compliance and Extent of Exposure ................................................................... 41 
7.7. 
Primary Efficacy Analysis .................................................................................................... 41 
7.8. 
Secondary Efficacy Analysis ................................................................................................ 42 
7.9. 
Safety Analysis ..................................................................................................................... 44 
7.10. 
Additional Analyses .......................................................................................................... 48 
8. 
General Considerations ................................................................................................................. 50 
8.1. 
Software to be used ............................................................................................................... 50 
8.2. 
Programs and Tables Quality Control ................................................................................... 50 
9. 
Data Storage .................................................................................................................................. 50 
Appendices ............................................................................................................................................ 51 
Appendix A. ABPM Measurement Specifics ....................................................................................... 51 
ABPM Measurement Weighting ....................................................................................................... 51 
ABPM Study Measurements ............................................................................................................. 51 
ABPM Validity ................................................................................................................................. 52 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 6 of 190
 
 
ABPM Statistics ................................................................................................................................ 53 
Appendix B. List of Tables ................................................................................................................... 54


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 7 of 190
 
 
1. Introduction 
This Statistical Analysis Plan (SAP) describes statistical analyses for KIT-302-03-02 study. 
1.1. 
Background 
KIT-302 is an oral fixed combination drug product (FCDP) consisting of the non-steroidal anti-
inflammatory drug (NSAID) celecoxib and the calcium (Ca) channel blocker antihypertensive drug 
amlodipine besylate.  KIT-302 is being developed as a “convenience reformulation” FCDP intended to 
facilitate and improve patient compliance with the once a day (qd) administration of its individual 
components, amlodipine and celecoxib, when used together for the intended patient population.  It is 
also intended to provide prescribers with detailed data on how the combination affects the 
antihypertensive effect of the calcium channel blocker. 
The proposed indications in the usage section of the KIT-302 product labeling are anticipated to read 
as follows: “KIT-302 is indicated for patients who require the use of a NSAID for chronic treatment for 
the relief of the signs and symptoms of osteoarthritis and who also require the treatment of hypertension 
to lower blood pressure.  Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular 
events, primarily strokes and myocardial infarctions.”  KIT-302 is not indicated to treat any other type 
of pain, and is not indicated for short term or intermittent treatment of osteoarthritis.   
The formulation of KIT-302 consists of celecoxib and amlodipine besylate co-formulated in a single 
immediate release tablet.  The dosage form was developed so that it would show bioequivalence (BE) 
to the individually marketed prescription celecoxib capsules and amlodipine besylate tablets given 
together. 
In 2015, Kitov completed a phase 3 pivotal study (KIT-302-03-01) comparing amlodipine besylate 
monotherapy at a dose of 10 mg/day [over-encapsulated (OE) 10 mg amlodipine tablet + matched 
placebo for OE celecoxib capsule], with the combination of the components of KIT-302 at a dose of 
10 mg amlodipine plus 200 mg celecoxib/day (OE 10 mg amlodipine tablet + OE 200 mg celecoxib 
capsule).  The study also included a double placebo arm and a celecoxib monotherapy arm at a dose of 
200 mg/day (matched placebo for OE amlodipine tablet + OE 200 mg celecoxib capsule).  Adult 
subjects with newly diagnosed hypertension who required pharmacological therapy to control their 
hypertension were randomized to one of the four treatment arms and treated for two weeks.  Subjects 
underwent 24-hour ambulatory blood pressure monitoring at baseline, during the initial 24 hours of 
therapy, after one week of therapy and after two weeks of therapy.   
Study No. KIT-302-03-01 documented that while celecoxib had a negligible effect on blood pressure 
(BP), and amlodipine reduced BP significantly, adding celecoxib to the amlodipine did not impair the 
antihypertensive effects of amlodipine but rather tended to enhance amlodipine’s effect, although the 
synergistic effect only reach statistical significance for average night-time (01:00 to 06:00) ambulatory 
diastolic blood pressure (DBPnight) and average 24-hour ambulatory diastolic blood pressure (DBP24h).  
The trending towards a synergistic antihypertensive effect was an unexpected finding, however this 
finding was consistent throughout the study’s data whether measuring daytime or night-time systolic 
blood pressure (SBP) or diastolic blood pressure (DBP), and whether measuring BP by using the 
ambulatory blood pressure monitor (ABPM) device or by taking the measurement manually in the 
clinic.  This internal consistency strongly suggested that the effect is real.  Study No. KIT-302-03-02 
was designed to confirm this effect. 
In attempting to explain the synergistic antihypertensive effect, a review of the plasma concentrations 
of amlodipine in the two amlodipine-receiving treatment arms was performed.  This analysis 
documented a lower plasma concentration of amlodipine in the treatment arm receiving both celecoxib 
and amlodipine compared to the treatment arm receiving only amlodipine.  It can therefore be concluded 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 8 of 190
 
 
that the enhanced antihypertensive effect when celecoxib was added was not due to an increased 
amlodipine plasma concentration through some pharmacokinetic (PK) drug-drug interaction (DDI). 
An alternative explanation for the antihypertensive synergistic effect may be found in the renal data.  
Specifically, although patients treated with amlodipine had improved renal function as evidenced by a 
decreased serum creatinine, there was a trend towards an even greater reduction in serum creatinine 
among patients treated with both amlodipine and celecoxib.  Such an enhancement in renal function 
might be expected to improve BP control and thus, at least partially explains the synergistic 
antihypertensive effect.  However, since this renal synergy did not reach statistical significance, 
confirmation would require future clinical investigations.  Study No. KIT-302-03-02 was designed to 
confirm this effect.  
Further evidence for a renal component in the synergistic antihypertensive effect can be identified in 
the adverse event (AE) tables.  Specifically, patients treated with amlodipine had a nearly 16% reporting 
rate of peripheral oedema; such an adverse reaction has been a long-recognized side effect of 
amlodipine.  However, among those patients receiving both amlodipine and celecoxib, the rate of 
reported peripheral oedema was nearly halved.  Thus, it would appear possible that the addition of 
celecoxib to amlodipine is in some way acting as a diuretic, thereby preventing the peripheral oedema 
and thus, enhancing the antihypertensive effect.  Since this indirect measure of renal synergy did not 
reach statistical significance, confirmation would require future clinical investigations.  Study No. 
KIT-302-03-02 was designed to confirm this effect. 
1.2. 
Statistical Analysis Plan Summary 
This Statistical Analysis Plan (SAP) describes the statistical analysis for the KIT-302-03-02 study.  The 
SAP provides full details of the analyses, the data displays and the algorithms to be used for data 
derivations.  The analysis will be done using statistical software Statistical Analysis System (SAS) 
version 9.4 or higher. 
1.3. 
Changes from Protocol 
The following statistical analysis changes from the protocol will be implemented: 
1.3.1. Validity of ABPM measurements 
Section 10.7 of the protocol defines an ABPM measurement as valid based on the following six criteria: 
 
a. The time of the first study measurement is between 07:00 and 10:00. 
b. The duration, from the first study measurement to the last study measurement, is at least 25 h 
(1500 min). 
c. There are at least 21 study measurements recorded during the standard daytime period (09:00 
to 21:00). 
d. There are at least 8 study measurements recorded during the standard night-time period (01:00 
to 06:00). 
e. There are at least 35 study measurements recorded after the white-coat window. 
f. There are no more than 3 hours with a total measurement weight of less than 20 min and no 
more than 2 consecutive hours with total measurement weights each of less than 20 min. 
 
For the efficacy analysis, the validity of ABPM measurements will instead be based on valid daytime 
measurements (i.e., bullet c), as the remainder of the period has no effect on the primary endpoint, 
which is average daytime (9:00 to 21:00) ambulatory systolic blood pressure (SBPday).  Thus, all ABPM 
measurements with an assigned day validity of valid will be considered valid, regardless of the assigned 
night, 24h, overall, or other validities. 
 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 9 of 190
 
 
The impact of redefining a valid ABPM measurement based only on the validity of the daytime 
measurements (i.e., bullet c) is that the analyses of the secondary ABPM efficacy parameters [average 
24-hour ambulatory systolic blood pressure (SBP24h) and DBP24h] and exploratory ABPM efficacy 
parameters [average night-time (01:00 to 06:00) ambulatory systolic blood pressure (SBPnight) and 
DBPnight] may include invalid measurements with respect to the 24-hour period (i.e., may not meet 
criterion d or e) or night-time period (i.e., may not meet criterion d), respectively.  It is anticipated that 
this will be a very small number of cases and will not impact the secondary and exploratory efficacy 
conclusions drawn.  Sensitivity analyses will be conducted to verify this point (see Section 1.3.3.1 
below). 
It should be noted that for establishing eligibility, the validity of the ABPM continued to be based on 
the definition of ABPM validity in the protocol.  Thus, in order to be enrolled, subjects had to have a 
baseline ABPM that met all of the criteria above (a, b, c, d, e, and f). 
Documentation of the individual validity criteria Dabl applied to assign overall, daytime, nighttime, 
24h, and other ABPM validity flags is provided in “Note to File – Link of Individual Protocol-Specified 
ABPM Validity Criteria to Dabl Daytime, Nighttime, and 24h Validity Flags”, a copy of which is 
available in the Trial Master File. 
1.3.2. Definition of Intent-to-Treat (ITT) and Modified Intent-to-Treat (mITT) 
populations 
The definition of the ITT population as stated in the protocol was at risk of losing randomized subjects 
and will be changed to remain faithful to the ITT principal.  The ITT population will include all 
randomized subjects with a valid ABPM measurement at Baseline (according to the definition of 
validity described in Section 1.3.1 above).  The protocol definition requires valid Baseline and valid 
follow-up ABPM measurements, either Day 6 or Day 13.  This definition will instead be used for a 
mITT population, and the mITT population will be used for sensitivity analyses (see Section 1.3.3.2 
below). 
1.3.3. Sensitivity analyses 
1.3.3.1. Sensitivity analysis for the validity of ABPM measurements 
The following sensitivity analyses will be performed to verify that redefining a valid ABPM 
measurement based only on the validity of the daytime measurements (see Section 1.3.1 above for 
further detail) will not impact the secondary and exploratory ABPM efficacy conclusions drawn: 
1. ITT for SBP24h excluding SBP24h values that had an entry of valid for day validity and an 
entry of invalid for night or 24h validity (i.e., did not meet criterion d or e, respectively) 
2. ITT for DBP24h excluding DBP24h values that had an entry of valid for day validity and an 
entry of invalid for night or 24h validity (i.e., did not meet criterion d or e, respectively) 
3. ITT for SBPnight excluding SBPnight values that had an entry of valid for day validity and 
an entry of invalid for night validity (i.e., did not meet criterion d) 
4. ITT for DBPnight excluding DBPnight values that had an entry of valid for day validity and 
an entry of invalid for night validity (i.e., did not meet criterion d) 
 
1.3.3.2. Sensitivity analysis of ITT versus mITT population 
A sensitivity analysis will be conducted to insure the change in definition of the ITT population (see 
Section 1.3.2 above) does not impact the study conclusions.  A mITT population will be based on the 
definition originally presented as the ITT population in the protocol (valid Baseline and at least one 
valid follow-up ABPM measurement) and a second set of analyses will be conducted purely to 
demonstrate the definition does not have an impact on the primary and secondary efficacy analyses.  
The following analyses will be conducted: 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 10 of 190
 
 
1. mITT for SBPday 
2. mITT for SBP24h 
3. mITT for DBP24h 
1.3.3.3. Sensitivity analysis of baseline effect 
To assess the impact of baseline, a further sensitivity analysis will be conducted on the primary endpoint 
(mean change of SBPday) using a regression model adjusted from Baseline on ITT, mITT, and per-
protocol (PP) populations. 
1.3.4. Exploratory efficacy analyses 
Exploratory efficacy analyses will be conducted to investigate the potential effect of treatment on: 
1. SBPnight  
2. DBPnight 
3. Average daytime (9:00 to 21:00) ambulatory diastolic blood pressure (DBPday) 
These analyses will include two-sample t-tests to test one-side hypotheses of superiority for pairwise 
comparisons between treatment arms 1 and 2, 1 and 3, and 2 and 3.   
Further, two-sample t-tests to test one-side hypotheses of superiority for pairwise comparisons 
between treatment arms 1 and 3 and 2 and 3 will be performed for SBPday, SBP24h, and DBP24h.  The 
comparison of treatment arms 1 and 2 for these endpoints are covered separately under the respective 
primary and secondary efficacy analyses.   
All exploratory efficacy analyses will be conducted on the ITT population including LOCF (and 
MMRM if possible) for subjects who were withdrawn from treatment early.  Sensitivity analyses will 
be used to compare these results to those of the PP data set. 
1.3.5. Definition of one-sided confidence interval (CI) 
For clarity, the non-inferiority trial will be based on comparing the change from baseline to end of study 
for the OE amlodipine besylate tablet and OE celecoxib capsule arm (treatment arm 1) minus 0.5 * the 
OE amlodipine besylate tablet and matched placebo for OE celecoxib capsule arm (treatment arm 2) 
with 0.  A one-sided 97.5% CI for δ will be computed.  This is consistent and equivalent with the 
hypothesis section of the protocol, which states that the primary efficacy endpoint will be that the lower 
limit of the 95% CI for SBPday reduction in treatment arm 1 will be at least 50% of the mean reduction 
in treatment arm 2.  This statement is to clear up places in the protocol and SAP that conceptually state 
the comparison in less technical language.  
1.3.6. Analysis populations 
In addition to adding the mITT population noted above, a Randomized population (defined as all 
randomized subjects) will be added to produce all listings, except for screening failures and the listing 
of plasma amlodipine concentrations.  The Randomized population will also be used to produce a 
summary tabulation of the number and percentage of subjects who completed the study and who 
discontinued the study after randomization by treatment arm and overall, and the number and 
percentage of patients with a given primary reason for discontinuation (AE, withdrawal of consent, 
lost to follow-up, protocol violation, study terminated, or other) by treatment arm and overall.  The 
Randomized population will also be used to produce a summary tabulation of the number of subjects 
in the randomized population, the ITT population, the mITT population, the PP population, the safety 
population, and the PK population. 
An Overall Trial population (defined as all patients screened) will be added and used to produce the 
listing of screening failures, as well as a tabular summary of the number of patients at Initial 
Screening Visit, number of patients at Final Screening Visit, number of patients at Day 0 visit, 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 11 of 190
 
 
number of patients randomized, and number of patients at each of the remaining study visits (Days 6, 
7, 13, 14 and 28) by treatment arm and overall.   
The protocol includes a PK assessment at Day 14 for subjects enrolled at Investigational Sites that 
have ultraviolet- (UV-) shielded lights; however, a formal definition of the PK population for analysis 
was not included in the protocol.  A definition of the PK population was added to the SAP (see 
Section 4.1).  The listing of plasma amlodipine concentrations will use all subjects that were enrolled 
at an Investigational Site that had UV-shielded lights, and the PK population will be used for all 
analyses (tabular summaries and box plot). 
1.3.7. Definition of change from baseline 
For all efficacy endpoints, the mean change will be computed considering the difference between the 
value at endpoint and the value at baseline (Endpoint minus Baseline).  The protocol states the mean 
change as baseline minus endpoint.  This change does not affect the absolute value of the results but 
gives a more intuitive interpretation of the direction of change (i.e., with a negative value indicating a 
decrease in BP over time and a positive value indicating an increase in BP over time). 
1.3.8. Peak and trough analyses 
SBP and DBP at the expected peak and trough times for amlodipine for the ITT population at Day 6 
and Day 13 will be summarized by treatment arm by descriptive statistics.  Additionally, the 
difference between Day 6 and Day 13 will be summarized by treatment arm by descriptive statistics, 
and compared between treatment arms using t-test.  No last observation carried forward (LOCF) will 
be used for this analysis.  Details of how peak and trough measurements will be selected from the 
ABPM measurements are included in Section 7.10. 
1.3.9. Safety analyses 
a. Oedema events 
A safety table extracting the occurrences of oedema events, which include treatment emergent adverse 
events (TEAEs) with preferred terms (PTs) of oedema, oedema peripheral, peripheral swelling, 
swelling, and joint swelling, from the adverse events table will be produced.  See Section7.9 for 
further detail.  The rates of oedema events for treatment arms 1 and 2 will be reported and compared 
using exact logistic regression, reporting the odds ratio.  The Fisher’s exact test will be run to compare 
the number of oedema events that occurred while on treatment (Day 0 to Day 14+1) and post-
treatment (>Day 14+1) between treatment arms 1 and 2. 
b. Other PTs of interest 
The protocol specified a comparison of AE rates for terms associated with hypotension, defined as 
dizziness, falls, light-headedness, and vertigo.  The definition will be changed to TEAEs with PTs of 
orthostatic hypotension, fall, dizziness, dizziness postural, and vertigo.  The use of PTs and the 
addition of orthostatic hypotension to the list provides a more precise and comprehensive analysis, as 
well as allows a direct comparison to a similar analysis conducted for the prior trial (KIT-302-03-01).  
Note, light-headedness is coded under dizziness as a PT. 
c. Adverse drug reaction (ADR) 
For the summary tabulations of TEAEs by assigned relationship to study drug, adverse reactions and 
suspected adverse reactions will be combined and presented as ADRs (i.e., pooled).  The TEAE 
listing will continue to use the individual relationship assignments (i.e., adverse reaction, suspected 
adverse reaction, and unrelated), as specified in the protocol.  The same approach was taken for the 
prior trial (KIT-302-03-01), and therefore, this change will allow for comparison across studies.  A 
statistical evaluation of the rate of treatment-emergent ADRs among treatment arms using a Chi-


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 12 of 190
 
 
square test or Fisher’s exact test (if more than 20% of the cells in a contingency table had expected 
counts less than 5) will be added.  
d. Unexpected adverse event (UAE) 
A tabulation of treatment-emergent UAEs (defined in Section 6.4) will be added.  The summary will 
include the number of events, as well as the number and percentage of subjects.  Subjects will be 
counted once per category [specific system organ class (SOC) or PT], regardless of the number of 
events that may have occurred for that patient in that category.  The tabulation will be based on the 
respective Principal Investigator (PI) assignments of expectedness.  A statistical evaluation of the 
rate of treatment-emergent UAEs among treatment arms using a Chi-square test or Fisher’s exact test 
(if more than 20% of the cells in a contingency table had expected counts less than 5) will be 
performed. 
As with the prior trial (KIT-302-03-01), there are several TEAEs designated as unexpected by one or 
more PIs for one or more subjects that the Sponsor considered as expected based on the product 
labelings for the study drugs, including dyspepsia, flatulence, vomiting, chest pain, pain (lower body 
pain), thirst, nasopharyngitis (cold symptoms), pharyngitis, sinusitis, alanine aminotransferase 
increased, increased appetite, arthralgia, back pain, joint swelling (swelling of knee), dizziness, 
headache, cough, epistaxis, dry skin, purpura, and rash.   
Further, there were several TEAEs designated as expected by one or more PIs for one or more 
subjects that the Sponsor considered as unexpected as they were not listed in the product labelings for 
the study drugs and were not listed as expected AEs in the protocol, including toothache, seasonal 
allergy (hayfever symptoms), urinary tract infection, plantar fasciitis, dysphoria, epididymal cyst, 
blister, pigmentation disorder, feeling cold, and peripheral coldness.  It should be noted that in the 
prior study (KIT-302-03-01), the Sponsor assigned pollakiuria as an unexpected event in error.  
Micturition frequency is listed in the labelings for both study drugs.  As such, the Sponsor considers 
the pollakiuria events in this study and the prior study as expected. 
The Sponsor’s assignments of expectedness will be noted in the main body of the clinical study 
report, and a footnote will be added to the above tabular summary to clarify that it is based on the PI’s 
assignments, which were not all consistent with the protocol-specified definition of UAE.  A similar 
approach was taken for the prior trial (KIT-302-03-01), and thus will allow for comparison across 
studies.  To facilitate the preparation of this text for the main body of the clinical study report, an 
analysis will be run based on the above expectedness changes (Sponsor’s assignments), although, the 
table itself will not be included in the clinical study report.   
e. Pre-treatment adverse events (PTAEs) 
If there are no serious PTAEs or PTAEs that led to withdrawal, the respective protocol-specified 
tabular summaries will not be produced.  The protocol-specified tabular summary of all PTAEs will 
be produced, regardless. 
f. Exact logistic regression analyses of TEAEs and treatment-emergent serious adverse 
events (SAEs) 
An exact logistic regression to compare TEAE rates between amlodipine + celecoxib and amlodipine 
+ placebo, with the TEAE (1 = at least one TEAE occurred for the subject; 0 = otherwise) as the 
dependent variable, and treatment (amlodipine + celecoxib and amlodipine + placebo) as fixed 
effects, will be added. 
An exact logistic regression to compare treatment-emergent SAE rates between amlodipine + 
celecoxib and amlodipine + placebo, with the treatment-emergent SAE (1 = at least one treatment-
emergent SAE occurred for the subject; 0 = otherwise) as the dependent variable, and treatment 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 13 of 190
 
 
(amlodipine + celecoxib and amlodipine + placebo) as fixed effects, will be added, with the caveat 
that if there are no treatment-emergent SAEs, the tabular summary will not be produced. 
g. Physical examination 
The physical examination summary tabulation will be limited to the comprehensive physical 
examinations at the Initial Screening Visit and Day 14 and will not include the targeted physical 
examinations at Days 0, 7 and 28.  The targeted physical examination findings will still be provided as 
a listing as specified in the protocol.  A shift table presenting the number and the percentage of 
subjects in each bivariate category (Initial Screening Visit versus Day 14) with regards to 
Investigator’s interpretation [normal, abnormal not clinically significant (NCS), abnormal clinically 
significant (CS), not done, and missing] by treatment arm will be done in place of a frequency only 
table.  Due to the limited number of events, the comparisons among treatment arms using Chi-square, 
binomial, and logistic analyses will not be done since they would not provide meaningful analyses. 
h. Vital signs 
Descriptive statistics [n, mean, standard deviation (SD), median and range] will be added for the 
change from baseline at each visit (Days 7, 14, and 28) for each vital sign (clinic visit resting SBP and 
DBP, pulse rate, respiration rate, and oral body temperature) for the safety population.  The protocol-
specified comparisons among treatment arms using ANCOVA will be limited to SBP and DBP (and 
not performed for pulse rate, respiration rate, and oral body temperature).  Further, the resting SBP 
and DBP ANCOVA comparisons will be limited to the change from baseline to Day 14 (and not 
evaluated for the change from baseline to Days 7 or 28) since the effect would be more limited after 
only 7 days, and since subjects would have been off study drugs for 14 days at Day 28.  The LOCF 
method of imputation will be applied for missing values. 
i. 
Orthostatic hypotension 
Descriptive statistics (n, mean, SD, median and range) will be added for the change from baseline at 
each visit (Days 7 and 14) for the orthostatic hypotension BP measurements (i.e., SBP and DBP after 
supine 5 minutes, standing 1 minute and standing 3 minutes, as well as the respective differences 
between standing and supine) for the safety population.  The protocol-specified comparisons of the 
orthostatic hypotension BP measurements among treatment arms using ANCOVA will be limited to 
the change from baseline to Day 14 (and not evaluated for the change from baseline to Day 7) since 
any effect is anticipated to be maximal at Day 14.  Further, the comparisons of the orthostatic 
hypotension diagnoses among treatment arms will be limited to Chi-square test or Fisher’s exact test 
(and will not include logistic analyses as noted in the protocol) due to the limited number of subjects.   
j. Hematology, serum chemistry, and urinalysis 
For the majority of the hematology, serum chemistry, and urinalysis tests, the comparisons of the 
safety population data among treatment arms using Chi-square, binomial, and logistic analyses for 
dichotomous variables (e.g., negative/positive) and ANCOVA for continuous variables will not be 
done due to the limited number of subjects.  The exceptions are serum creatinine and blood urea 
nitrogen (BUN), where comparisons between treatment arms will be performed using an ANCOVA 
model with change from baseline to Day 14 as the dependent variable, treatment as the fixed effect, 
and baseline as the covariate. 
The laboratory reference range for assigning low “L” flags to the creatinine clearance results differed 
for the Celerion, Belfast laboratory (>90 mL/min) versus the centralized laboratory used for the 
remaining sites (ACM Global Central Laboratories; ≥ 60 mL/min).  The serum chemistry shift table 
analysis will be based on the laboratory assigned flags (i.e., no reassignment of the Celerion, Belfast 
laboratory flags based on the ACM laboratory reference range will be made).  The main body of the 
clinical study report will note the difference in the creatinine clearance reference range for the two 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 14 of 190
 
 
laboratories and will note by treatment group any cases where a Celerion, Belfast low creatinine 
clearance value would be reassigned as Normal if the ≥ 60 mL/min criterion was used.  
Documentation of the differing creatinine clearance reference ranges for ACM and Celerion, Belfast 
is included in Appendix 16.1.10 of the clinical study report and in the individual subject laboratory 
reports that are included with the consolidated case report form PDF files, copies of which are 
included in the Trial Master File.  
k. Electrocardiogram (ECG) 
For analysis of ECG assessments, a shift table presenting the number and the percentage of subjects in 
each bivariate category (Initial Screening Visit versus Day 14) with regards to Investigator’s 
interpretation (normal, abnormal NCS, abnormal CS, not done) by treatment arm will be done in place 
of a frequency only table.  The protocol-specified comparisons among treatment arms using 
Chi-square, binomial, and logistic analyses will not be done since, based upon what is already known 
about amlodipine and celecoxib and what was demonstrated in the prior trial (KIT-302-03-01), 
minimal ECG effects are anticipated. 
1.3.10. BLQ computation for plasma concentration 
The protocol specifies that all plasma amlodipine concentration values below the lower limit of 
quantification (LLOQ) will be reported as zero.  This will be modified as follows: 
For the individual patient data listing of amlodipine plasma concentrations, all values below the 
LLOQ will be reported as below the limit of quantitation (BLQ), as in the bioanalytical report 
[Determination of Amlodipine in human plasma (lithium heparin) samples from “A Prospective 
Randomized Placebo Controlled Study to Evaluate the Effect of Celecoxib on the Efficacy and Safety 
of Amlodipine on Renal and Vascular Function in Subjects with Existing Hypertension Requiring 
Antihypertensive Therapy” by LC-MS/MS, bioanalytical report amendment number ACA20019 
Am 1, Celerion Switzerland AG, March 22, 2018].  
For the summary of non-transformed amlodipine plasma concentration values by treatment group by 
descriptive statistics (n, mean, SD, median, and range), as well as the t-test analysis of the non-
transformed values and the box plot analysis of non-transformed values, all BLQ values will be 
treated as zero. 
For the summary of log-transformed amlodipine plasma concentration values by treatment group by 
descriptive statistics (n, mean, SD, median, and range), as well as the t-test analysis of the log-
transformed values, all BLQ values will be treated as 0.04 ng/mL rather than 0.  Zero cannot be log-
transformed.  Assignment of the BLQ values to a nonzero number will allow computation of the log 
transformation.  The selection of 0.04 ng/mL as the nonzero number for BLQ assignment was based 
on the LLOQ of the validated bioanalytical method [i.e., 0.05 ng/mL; Validation of an LC/MS/MS 
Method for the Determination of Amlodipine in Human Plasma (Li Heparin), method validation 
report number VZZ00140-01, MDS Pharma Services Switzerland AG, July 5, 2006; Validation of an 
LC-MS/MS Method for the Determination of Amlodipine in Human Plasma (Lithium Heparin), 
method validation report number VZZ46541, Celerion Switzerland AG, January 20, 2016] and 
selecting the next lowest number at the hundredth decimal place. 
1.3.11. Sample size formula 
Changed the α (one-sided level of significance) in the sample size formula to 0.025.  The protocol listed 
0.05 in error.  The planned number of subjects (approximately 105) was based on the 0.025 value. 
1.3.12. Demographic and baseline characteristics 
A summary tabulation for the Safety Population, including demographic characteristics (age, sex and 
race), Initial Screening Visit characteristics [height, weight, body mass index (BMI), pulse rate, 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 15 of 190
 
 
respiration rate, oral body temperature, SBP left arm, SBP right arm, DBP left arm, DBP right arm, 
and ECG], and Baseline Day 0 characteristics (weight, SBP, and DBP) by treatment arm and overall 
will be added.  The Day 0 SBP and DBP to be included in this table will be for the arm with the 
higher average resting SBP determined as part of the manual vital signs at the Initial Screening Visit 
(i.e., the arm used for all ABPM and manual vital sign assessments throughout the remainder of the 
study).  Descriptive statistics will be generated as appropriate (i.e., n, mean, SD, median and range for 
continuous data and number and percentage of patients for categorical data).   
1.3.13. Investigational site-specific analyses 
An Investigational Site-specific summary tabulation for the Safety Population, including demographic 
characteristics (age, sex and race), Initial Screening Visit characteristics (height, weight, BMI, pulse 
rate, respiration rate, oral body temperature, SBP left arm, SBP right arm, DBP left arm, DBP right 
arm, and ECG), and Baseline Day 0 characteristics (weight, SBP, and DBP) by treatment arm and 
overall will be added.  The Day 0 SBP and DBP to be included in this table will be for the arm with 
the higher average resting SBP determined as part of the manual vital signs at the Initial Screening 
Visit.  Descriptive statistics will be generated as appropriate (i.e., n, mean, SD, median and range for 
continuous data and number and percentage of patients for categorical data).   
An Investigational Site-specific summary tabulation for the Safety Population, including SBPday, 
SBPnight, SBP24h, DBPday, DBPnight and DBP24h at baseline (Day -1 to Day 0) by treatment arm and 
overall will be added.  The summary will include pooled values (i.e., for all sites) as well.  Descriptive 
statistics will be generated (i.e., n, mean, SD, median and range).   
A summary tabulation for the ITT Population, including the mean ± SD SBPday at baseline, end of 
study, and the change from baseline to end of study for the patients at Sites 301 (Queen Mary School 
of Medicine & Dentistry), 302 (Celerion, Belfast), 303 (Rowden Surgery), and 304 (Medicines 
Evaluation Unit), the four largest recruiting sites, and the patients at all remaining sites (pooled) by 
treatment arm will be added as a means of evaluating the comparability of the primary efficacy 
endpoint across sites.  Pooling of data for 4 of the 8 sites (that randomized patients) will be done due 
to the small numbers of patients per treatment arm per Investigational Site.  The table will also 
include a row that includes the summary statistics for the whole ITT population (i.e., including all 
sites) for comparison. 
1.3.14. Past and concomitant diseases 
Summary tabulations for the Safety Population, including the number and percentage of subjects with 
past and concomitant diseases by SOC and PT, and further categorized by treatment arm will be 
added.   
Past diseases will be defined as medical conditions that initiated and ended prior to the Initial 
Screening Visit (i.e., any disease/history listed on the “Cardiovascular History” or “Medical History 
and/or Concomitant Diseases” case report forms (CRFs) that has a stop date that is prior to the Initial 
Screening Visit date, if a stop date is available, and that has “no” checked for “Ongoing”; any surgery 
listed on the “Surgical History” CRF that has a date that is prior to the Initial Screening Visit date).   
Concomitant diseases will be defined as medical conditions that were ongoing at the Initial Screening 
Visit (i.e., any disease/history listed on the “Cardiovascular History” or “Medical History and/or 
Concomitant Diseases” CRFs that has no stop date entered and that has “yes” checked for “Ongoing”; 
any surgery listed on the “Surgical History” CRF that has a date equal to the Initial Screening Visit 
date).  Any disease that initiates after completion of the Initial Screening Visit and before 
administration of the first dose of study drugs (Day 0) will be recorded as a PTAE (and will not be 
considered as a concomitant disease for this analysis).   


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 16 of 190
 
 
Past and concomitant diseases will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA).  Patients will be counted once per SOC category, regardless of the number of 
diseases/PTs they had within that SOC category.   
1.3.15. Previous medications 
A summary tabulation for the Safety Population, including the number and percentage of subjects 
with previous medications by Anatomical Main Group [1st level of the Anatomical Therapeutic 
Chemical (ATC) classification], Chemical Subgroup (4th level of the ATC classification) and 
Preferred Name, and further categorized by treatment arm will be added.  Per protocol, all 
medications taken within 30 days prior to the Initial Screening Visit were to be recorded.  Previous 
medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD).   
Previous medications will be defined as medications with a start date < date of first randomized study 
drug intake and a stop date < date of first randomized study drug intake.   
 
In case of missing or partial dates, a set of rules for the imputation method is described in Section 5. 
1.3.16. Concomitant, posterior, and unclassified medications 
A summary tabulation for the Safety Population, including the number and percentage of patients with 
concomitant medications by Anatomical Main Group, Chemical Subgroup and Preferred Name, and 
further categorized by treatment arm will be added.  Per protocol, all medications taken from the first 
dose of study drugs (Day 0) through the final study visit assessment were to be recorded; therefore, 
the concomitant medications tabulation will not include medications that started after the final study 
visit assessment.  Concomitant medications will be coded using the WHO-DD. 
Concomitant medications will be defined as medications (other than the study drugs) with either: 
a) a start date ≥ date of first randomized study drug intake and ≤ date of final study 
visit assessment; or 
b) a start date < date of first randomized study drug intake and a stop date ≥ date 
of first randomized study drug intake 
Posterior medications will be defined as medications with a start date > date of final study visit 
assessment. 
For the medications listing, medications will be classified as either Type 1 (previous medication), 
Type 2 (concomitant medication), Type 3 (posterior medication), or Type 4 (unknown).  Tabular 
summaries will be prepared for each classification (i.e., previous medications (see Section 1.3.15), 
concomitant medications, posterior medications, and medications that could not be classified as 
previous, concomitant, or posterior due to unknown or partial start or stop dates).  If there are no Type 
4 medications, then the corresponding tabular summary will not be produced. 
In case of missing or partial dates, a set of rules for the imputation method is described in Section 5. 
1.3.17. Treatment compliance and extent of exposure 
A summary tabulation for the Safety Population, including treatment compliance and extent of 
exposure by treatment arm and overall will be added.  The total number of white capsules (celecoxib 
or matched placebo) taken, total number of orange capsules (amlodipine or matched placebo) taken, 
percentage of white capsule planned dose taken (out of 14 capsules), percentage of orange capsule 
planned dose taken (out of 14 capsules) and total treatment duration will be summarized by 
descriptive statistics for continuous variables (n, mean, SD, median and range).  The percentage of 
white capsule planned dose taken and percentage of orange capsule planned dose taken will also be 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 17 of 190
 
 
summarized by category (i.e., <75%, 75%≤X<100% and 100%) using descriptive statistics for 
categorical data (number and percentage of patients).  
1.3.18. Hierarchical analysis of secondary efficacy endpoints 
Per the protocol, a serial gatekeeping strategy was to be used to evaluate the effect of amlodipine 
tablets (10 mg) and celecoxib capsules (200 mg) given together on the secondary efficacy endpoints.  
If and only if the statistical significance was achieved for the primary efficacy endpoint, the secondary 
hierarchical analysis was to be used to evaluate the secondary endpoints (i.e., body weight, SBP24h, 
DBP24h, and creatine clearance) and was only to proceed to the next endpoint in the list if the alpha is 
met for the prior analyses.  While defining success at the secondary efficacy level will remain based 
on the hierarchical approach, regardless of the outcome, all four secondary efficacy endpoints (body 
weight, SBP24h, DBP24h, and creatine clearance) will be analyzed for informational purposes and to 
allow comparisons to the trends and statistically significant differences observed in the prior trial 
(KIT-302-03-01).     
1.4. 
Study Summary 
This is a prospective randomized placebo controlled study to evaluate the effect of celecoxib on the 
efficacy and safety of amlodipine on renal and vascular function in subjects with existing 
hypertension requiring antihypertensive therapy. 
1.5. 
Version History 
SAP v0.1 – Draft version (May 12, 2017). 
SAP v1.1 – Draft version (August 30, 2017) 
SAP v2.1 – Draft version (October 9, 2017)  
SAP v3.0 – Final version pre-unblinding (October 12, 2017)  
SAP v4.0 – Final version post-unblinding (April 20, 2018) 
Specifications are based on the following documents: 
 
Study protocol (Version 4: December 16, 2016) 
 
CRF (Version 1.4, April 13, 2017) 
2. Study Objectives and Endpoints 
2.1. 
Primary Objective(s) 
Efficacy: 
The primary efficacy objective of this study is to demonstrate that the mean reduction in SBPday after 
oral administration of amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together qd 
for 14 days in adult subjects with existing hypertension is no less than half the mean reduction in 
SBPday after oral administration of amlodipine tablets (10 mg) given alone (i.e., with matched 
celecoxib placebo) qd for 14 days in the same population. 
2.2. 
Secondary Objective(s) 
Efficacy: 
The secondary objectives of this study are as follows: 
1. To evaluate the effect of amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given 
together qd for 14 days in adult subjects with existing hypertension on secondary efficacy 
endpoints using a serial gatekeeping strategy.  If and only if the primary efficacy endpoint is 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 18 of 190
 
 
statistically achieved, a secondary hierarchical analysis will be used to evaluate the endpoints 
listed below, and will only proceed to the next endpoint in the list if the alpha is met for the 
prior analyses. 
a. Difference in mean change in body weight from baseline to end of treatment between 
treatment arms [amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given 
together, amlodipine tablets (10 mg) given alone (with matched celecoxib placebo), and 
placebo]; 
b. Difference in the mean reduction in SBP24h from baseline to end of treatment between 
amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together and 
amlodipine tablets (10 mg) given alone (with matched celecoxib placebo) treatment arms; 
c. Difference in the mean reduction in DBP24h from baseline to end of treatment between 
amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together and 
amlodipine tablets (10 mg) given alone (with matched celecoxib placebo) treatment arms;  
d. Difference in the mean change in creatinine clearance from baseline to end of treatment 
between amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together and 
amlodipine tablets (10 mg) given alone (with matched celecoxib placebo) treatment arms.  
2. To evaluate the safety of amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given 
together qd for 14 days in adult subjects with existing hypertension. 
3. To evaluate the effect of celecoxib on the mean plasma concentrations of amlodipine in adult 
subjects with existing hypertension after 14 days of treatment with amlodipine tablets (10 mg) 
and celecoxib capsules (200 mg) given together compared to amlodipine tablets (10 mg) 
given alone (with matched celecoxib placebo). 
2.3. 
Primary Endpoint(s) 
Efficacy: 
The primary efficacy endpoint for this trial is the difference in the mean reduction in SBPday from the 
baseline (Day –1 to Day 0) ABPM measurement to the final (Day 13 to Day 14) ABPM measurement, 
where a subject completes the 14-day treatment plan, or to the Day 6 to Day 7 ABPM measurement, 
where a subject is withdrawn from treatment at Day 7, between subjects treated with amlodipine 
tablets (10 mg) and celecoxib capsules (200 mg) given together (arm 1) and amlodipine tablets (10 
mg) given alone (i.e., with matched celecoxib placebo) (arm 2).  
The primary efficacy endpoint is that the lower limits of the 97.5% one-sided CI for the difference in 
SBPday reduction in treatment arm 1 and 50% of the mean reduction in treatment arm 2 is less than 0.  
Note, as detailed in section 6.7, because the preferred outcome is a larger reduction, a negative value 
indicates a larger reduction in arm 1 as compared to arm 2. 
2.4. 
Secondary Endpoint(s) 
Efficacy: 
Subjects were to be randomized 3:3:1 to one of three treatment arms: 
1. OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule; 
2. OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule; 
3. Matched placebo for OE amlodipine tablet + matched placebo for OE celecoxib capsule. 
A serial gatekeeping strategy was to be used to evaluate the effect of amlodipine tablets (10 mg) and 
celecoxib capsules (200 mg) given together on secondary efficacy endpoints.  If and only if the 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 19 of 190
 
 
statistical significance was achieved for the primary efficacy endpoint, a secondary hierarchical 
analysis was to be used to evaluate the endpoints listed below, and was only to proceed to the next 
endpoint in the list if the alpha is met for the prior analyses. 
1. Difference in mean change in body weight from baseline (Day 0) to Day 14 measurement (or 
if a LOCF is required, the Day 7 measurement) between treatment arms [amlodipine tablets 
(10 mg) and celecoxib capsules (200 mg) given together (arm 1), amlodipine tablets (10 mg) 
given alone (with matched celecoxib placebo) (arm 2), and placebo (arm 3)]; 
2. Difference in the mean reduction in SBP24h from the baseline (Day -1 to Day 0) ABPM 
measurement to the Day 13 to Day 14 ABPM measurement (or if a LOCF is required, the 
Day 6 to Day 7 ABPM measurement) between subjects treated with amlodipine tablets (10 
mg) and celecoxib capsules (200 mg) given together (arm 1) and amlodipine tablets (10 mg) 
given alone (with matched celecoxib placebo) (arm 2);  
3. Difference in the mean reductions in DBP24h from the baseline (Day –1 to Day 0) ABPM 
measurement to the Day 13 to Day 14 ABPM measurement (or if a LOCF is required, the 
Day 6 to Day 7 ABPM measurement) between subjects treated with amlodipine tablets (10 
mg) and celecoxib capsules (200 mg) given together (arm 1) and amlodipine tablets (10 mg) 
given alone (with matched celecoxib placebo) (arm 2); 
4. Difference in the mean change in creatinine clearance from baseline (Day 0) to the Day 14 
measurement (or if a LOCF is required, the Day 7 measurement) between subjects treated 
with amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together (arm 1) and 
amlodipine tablets (10 mg) given alone (with matched celecoxib placebo) (arm 2). 
3. Study Design 
This is a multi-center, randomized, double blind, placebo controlled trial to evaluate the effect of 
celecoxib on the efficacy, safety, and pharmacokinetics of amlodipine in subjects with existing 
hypertension requiring antihypertensive therapy.  
Approximately 105 adult subjects who required and were currently using pharmacological therapy 
with a single agent that was not a calcium channel blocker to control their hypertension were to be 
randomized 3:3:1 to one of three treatment arms:  
1. OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule; 
2. OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule; 
3. Matched placebo for OE amlodipine tablet + matched placebo for OE celecoxib capsule. 
All drugs were to be administered orally qd for 14 days (Days 0-13) for a total of 14 doses.  With the 
exception of Day 0, when study drug intake was to be after determination of eligibility (and at least 25 
hours after the Day -1 ABPM is initiated), Days 6 and 13, when study drug intake was to be at the 
time of fitting the ABPM (following fitting) and Day 7, when study drug intake was to be 24 h ± 1 h 
after the Day 6 dose, the subjects were to be instructed to take the study drugs between 07:00 and 
10:00, and preferably at approximately the same time each day. 
Initial Screening Visit (Day -14 to -10): Each subject was to be provided with oral and written 
information (ICF) describing the study and have any questions answered. Subjects that consented in 
writing to participate in the study were to undergo eligibility assessments, including complete medical 
history, comprehensive physical examination, height, body weight in underwear and light gown, BMI, 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 20 of 190
 
 
vital signs (BP, pulse rate, respiration rate, and oral body temperature), 12-lead ECG, hematology, 
serum chemistry, urinalysis, serum pregnancy test for women of childbearing potential (WCBP), urine 
drug screen, and record medications taken within 30 days prior to initial screening visit.  
Subjects who met eligibility criteria based on the above initial screening visit procedures were to be 
instructed to cease taking their current BP medication.  Monitoring for PTAEs was to begin upon 
completion of the initial screening visit procedures and continue through the 9 to 13 days of washout, 
the final screening visit on Day -1, and the baseline procedures on Day 0 (i.e., prior to the 
administration of the first dose of study drugs).  Any untoward medical occurrence that initiated or 
worsened after completion of the initial screening visit procedures and before administration of the 
first dose of study drugs was to be recorded as a PTAE.  Subjects were to be instructed to return to the 
clinic in 9 to 13 days. 
Final Screening Visit (Day -1) Subjects were to return to the clinic after 9 to 13 days of washout for 
their final screening visit (Day -1).  They were to undergo the following procedures: solicit for history 
of PTAEs since the previous visit and record medications taken since prior visit.  Those who 
continued to meet eligibility criteria were to be given an ABPM, instructed in its use, and have the 
positioning of their ABPM checked.  They were to be instructed to wear it at all times for the next 25 
hours and to return to the clinic the following day.  
Study Day 0: When the subjects returned to clinic the following day, the ABPM was to be collected 
and the data contained therein downloaded and analysed.  If subjects were found to be hypertensive, 
based upon their ABPM measurement, they were to undergo additional baseline procedures as 
described below.  If the subject’s BP was too elevated for them to continue safely in the study (i.e., 
SBP24h > 169 mmHg or DBP24h > 110 mmHg), the subject was not to be enrolled and they were to be 
instructed to resume taking their prescribed BP medication as directed by the study doctor or general 
practitioner.  If the subject was found to be normotensive (SBPday ≤ 135 mmHg), the subject was not 
to be enrolled.  The subject’s primary care doctor was to be informed that he/she had been found not 
to be hypertensive.  No subject was to be randomized until these baseline ABPM data were reviewed 
and it was documented that the subject met entry BP criteria.  
Subjects who met the BP criteria (SBPday > 135 and ≤ 169 mmHg and DBPday ≤ 110 mmHg) 
following completion of the 10 to 14 day washout period were to undergo the following additional 
baseline procedures: solicit for history of PTAEs since the previous visit, targeted physical 
examination, body weight in underwear and light gown, vital signs, orthostatic hypotension 
evaluation, serum chemistry, and record medications taken since last visit.  Subjects that continued to 
meet all eligibility requirements were to be enrolled in the study and randomized 3:3:1 to one of three 
treatment arms.  The subjects were then to be administered their first dose of study drugs in the clinic. 
Monitoring for TEAEs was to begin immediately following administration of the first dose of study 
drugs and was to continue throughout the study.  Any untoward medical occurrence that initiated or 
worsened after the first dose of study drugs and within 14 days of the last dose of study drugs was to 
be recorded as a TEAE.  Subjects were to remain in the clinic under observation for one hour 
following their first dose and were to be solicited for TEAE history prior to leaving the clinic.  
Subjects were to be provided with sufficient study drugs for the remainder of the 2-week treatment 
period, and instructed to take the study drugs qd in the morning.  Subjects were to be provided with a 
diary and instructed to record any concomitant medications taken and details of study drug 
administration.  Subjects were to be instructed to return to clinic the morning of Day 6. 
Study Day 6: Subjects were to return to clinic on the morning of Day 6 and were to be solicited for 
history of TEAEs since the previous visit.  The study drug containers were to be collected and unused 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 21 of 190
 
 
study drug counted and recorded.  The diary was to be reviewed for details of study drug 
administration and any concomitant medications taken since the previous visit.  Subjects were to be 
given an ABPM, instructed in its use, and have the positioning of their ABPM checked.  The subjects 
were then to be administered their Day 6 dose of study drugs, and instructed to wear the ABPM at all 
times for the next 25 hours.  Subjects were to be given back their remaining study drug supply and 
diary, instructed to record any concomitant medications taken and details of study drug 
administration, and to return to clinic the following day.  
Study Day 7: The Day 7 study drugs were to be self-administered at home within 24 hours ± 1 hour 
from the Day 6 dose.  Subjects were to return to clinic on the morning of Day 7 (after the home 
administration of study drugs).  The diary was to be reviewed for any concomitant medications taken 
and for details of study drug administration since the previous visit.  The study drug containers were 
to be collected and unused study drug counted and recorded.  Subjects were to be solicited for history 
of TEAEs since the previous visit.  A targeted physical examination was to be performed and body 
weight in underwear and light gown and vital signs were to be measured.  An orthostatic hypotension 
test was to be performed.  Subjects were to have BP as measured by the ABPM recorded and the 
ABPM collected.  Subjects were to have blood collected for measurement of creatinine (and 
calculation of creatinine clearance) and electrolytes. 
If the Investigator determined that it was safe for the subject to continue in the study, the subject was 
to have their remaining study drug supply returned to them, and instructed to take the study drugs at 
home on Days 8-12, between 0700 and 1000 hours, and preferably at approximately the same time 
each day.  Subjects were to be given back their diary and instructed to record any concomitant 
medications taken and details of study drug administration, and instructed to return to the clinic in 6 
days (on the morning of Day 13). 
If the subject’s BP was too elevated for them to continue safely in the study (i.e., SBP24h > 169 mmHg 
or DBP24h > 110 mmHg), blood was to be drawn for renal profile testing.  The subject was to be 
instructed to cease taking study drugs, instructed to resume taking their prescribed BP medication as 
directed by the study doctor or general practitioner, given back their diary and instructed to record any 
concomitant medications taken between visits, and instructed to return to the clinic in 7 days 
(Day 14). 
Study Day 13: Subjects were to return to clinic on the morning of Day 13 (except for those 
discontinued from study drug due to excessive hypertension or other safety reasons) and were to be 
solicited for history of TEAEs since the previous visit.  The diary was to be reviewed for details of 
study drug administration and any concomitant medications taken since the previous visit.  The study 
drug containers were to be collected and any unused study drug counted and recorded.  Subjects were 
to be given an ABPM, instructed in its use, and have the positioning of their ABPM checked.  The 
subjects were then to be administered their Day 13 dose of study drugs (final dose), and instructed to 
wear the ABPM at all times for the next 25 hours.  Subjects were to be given back their diary and 
instructed to record any concomitant medications taken between visits, and instructed to return to 
clinic the following day.  
Study Day 14: Subjects were to return to clinic on the morning of Day 14.  The diary was to be 
reviewed for any concomitant medications taken since the previous visit.  Subjects were to be 
solicited for history of TEAEs since the previous visit.  A comprehensive physical examination was to 
be performed and body weight in underwear and light gown and vital signs were to be measured.  BP 
as measured by the ABPM was to be recorded and the ABPM collected.  An orthostatic hypotension 
evaluation was to be performed.  The following additional evaluations were to be performed: 12-lead 
ECG, hematology, serum chemistry, urinalysis, and urine pregnancy test for WCBP.  


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 22 of 190
 
 
In addition, subjects were to have a blood sample collected 24 hours ± 1 hour post-dose for 
measurement of amlodipine concentrations.  Only subjects enrolled at Investigational Sites that had 
UV-shielded lights were to participate in the PK blood collections.  Due to the design of the trial 
(randomized, double-blind, placebo-controlled), this blood sample was to be collected and analyzed 
for all participating subjects, regardless of whether they were in a treatment arm that received 
amlodipine. 
Following the Day 14 evaluations, the subjects were to be instructed to resume taking their prescribed 
BP medication as directed by the study doctor or general practitioner, given back their diary and 
instructed to record any concomitant medications taken between visits, and instructed to return to the 
clinic in 14 days (Day 28). 
Study Day 28: Subjects were to return to clinic on Day 28 for their final study visit (follow-up visit). 
The diary was to be reviewed for any concomitant medications taken since the prior visit.  Subjects 
were to be solicited for history of TEAEs since the previous visit.  A targeted physical examination 
was to be performed and vital signs were to be measured.  For subjects whose study drugs were 
discontinued at Day 7, this follow-up visit was still occur on Day 28 (i.e., these subjects were to return 
to the clinic for both the Day 14 and Day 28 visits). 
The schedule of events is provided in the table below. 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 23 of 190
 
Event  
Screening 
Baseline/
1st Dose 
Remainder of Treatment Period 
Follow-up 
Initial 
Screening Visit 
Final 
Screening
Visit 
Day 0 
Day 6 
Day 7 
Day 13 
Day 14 (a) 
Day 28 (a) 
Day –14 to -10 
Day -1 
Informed consent (b) 
X 
 
 
 
 
 
 
 
Record demographic data 
X 
 
 
 
 
 
 
 
Complete medical history 
X 
 
 
 
 
 
 
 
Monitor for pretreatment adverse events 
(PTAEs)(k) 
X 
X 
X 
 
 
 
 
 
Record prior medications 
X 
X 
X 
 
 
 
 
 
Record concomitant medications (CM) 
 
 
X 
X 
X 
X 
X 
X 
Height and BMI 
X 
 
 
 
 
 
 
 
Body weight while only wearing underwear 
and a light gown 
X 
 
X 
 
X 
 
X 
 
Comprehensive physical examination (c) 
X 
 
 
 
 
 
X 
 
Targeted physical examination (d) 
 
 
X 
 
X 
 
 
X 
Vital Signs (e) 
X (e) 
 
X 
 
X 
 
X 
X 
Provide ABPM and instruct on use 
 
X 
 
X 
 
X 
 
 
25-hour monitoring of BP via ABPM (f) 
 
X 
 
X 
 
X 
 
 
Orthostatic hypotension evaluation 
 
 
X 
 
X 
 
X 
 
12-lead ECG 
X 
 
 
 
 
 
X 
 
Hematology (g) 
X 
 
 
 
 
 
X 
 
Serum chemistry (g) 
X 
 
X 
 
X (g) 
 
X 
 
Serum pregnancy test (h) 
X 
 
 
 
 
 
 
 
Urine pregnancy test (h) 
 
 
 
 
 
 
X 
 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 24 of 190
 
Event  
Screening 
Baseline/
1st Dose 
Remainder of Treatment Period 
Follow-up 
Initial 
Screening Visit 
Final 
Screening
Visit 
Day 0 
Day 6 
Day 7 
Day 13 
Day 14 (a) 
Day 28 (a) 
Day –14 to -10 
Day -1 
Urinalysis (g) 
X 
 
 
 
 
 
X 
 
Urine drug screen (g) 
X 
 
 
 
 
 
 
 
Review inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
Randomization (i) 
 
 
X 
 
 
 
 
 
Administer study drug in clinic (j) 
 
 
X 
X 
 
X 
 
 
Provide diary to record CMs and study drug 
details 
 
 
X 
 
 
 
 
 
Review diary 
 
 
 
X 
X 
X 
X 
X 
Collect study drug containers/capsule count 
 
 
 
X 
X 
X 
 
 
Monitor for treatment emergent adverse 
events (TEAEs) (k) 
 
 
X 
X 
X 
X 
X 
X 
Blood collection for PK (l) 
 
 
 
 
 
 
X 
 
a. 
If a subject was discontinued from study drug early, all study evaluations described for Day 14 and Day 28 were to be performed if feasible. Study drug-
related AEs (adverse reaction or suspected adverse reaction per the definitions in Section 8.1.3 of the protocol) were to be followed until resolution or 
stabilization. 
b. ICF must have been signed prior to performing any other screening evaluations 
c. 
Comprehensive physical examination was to include the following organ or body system assessments: skin; head, eyes, ears, nose, and throat; thyroid; lungs; 
cardiovascular; abdomen (liver, spleen); lymph nodes; and extremities, as well as an abbreviated neurological exam 
d. Targeted physical examination were to specifically target the cardiovascular system and were to include vital signs, plus an examination of the extremities to 
check for the presence of edema, as well as an examination to document any other evidence of a cardiovascular problem. Any areas of concern from the 
medical history or noted on the prior physical examination or indicated by subject symptoms or other findings as determined by the Investigator or designee 
may also have been examined. 
e. 
BP, pulse rate, respiration rate, and oral body temperature. At the Initial Screening Visit, the arm with the higher average clinical visit systolic BP was to be 
determined and used for all further BP measurements including ABPM measurements (see Section 8.3 of the protocol). 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 25 of 190
 
f. 
BP was to be continually recorded with an ABPM on one to three 25-hour periods during the trial: Day -1 to Day 0, Day 6 to Day 7, and Day 13 to Day 14 
(see Section 7.1 of the protocol for further detail) 
g. See Appendix B of the protocol for a list of the specific hematology, serum chemistry, urinalysis, and drug tests. The serum chemistry tests at Day 7 was to 
be limited to creatinine (and calculation of creatinine clearance) and electrolytes (sodium, bicarbonate, calcium, chloride, phosphorous, and potassium), 
rather than the full panel listed in Appendix B. 
h. Only for WCBP 
i. 
Only after all other baseline procedures have been completed and the subject’s eligibility was confirmed. Subjects were to be randomized 3:3:1 to one of 
three treatment arms (see Section 5.2 of the protocol)  
j. 
Subjects were to take study drug by mouth qd for 14 days (Days 0-13) for a total of 14 doses. With the exception of Days 0, 6 and 13, when study drug 
intake was at the time of clinic visit, the subjects were to be instructed to take the study drugs between 0700 and 1000 hours, and preferably at approximately 
the same time each day. At each dose, subjects were to take one capsule from each of the two containers (OE amlodipine besylate tablet or matched placebo 
for the OE amlodipine besylate tablet and OE celecoxib capsule or matched placebo for OE celecoxib capsule). The first dose of study drug (morning dose 
on Day 0) and the Day 6 and Day 13 doses were to be taken in the clinic, and all remaining doses were to be self-administered at home. Subjects were to be 
provided with a diary to record the details of study drug administration. 
k. Monitoring for PTAEs was to begin upon completion of the initial screening visit procedures and was to continue through the 9 to 13 days of washout, the 
final screening visit on Day -1, and the baseline procedures on Day 0 (i.e., prior to the administration of the first dose of study drugs). Monitoring for TEAEs 
was to begin immediately following administration of the first dose of study drugs and was to continue throughout the study. Subjects were to be solicited 
for PTAE history at Day -1 and Day 0 (pre-dose). Subjects were to be solicited for TEAE history prior to leaving the clinic on Day 0 and on Days 6, 7, 13, 
14, and 28. In order to avoid bias in eliciting AEs, subjects were to be asked general, non-leading questions such as "How are you feeling?" 
l. 
For PK analysis, blood samples were to be obtained at 24 hours ± 1 hour post-dose for measurement of amlodipine concentrations. Only subjects enrolled at 
Investigational Sites that had UV-shielded lights were to participate in the PK blood collection. Due to the design of the trial (randomized, double-blind, 
placebo-controlled), this blood sample was to be collected and analyzed for all participating subjects, regardless of whether they were in a treatment arm that 
received amlodipine. 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 26 of 190
 
 
3.1. 
Sample Size 
The sample size was based on findings of the KIT-302-03-01 study, and on the hypothesis that the 
mean reduction in SBPday from baseline to Day 14 of subjects treated with amlodipine tablets (10 mg) 
and celecoxib capsules (200 mg) given together (arm 1) minus half the mean reduction in SBPday from 
Baseline to Day 14 of subjects treated with amlodipine tablets (10 mg) given alone (with matched 
celecoxib placebo) (arm 2) is at least 0.  
Sample size was based on the formula 
𝑛= ቜ2 ൬
𝑍ଵିఈ+ 𝑍ଵିఉ
𝑑
൰
ଶ
𝑠ଶቝ 
Where: 
s is the SD (8.7) 
d is the anticipated mean difference (6.2) 
α is the one-sided level of significance (0.025) 
1-β is the power, one-sided (80%) 
 is the ceiling function 
The margin was based on a mean reduction of 8.8 mmHg in SBPday for the amlodipine + placebo arm 
and a mean reduction of 10.6 mmHg for the amlodipine + celecoxib arm as seen in the previous study, 
KIT-302-03-01.  To ensure that at least half the effect is maintained, a value of 10.6 – 0.5(8.8) = 6.2 
mmHg should be set for d.   
The SD was based on an 8.1 mmHg SD for the amlodipine + placebo arm and a 9.2 mmHg SD for the 
amlodipine + celecoxib arm in the previous study (KIT-302-03-01).  The pooled SD for the power and 
sample size justification is 8.7 mmHg. 
The final sample size was rounded up to allow for a loss to follow-up.  The study selected a round 
number at least 10% larger than the number necessary to protect against potential subjects not fully 
participating in the entire trial. 
Approximately 105 subjects were to be randomized.  Therefore, a sufficient number of subjects were 
to be screened so as to achieve approximately 105 subjects entering the randomization phase (starting 
at Day 0). 
3.2. 
Randomization 
This is a randomized, double blind, placebo controlled study.  Per protocol, approximately 105 
subjects were to be randomized 3:3:1 to one of three treatment arms: 
1. OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule; 
2. OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule; 
3. Matched placebo for OE amlodipine tablet + matched placebo for OE celecoxib capsule. 
 
The description that follows is based on the final protocol, as well as “Note to File - Explanation of 
6:6:1 Randomization” (dated March 30, 2018), a copy of which is available in the Trial Master File.  
Randomization was to take place on Day 0 when the subject returned to clinic and was found to have 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 27 of 190
 
 
hypertension based upon the ABPM recordings and continued to meet eligibility criteria following 
baseline procedures.  Once the 105th subject was randomized to treatment (Day 0), any subject that 
was currently participating in the washout period was to be allowed to complete the washout period 
and if found eligible was to be enrolled into the trial.  These subjects were to continue to be 
randomized 3:3:1 as noted above.  No further subjects were to be brought in for the Initial Screening 
Visit once the 105th subject was randomized. 
A computer-generated randomization schedule was used for assigning the sequence in which subjects 
were assigned to treatment arms.  Generation of the randomization schedule and shipment of blinded 
study drug patient kits to the Investigational Sites were performed by PCI Pharma Services, Western 
Avenue, Bridgend Industrial Estate, Bridgend, CF31 3TY, United Kingdom (PCI Bridgend).  PCI 
Bridgend used PRISM ClinTrial labeling software to generate the randomization codes.  The 
randomization codes were prepared in blocks of 7 to ensure the appropriate number of subjects per 
treatment arm (i.e., 3 + 3 + 1).  The software generated unique 3-digit patient kit numbers in an 
ascending, consecutive, numerical sequence from 501 to 997 (71 blocks). 
Labeling of the patient kits was performed by PCI Pharma Services, Inc., 4545 Assembly Drive, 
Rockford, IL 61109 US (PCI Rockford).  As the trial only called for approximately 105 randomized 
subjects, not all of the 497 randomization codes were used for labeling.  Further, due to how PCI 
Rockford ran the labeling, the resulting kits available for distribution had gaps in the sequence.  
Specifically, 1) the labeling was done in multiple runs, 2) each run started with the highest number of 
the planned batch and ran backwards to the lowest planned number (e.g., if 1-100 kit numbers were to 
be labeled in a run, PCI started with kit number 100 and worked back to 1), and 3) extra labels 
ordered to avoid having to reorder during the run if a label was damaged were scrapped if not used 
(e.g., if 100 kits were to be labeled, 120 numbers would be ordered, and any of the additional 20 
numbers that were not used during the run were no longer available for labeling). 
The randomization code was issued to William Berlin, PhD., Berlin Pharmaceutical Consulting, LLC, 
Rockville, MD, US who was unblinded to the study.  William provided the contract research 
organization (CRO) responsible for project management and study monitoring (Java Clinical 
Research Ltd, Denshaw House, 120-121 Baggot Street Lower, Dublin 2, Ireland) the list of available 
kit numbers to enable them to request the next set of kits in the sequence for dispatch; however, the 
CRO remained blinded to the study. 
Initial shipments of study drug to individual Investigational Sites were to include 5 patient kits with 
sequential randomization numbers.  Due to the labeling issue noted above, the sequential numbers 
were not necessarily consecutive.  Additionally, the initial shipments for four of the Investigational 
Sites included more than 5 kits to meet the anticipated higher enrollment rates at these sites (Site 301 - 
Queen Mary School of Medicine & Dentistry: 10 kits, Site 302 – Celerion, Belfast: 14 kits, Site 303: 
Rowden Surgery: 7 kits, and Site 304 - Medicines Evaluation Unit: 21 kits).  The kit numbers for 
these larger shipments were also sequential, but again, not necessarily consecutive.   
As subjects were enrolled, the Investigator was to take the next sequential kit number in the block 
provided and assign it to the subject.  Due to the issues with labeling noted above (resulting in gaps in 
available kit numbers), the kit numbers were assigned sequentially, but were not necessarily 
consecutive.  Further, due to the variation in the number of kits initially sent to each site (ranging 
from 5 to 21), the initial shipment may have included less than a full block or up to two full blocks 
and two partial blocks.   
The Investigational sites were to be re-supplied in the same fashion (i.e., 5 patient kits); however, to 
accommodate differences in enrollment rate, the number of kits in the resupply shipments ranged 
from 2 to 10, with each shipment containing sequential randomization numbers.  The Investigator was 
to take the next sequential kit number in the resupply shipment and assign it to the subject.  The 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 28 of 190
 
 
sequential numbers were not necessarily consecutive due to the labeling issue noted above.  At the 
end of the study, any unused kits were returned to the distributor. 
Subjects were to be randomized 3:3:1, however, the final overall randomization was 6:6:1.  The 
difference is attributed to 1) the labeling issues noted above that led to gaps in the available kit 
numbers, 2) the distribution of the kits in sequential order from lowest to highest available kit number, 
3) the number of kits shipped initially and as re-supply, and4) only using some of the kits shipped as 
fewer subjects were enrolled than kits shipped.   
As both the primary and secondary efficacy endpoints are based on comparisons of treatment arms 1 
and 2, and the ratio of these two arms are similar under a 3:3:1 and a 6:6:1 randomization, this 
difference from the planned randomization is not anticipated to impact the trial outcomes.  A site-
specific analysis of the primary endpoint will be done (see Section 1.3.13) to evaluate for any impact 
that variation in the randomization ratio across sites may have on the outcome. 
4. Analysis Sets 
4.1. 
Study Populations 
There are seven populations for this study, the ITT, mITT, PP, Safety, PK, Randomized, and Overall 
Trial populations. 
ITT population: The definition of the ITT population as stated in the protocol was at risk of losing 
randomized subjects and will be changed to remain faithful to the ITT principal.  The ITT population 
will include all randomized subjects with a valid ABPM measurement at baseline (Day -1 to Day 0) 
according to the definition of validity described in Section 1.3.1.  The protocol definition required 
valid Baseline and valid follow-up ABPM measurements, either Day 6 or Day 13.  This definition 
will instead be used for a mITT population (see below), and the mITT population will be used for 
sensitivity analyses as described in Section 1.3.3.2.  
In the event there are no Day 6 to Day 7 and no Day 13 to Day 14, baseline will be carried forward. 
mITT population: The definition of the mITT population will follow the definition of the ITT 
population in the protocol with regards to the number of ABPMs required (although based on the 
revised ABPM validity definition in Section 1.3.1).  Thus, the mITT population will be comprised of 
randomized subjects with at least a valid baseline (Day –1 to Day 0) ABPM measurement and either 
a. A valid final (Day 13 to Day 14) ABPM measurement, where a subject completes the 
treatment program. 
or 
b. A valid Day 6 to Day 7 ABPM measurement, where a subject is withdrawn from the 
treatment program at that point because of an SBP24h > 169 mmHg and/or a 
DBP24h > 110 mmHg, or if they are withdrawn for any other reason. 
Subjects that do not have the two paired valid ABPM measurements, as required (baseline and final, 
for those who complete the treatment program, or baseline and Day 6 to Day 7, for those withdrawn 
from the study), will not be included.  In the event there is no Day 13 to Day 14 ABPM measurement, 
the Day 6 to Day 7 ABPM measurement will be carried forward. 
PP population: The PP population will be comprised of randomized subjects with at least a valid 
baseline (Day -1 to Day 0) ABPM measurement and also a valid final (Day 13 to Day 14) ABPM 
measurement. 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 29 of 190
 
 
Dropouts and subjects who had major violations of the protocol will be excluded.  Major protocol 
violations will include missing more than 25% of scheduled doses of study drugs, and taking 
prohibited medications including any NSAIDs or calcium channel blockers (other than the study 
drugs). 
All randomized subjects should receive their initial dose of study drugs in the clinic immediately 
following randomization. 
Safety population: All randomized subjects who received at least one dose of study drug will be 
included in the safety population.  Analysis of safety variables, demographic and screening/baseline 
characteristics, past and concomitant diseases, previous and concomitant medications, and treatment 
compliance and extent of exposure will be performed on the safety population. 
PK population: All subjects that were enrolled at an Investigational Site that had UV-shielded lights 
and who had a blood sample drawn on Day 14, 24 hours ± 1 hour after receiving the final dose of 
study drugs, for the measurement of plasma amlodipine concentration.  This population will be used 
to produce the summary tabulation, t-test analysis, and box-plot analysis of the non-transformed 
plasma amlodipine concentration values, as well as the summary tabulation and t-test analysis of the 
log-transformed values.  
 
Randomized population: All randomized subjects.  The Randomized population will be used to 
produce all listings, except screening failures and the listing of plasma amlodipine concentrations.  
The screening failures listing will use the Overall Trial population and the listing of plasma 
amlodipine concentrations will use all subjects that were enrolled at an Investigational Site that had 
UV-shielded lights.  The Randomized population will also be used to produce a summary tabulation 
of subjects who completed the study and who discontinued the study after randomization, and the 
primary reason for discontinuation.  The Randomized population will also be used to produce a 
summary tabulation of the number of subjects in the randomized population, the ITT population, the 
mITT population, the PP population, the safety population, and the PK population. 
Overall Trial population: All patients screened.  This population will be used to produce a listing of 
screening failures and a tabular summary of the number of patients at Initial Screening Visit, at Final 
Screening Visit, at Baseline, randomized, and at each remaining study visit. 
4.2. 
Misallocations 
In case an error occurs in treatment allocation, the following rule will be followed: if a patient was 
randomized but received the incorrect study drug, he/she will be reported under his/her randomized 
treatment group for all analyses performed on the randomized, ITT, mITT, and PP populations, but 
he/she will be reported under the treatment actually received for all analyses performed on the safety 
and PK populations. 
4.3. 
Protocol Deviations 
All the protocol violations will be discussed case by case before unblinding of the treatment code with 
the clinical team during the blind review of the data and described in the Data Review Report. 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 30 of 190
 
 
5. Definitions and Data Conventions 
This section contains definitions and conventions that will be used for analysis. 
General, demographic and baseline characteristics 
Age and BMI (kg/m2) 
Age and BMI will not be recalculated.  The values automatically derived in the CRF will be used in 
the analysis. 
Past disease and concomitant disease 
Past disease: A medical condition that initiated and ended prior to the Initial Screening Visit.  Thus, 
any disease/history listed on the “Cardiovascular History” or “Medical History and/or Concomitant 
Diseases” CRFs that has a stop date that is prior to the Initial Screening Visit date, if a stop date is 
available, and that has “no” checked for “Ongoing”.  Any surgery listed on the “Surgical History” 
CRF that has a date that is prior to the Initial Screening Visit date is considered as a past disease. 
Concomitant disease: A medical condition that is ongoing at the Initial Screening Visit.  Thus, any 
disease/history listed on the “Cardiovascular History” or “Medical History and/or Concomitant 
Diseases” CRFs that has no stop date entered and that has “yes” checked for “Ongoing”.  Any surgery 
listed on the “Surgical History” CRF that has a date equal to the Initial Screening Visit date is 
considered as a concomitant disease.  Any disease that initiates after completion of the Initial 
Screening Visit procedures and before administration of the first dose of study drugs on Day 0 will be 
recorded as a PTAE (and will not be considered as a concomitant disease for the purpose of the 
concomitant disease listing and tabulation).  
Previous, concomitant, posterior, and unclassified medications 
Previous medication: Medications with a start date < date of first randomized study drug intake and 
a stop date < date of first randomized study drug intake.   
Concomitant medication: Medications (other than the study drugs) with either: 
a) a start date ≥ date of first randomized study drug intake and ≤ date of final study 
visit assessment; or 
b) a start date < date of first randomized study drug intake and a stop date ≥ date 
of first randomized study drug intake 
Posterior medication: Medications with a start date > date of final study visit assessment. 
For the medications listing, medications will be classified as either Type 1 (previous medication), 
Type 2 (concomitant medication), Type 3 (posterior medication), or Type 4 (unknown).  Tabular 
summaries will be prepared for each classification (i.e., previous medications, concomitant 
medications, posterior medications, and medications that could not be classified as previous, 
concomitant, or posterior due to unknown or partial start or stop dates).  If there are no Type 4 
medications, then the corresponding tabular summary will not be produced. 
 
 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 31 of 190
 
 
The table that follows provides the imputation method to be used for assigning medication 
classification, including in instances when all or part of a start or stop date is missing. 
 
Information Available for Start Date
Information Available for Stop Date
Type
Full start date available and:
Full end date available and:
<date of 1st dose
<date of 1st dose
1
<date of 1st dose
>= date of 1st dose
2
>= date of 1st dose & <= date of final 
assessment 
after start date
2
> date of final assessment
> date of final assessment
3
Full start date available and:
Partial or Unknown Stop Date
<date of 1st dose
Nothing (D, M, & Y unknown)
4
= date of 1st dose
Nothing (D, M, or Y unknown)
2
> date of 1st dose, but ≤ date of final 
assessment 
Nothing (D, M, or Y unknown)
2
> date of final assessment
Nothing (D, M, or Y unknown)
3
Partial or Unknown Start Date
Full stop date available and:
Only Y known
= date of 1st dose
2
Only M & Y known
2
Only Y known
> date of 1st dose, but ≤ date of final 
assessment 
2
Only M & Y known
2
Only Y known
> date of final assessment
If < Y of 1st dose
2
If = Y of 1st dose
4
If > Y of 1st dose
4
Only M & Y known
If < M & Y of 1st dose
2
If = M & Y of 1st dose
4
If > M & Y of 1st dose
4
Only Y known
< date of 1st dose
1
Only M & Y known
< date of 1st dose
1


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 32 of 190
 
 
Information Available for Start Date
Information Available for Stop Date
Type
Partial or Unknown Start Date
Partial or Unknown Stop Date
Nothing (D, M, or Y unknown)
Nothing (D, M, or Y unknown)
4
Only Y known
If > Y of final assessment
Nothing (D, M, or Y unknown)
3
If < or = Y of 1st dose
Nothing (D, M, or Y unknown)
4
Only M & Y known
If <= M & Y of 1st dose
Nothing (D, M, or Y unknown)
4
If > M & Y of final assessment
Nothing (D, M, or Y unknown)
3
If > M & Y of 1st dose and = M & Y of 
final assessment 
Nothing (D, M, or Y unknown)
4
D = day, M = month, Type 1 = previous medication, Type 2 = concomitant medication, Type 3 = posterior 
medication, Type 4 = unknown, Y = year  
Study drug intake 
Date of first randomized study drug intake is the actual date of study drug administration at Day 0 
reported in the “Study Drug Administration Recorded in the Diary Card” CRF. 
However, any discrepancy between the date of Day 0 reported elsewhere in the CRF and the date of 
administration at Day 0 reported in the “Study Drug Administration Recorded in the Diary Card” CRF 
will be evaluated during the Data Review Meeting.  
Date of last randomized study drug intake is the date of last study drug intake recorded in the “Study 
Termination” CRF.  If this date is missing, the last date of administration reported in the “Study Drug 
Administration Recorded in the Diary Card” CRF will be considered. 
However, any discrepancy between last date of administration reported in the “Study Drug 
Administration Recorded in the Diary Card” CRF and the date of last study drug intake recorded in 
the “Study Termination” CRF will be evaluated during the Data Review Meeting. 
Treatment Compliance & Extent of Exposure 
Each of the OE drug products was supplied in a separate container.  At each dose, subjects took one 
capsule from each of the two containers (i.e., OE 10 mg amlodipine tablet or matched placebo for the 
OE amlodipine tablet and OE 200 mg celecoxib capsule or matched placebo for the OE celecoxib 
capsule). 
So as to aid in identifying the study drugs, orange capsules were used to over-encapsulate the 
amlodipine tablets and for the matched placebo for the OE amlodipine tablets and white capsules were 
used to over-encapsulate the celecoxib capsules and for the matched placebo for the OE celecoxib 
capsule.   
Each study drug was supplied in 15-count high-density polyethylene bottles with child resistant 
closures.  The double-blind labeling kit (carton) contained one 15-count bottle of OE 10 mg 
amlodipine tablet or matched placebo for the OE amlodipine tablet and one 15-count bottle of OE 
200 mg celecoxib capsule or matched placebo for the OE celecoxib capsule. 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 33 of 190
 
 
All drugs were to be administered orally qd for 14 days (Days 0-13) for a total of 14 doses.  Thus, due 
to the 15-count packaging, the subjects were dispensed one extra dose of each drug (one extra orange 
capsule and one extra white capsule) that was to be returned at the end of the treatment period.   
The first dose was to be administered in the clinic on Day 0, as were the doses to be taken on Day 6 
and Day 13.  The remainder of the doses were to be self-administered at home.   
With the exception of Day 0, when study drug intake was after determination of eligibility (and at 
least 25 hours after the Day -1 ABPM was initiated), Days 6 and 13, when study drug intake was to be 
at the time of fitting the ABPM (following fitting) and Day 7, when study drug intake was to be 
24 h ± 1 h after the Day 6 dose, the subjects were to be instructed to take the study drugs between 
07:00 and 10:00, and preferably at approximately the same time each day. 
Subjects were to be provided with a diary to record details of study drug administration for each dose 
[date, time, and number of orange and white capsules taken], and were to be instructed to return the 
completed diary at the Day 6, Day 7, and Day 13 clinic visits.  Subjects were also to be instructed to 
bring both of their study drug containers (orange and white capsules) back to the clinic at Day 6, 
Day 7 and Day 13. 
The Investigational Site personnel were to collect the study drug containers and count and record 
unused study drug.  Subjects were to return 9 orange capsules and 9 white capsules on Day 6 (and 
after taking the Day 6 dose in the clinic, be left with 8 of each colored capsule to take home with 
them).  Subjects were to return 7 orange capsules and 7 white capsules on Day 7 (having taken the 
Day 7 dose at home before coming to the clinic).  Subjects were to return 2 orange capsules and 2 
white capsules on Day 13 (and after taking the Day 13 dose in the clinic, be left with 1 of each color 
of capsule that would not be taken, but returned to the pharmacy).   
Further, the Investigational Site personnel were to collect the diaries and review and record the study 
drug administration details in the CRF.  Doses taken in the clinic were to be witnessed by the 
Investigational Site personnel and were to be recorded by the Investigational Site personnel in the 
diary and CRF. 
The primary analysis of treatment compliance and extent of exposure will be based on the data 
entered in the “Study Drug Administration Recorded in the Diary Card”, and will be performed for 
the Safety population as described below.  The capsule count data will be provided in listing format 
only.   
The summary tabulation of treatment compliance and extent of exposure will include the following: 
1. Total number of orange capsules (OE 10 mg amlodipine besylate tablets or matched placebo), 
summarized by descriptive statistics (n, mean, SD, median, and range) for each treatment arm 
and overall 
2. Total number of white capsules (OE 200 mg celecoxib capsules or matched placebo), 
summarized by descriptive statistics (n, mean, SD, median, and range) for each treatment arm 
and overall 
3. Percentage of orange capsule planned dose taken, calculated by dividing the total number of 
orange capsules taken (derived from the “Study Drug Administration Recorded in the Diary 
Card” CRF) by 14 and multiplying by 100, and summarized by descriptive statistics (n, mean, 
SD, median, and range) for each treatment arm and overall 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 34 of 190
 
 
4. Percentage of white capsule planned dose taken, calculated by dividing the total number of 
white capsules taken (derived from the “Study Drug Administration Recorded in the Diary 
Card” CRF) by 14 and multiplying by 100, and summarized by descriptive statistics (n, mean, 
SD, median, and range) for each treatment arm and overall 
5. Percentage and number of subjects in each of three compliance categories for orange 
capsules, by treatment arm and overall.  The compliance categories for orange capsules will 
be: 
a. <75% (i.e., all subjects who had a percentage of orange capsule planned dose taken 
less than 75%) 
b. 75%<= X < 100% (i.e., all subjects who had a percentage of orange capsule planned 
dose taken greater than or equal to 75% and less than 100%) 
c. 100% (i.e., all subjects who had a percentage of orange capsule planned dose taken of 
100%) 
6. Percentage and number of subjects in each of three compliance categories for white capsules, 
by treatment arm and overall.  The compliance categories for white capsules will be: 
a. <75% (i.e., all subjects who had a percentage of white capsule planned dose taken 
less than 75%) 
b. 75%<= X < 100% (i.e., all subjects who had a percentage of white capsule planned 
dose taken greater than or equal to 75% and less than 100%) 
c. 100% (i.e., all subjects who had a percentage of white capsule planned dose taken of 
100%)  
7. Total treatment duration in days, calculated as the date of last study drug intake minus the 
date of first study drug intake + 1, and summarized by descriptive statistics (n, mean, SD, 
median, and range) for each treatment arm and overall. 
6. Efficacy Variables 
6.1. 
Primary Efficacy Variable 
SBPday 
The primary efficacy variable will be SBPday.  Appendix A of this SAP outlines the methodology for 
obtaining this variable. 
6.2. 
Secondary Efficacy Variables 
Body Weight 
The measurement of the change in body weight from baseline to the end of treatment will serve as an 
indirect measure of renal function and is the first secondary efficacy endpoint analyzed in the serial 
gatekeeping strategy.  Body weight will be measured while the subject is wearing only underwear and 
a light gown. 
SBP24h and DBP24hr 
The next secondary efficacy endpoints (after change in body weight) used in the serial gatekeeping 
strategy are the change in SBP24h from the baseline to the end of treatment and the change in DBP24h 
from baseline to the end of treatment, respectively   Appendix A of this SAP outlines the methodology 
for obtaining these variables. 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 35 of 190
 
 
For efficacy analyses, the validity of ABPM measurements will be based on valid daytime 
measurements.  The impact of defining valid SBP24h and DBP24h measurements based on valid 
daytime readings is that some invalid measurements with respect to the 24-hour period (i.e., not 
meeting criterion d or e listed in Section 1.3.1) will remain in the analysis of the 24-hour variables.  
Sensitivity analyses excluding measurements that had an entry of valid for day validity and an entry 
of invalid for night or 24h validity will be conducted to verify that the inclusion of the invalid 
measurements does not impact the secondary efficacy conclusions.  Details of the Sensitivity analyses 
are described in Section 7.10. 
Renal function 
The final secondary efficacy endpoint in the serial gatekeeping strategy is the change in creatinine 
clearance from baseline to end of treatment.  Creatinine clearance will be estimated by the Cockroft-
Gault equation as follows: 
𝐸𝑠𝑡𝑖𝑚𝑎𝑡𝑒𝑑 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒= (140 −𝑎𝑔𝑒) × 𝑏𝑜𝑑𝑦 𝑤𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)
72 × 𝑃஼௥(𝑚𝑔
𝑑𝐿)
 
Note: multiply by 0.85 for women 
6.3. 
Exploratory and Other Efficacy Variables 
Exploratory Efficacy Variables 
Exploratory efficacy variables will include DBPday, SBPnight, and DBPnight, and two-sample t-tests to 
test one-side hypotheses of superiority for pairwise comparisons between treatment arms 1 and 2, 1 
and 3, and 2 and 3 will be performed for each.  Further, SBPday, SBP24h, and DBP24h will serve as 
exploratory efficacy variables for the two-sample t-tests to test one-side hypotheses of superiority for 
pairwise comparisons between treatment arms 1 and 3 and 2 and 3 (the comparison of treatment arms 
1 and 2 for these endpoints are covered separately under the respective primary and secondary 
efficacy analyses).  Appendix A of this SAP outlines the methodology for obtaining these variables.  
For the efficacy analyses, the validity of ABPM measurements will be based on valid daytime 
measurements.  The impact of defining valid SBPnight and DBPnight measurements based on valid 
daytime readings is that some invalid night-time readings (i.e., not meeting criterion d listed in 
Section 1.3.1) will remain in the analysis of night-time variables.  Sensitivity analyses excluding 
measurements that had an entry of valid for day validity and an entry of invalid for night validity will 
be conducted to verify that inclusion of the invalid measurements does not impact the exploratory 
efficacy conclusions.  Details of the Sensitivity analyses are described in Section 7.10.  See Section 
6.2 regarding the impact of defining valid SBP24h and DBP24h measurements based on valid daytime 
readings. 
SBP and DBP at Amlodipine Peak and Trough 
Other efficacy variables will include SBP and DBP at the expected peak amlodipine concentration 
and at the trough amlodipine concentration at Day 6 and Day 13, and the difference of the values 
between Day 6 and Day 13.  The peak and trough values will be taken from the ABPM 
measurements.  See Section 7.10 for further definition of the peak and trough values. 
6.4. 
Safety Variables 
Safety will be assessed primarily based on reported TEAEs.  Clinically significant clinical laboratory 
abnormalities will be reported as AEs (i.e., as either PTAEs or TEAEs, depending on when they 
initiate or worsen). 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 36 of 190
 
 
PTAE 
Any untoward medical occurrence that initiates or worsens after completion of the Initial Screening 
Visit procedures and before administration of the first dose of study drugs will be recorded as a 
PTAE. 
TEAE 
Any untoward medical occurrence that initiates or worsens after the first dose of study drugs and within 
14 days of the last dose of study drugs will be recorded as a TEAE.   
In case of missing or incomplete dates and times not allowing a direct allocation to either of the two 
categories of AEs, a worst-case allocation will be done according to the available parts of the onset 
and the end dates.  The AE will be allocated to the first category allowed by the available data, 
according to the following order: 
 
TEAE 
 
PTAE. 
SAE 
A SAE is any untoward medical occurrence that results in death, is life-threatening, requires inpatient 
hospitalization or prolongation of existing hospitalization, results in persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, is a congenital 
anomaly/birth defect, or is an important medical event that, based upon appropriate medical 
judgement, may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the former outcomes (i.e., AE with seriousness not equal to ‘0’ on AE CRF). 
ADR 
An ADR is an AE with relatedness to Study Drug judged as an “Adverse Reaction” (i.e., an AE that is 
caused by the study drug) or a “Suspected Adverse Reaction” (i.e., an AE for which there is a 
reasonable possibility that the study drug caused the AE) [i.e., an AE with relatedness to study drug 
not equal to ‘unrelated’ on AE CRF]. 
Oedema events 
An oedema event is any TEAE with a PT of oedema, oedema peripheral, peripheral swelling, 
swelling, or joint swelling. 
Other PTs of interest 
Other PTs of interest will be defined as any TEAE with a PT of orthostatic hypotension, fall, 
dizziness, dizziness postural, or vertigo. 
UAE 
Per the protocol, an UAE is one for which the nature or severity of the event is not consistent with the 
applicable study drug information [i.e., the most current version of the Investigator’s Brochure (IB), 
the current product labeling for amlodipine tablets, and the current product labeling for celecoxib 
capsules] or listed in the protocol (as provided below). 
This study was to enroll older subjects with existing hypertension.  To that end, PTAEs and TEAEs 
could be expected due to the subjects’ age and underlying conditions.  These include: hypertension, 
hypertensive crisis, myocardial infarction, congestive heart failure, stroke both hemorrhagic and 
ischemic, any adult forms of cancer, and gastrointestinal ulcerations with complications including 
hemorrhage and perforation.   
 
By definition, PTAEs initiate prior to administration of the first dose of study drugs, and thus a 
comparison against study drug specific risk information is inappropriate for determining expectedness 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 37 of 190
 
 
of PTAEs.  Thus, only AEs that can be expected due to subject age and underlying conditions are 
relevant for the expectedness determination for PTAEs. 
 
TEAE leading to discontinuation 
A TEAE leading to discontinuation is a TEAE with ‘the Primary Reason for discontinuation’ equal to 
“Treatment Emergent Adverse Event” on the Study Termination CRF.   
PTAE leading to withdrawal 
A PTAE leading to withdrawal is a PTAE listed as the reason for the subject not being randomized to 
treatment on the “Study Termination” CRF. 
AE leading to death 
An AE leading to death is an AE with outcome equal to “Fatal” on AE CRF. 
Amlodipine dose and celecoxib dose  
The following variables will be derived for the logistic models: 
Treatment group 
Amlodipine dose 
Celecoxib dose 
Amlodipine + Celecoxib 
10 mg 
200 mg 
Amlodipine + Placebo 
10 mg 
0 mg 
Placebo + Placebo 
0 mg 
0 mg 
 
Count of AEs 
Two AEs with the same PT and classified in the same category (PTAE or TEAE) that do not overlap 
in date of occurrence will be considered as two different events when calculating the “number of 
events” in the tables. 
Secondary safety variables will include physical examination, body weight, vital signs, orthostatic 
hypotension evaluations, ECG, hematology, serum chemistry, and urinalysis. 
Physical examination 
The protocol-specified organ or body systems for the comprehensive physical examination will be 
used in the summary tabulation [i.e., skin; head, eyes, nose and throat; thyroid; lungs; cardiovascular; 
abdomen (liver, spleen), lymph nodes, extremities, and neurological (abbreviated exam)].  The 
targeted physical examination findings will only be provided as a listing. 
Body weight 
Body weight will serve a dual function as both a secondary efficacy endpoint (see Section 6.2) and as 
a safety endpoint.  For the latter, the body weight and change in body weight for the Safety population 
will be used for analysis. 
Vital signs 
Clinic visit resting systolic and diastolic blood pressure, pulse rate, respiration rate, and oral body 
temperature will be used for analysis. 
For resting systolic and diastolic blood pressures, the Average values of 3 recordings reported in the 
CRF (derived) will be used in the analysis.  The recordings 1, 2 and 3 will be only listed. 
The continuous recording of BP by ABPM will serve a dual function as both the official BP values for 
all efficacy determinations and calculations and as additional BP assessments for safety.  For the 
latter, the analyses will use the Safety population. 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 38 of 190
 
 
Orthostatic hypotension evaluation 
The average values of 3 recordings in supine position reported in the CRF (derived) will be used in 
the analysis.  The recordings 1, 2 and 3 (Start after 5 minutes rest in supine position) will be only 
listed.   
The orthostatic hypotension at each visit will be recalculated.  It will be considered equal to “Yes” if 
at least one of the following conditions will occur: 
 
the average SBP after supine for 5 minutes minus the SBP 1 minute after standing is greater 
than 25 mmHg;  
 
the average SBP after supine for 5 minutes minus the SBP 3 minutes after standing is greater 
than 25 mmHg; 
 
the average DBP after supine for 5 minutes minus the DBP 1 minute after standing is greater 
than 15 mmHg;  
 
the average DBP after supine for 5 minutes minus the DBP 3 minutes after standing is greater 
than 15 mmHg. 
Otherwise it will be considered equal to “No”. 
ECG 
The ECG diagnosis (normal, abnormal NCS, abnormal CS, not done, missing) will be used for the 
analysis. 
Hematology, serum chemistry, and urinalysis 
See Appendix B of the protocol for a full list of hematology, serum chemistry, and urinalysis 
variables that will be used for analysis.  Creatinine clearance will serve dual functions as a secondary 
efficacy endpoint (see Section 6.2) and a safety endpoint.  For the latter, the Safety population will be 
used for the analysis. 
6.5. 
Other Variables 
Pharmacokinetics 
The plasma concentration of amlodipine at Day 14, 24 ± hour post-dose will be used for analysis.   
For the individual patient data listing of amlodipine plasma concentrations, all values below the 
LLOQ will be reported as BLQ, as in the bioanalytical report.  
For the summary of non-transformed amlodipine plasma concentration values by treatment group by 
descriptive statistics (n, mean, SD, median, and range), as well as the t-test analysis of the non-
transformed values and the box plot analysis of non-transformed values, all BLQ values will be 
treated as zero. 
For the summary of log-transformed amlodipine plasma concentration values by treatment group by 
descriptive statistics (n, mean, SD, median, and range), as well as the t-test analysis of the log-
transformed values, all BLQ values will be treated as 0.04 ng/mL rather than 0.  Zero cannot be log-
transformed.  Assignment of the BLQ values to a nonzero number will allow computation of the log 
transformation.  The selection of 0.04 ng/mL as the nonzero number for BLQ assignment was based 
on the LLOQ of the validated bioanalytical method (i.e., 0.05 ng/mL) and selecting the next lowest 
number at the hundredth decimal place. 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 39 of 190
 
 
Baseline 
Baseline measurements for the various parameters are defined as follows:  
a. ABPM baseline measurements are taken for 25 hours between Day -1 and Day 0, 
initiating at the Final Screening Visit and completing at Day 0 (prior to study drug 
administration).  
b. Baseline values for the following variables are taken on Day 0 prior to study drug 
administration: 
 
Body weight* 
 
Orthostatic hypotension evaluation 
 
Vital signs (clinic visit BP measurements, pulse rate, respiration rate, and oral body 
temperature)* 
 
Serum chemistry* 
 
Targeted physical examination 
c. Baseline values for the following variable are taken at the Initial Screening Visit (Day -14 
to -10) will be the baseline for the following variables: 
 
BMI 
 
Hematology 
 
ECG 
 
Urinalysis 
 
Comprehensive physical examination  
*Baseline measurement for body weight, vital signs, and serum chemistry is Day 0 (prior to study 
drug administration); however, if the baseline measurement is missing and there is a prior 
measurement recorded (i.e., Initial Screening Visit), this value will be carried forward and used as the 
baseline measurement. 
7. Statistical Methodology 
7.1. 
Handling of Missing Data 
For ITT and mITT population, if at the time of the Day 7 clinic visit subjects have a too elevated BP 
to be able to continue safely in the study (i.e., SBP24h > 169 mmHg or DBP24h > 110 mmHg), blood 
will be drawn for renal profile testing, the study drug will be discontinued and the subjects will be 
instructed to resume taking their prescribed BP medication as directed by the study doctor or general 
practitioner.  In case of missing data, LOCF techniques will be used as follows: 
1. ITT population: LOCF from baseline (Day 0) 
2. mITT population: LOCF from Day 6 
Using this method, the end of study measurement is either Baseline, Day 6 or Day 13.  
No specific analysis for withdrawn patients will be presented. 
The number of patients with missing data will be presented under the “Missing” category, if present. 
Missing values will be included in the denominator count when computing percentages. 
When continuous data are being summarized, only the non-missing values will be evaluated for 
computing summary statistics.  
Missing or incomplete data will be treated as described in sections 5, 6.4, 6.5, 7.1, 7.9, 7.10.  Other 
critical missing data will be discussed prior to treatment unblinding, if any.  Decisions will be taken 
during the data review and will be fully documented in the Data Review Report. 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 40 of 190
 
 
The LOCF method of imputation will be applied for missing values in all ANCOVA models.  This 
method will not be applied to the descriptive statistics. 
7.2. 
Covariates and Subgroups 
All ANCOVA models will include the baseline value of the variable as a covariate and treatment 
group as fixed effect with no interaction term. 
7.3. 
General Methodology 
Descriptive statistics will be provided for all variables in the summary tables by treatment group and 
overall (except where noted as treatment group only) according to the type of variable summarized.  
Quantitative variables will be summarized by using n (sample size), arithmetic mean, SD, median and 
range (minimum and maximum).  
Categorical variables will be summarized by using frequency distributions and percentages. 
For the safety analyses, hypothesis testing will be carried out at the alpha = 0.05 level (two-sided) when 
comparing treatments.  P-value will be rounded to three decimal places.  Statistical significance will be 
declared if the rounded p-value will be less than or equal to 0.05. 
All data collected in the CRF will be presented in the listings. 
7.4. 
Patients Disposition 
Disposition of patients will be presented by treatment group and overall for all patients (i.e., the 
Overall Trial population will be used).  The summary will include the number of patients at the Initial 
Screening Visit, Final Screening Visit, and Day 0 visit (including patients that were not randomized), 
the number of patients randomized, and the number of patients at each of the remaining visits (Days 6, 
7, 13, 14 and 28). 
The number of patients included in each of the randomized, safety, ITT, mITT, PP and PK 
populations will be summarized for each treatment and overall. 
The number of patients who completed the study, the number of patients who completed study 
treatment, and the number of patients who discontinued from the study prematurely after 
randomization will also be presented by treatment group and overall for the randomized population.  
This summary will also include a breakdown of the primary reason for discontinuation following the 
categories on the CRF (i.e., TEAE, withdrawal of consent, lost to follow-up, protocol deviation, study 
terminated, and other). 
Major and minor protocol violations will be presented in the listings only. 
7.5. 
Demographic and Screening/Baseline Characteristics  
The demographic and screening/baseline characteristics will be summarized by treatment group and 
overall by means of descriptive statistics. 
The following characteristics will be provided for the Safety population: 
 
Age (years) 
 
Sex (male/female) 
 
Race (white, black, Hispanic, native American, Asian, other) 
 
Weight (kg) at Initial Screening Visit and Day 0 (prior to study drug administration) 
 
Height (cm) at Initial Screening Visit 
 
BMI (kg/m2) at Initial Screening Visit 
 
Pulse rate (beats/min) at Initial Screening Visit 
 
Respiration rate (breaths/min) at Initial Screening Visit 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 41 of 190
 
 
 
Oral body temperature (degrees Celsius) at Initial Screening Visit 
 
Resting SBP and DBP determined as part of manual vital signs at Initial Screening Visit (average 
of 3 recordings for left and right arm) and at Day 0 (average of 3 recordings for the arm with the 
higher average resting SBP determined as part of the manual vital signs at the Initial Screening 
Visit) 
 
ECG result at Initial Screening Visit (normal, abnormal NCS, abnormal CS, no result) 
 
SBPday, SBPnight, SBP24h, DBPday, DBPnight and DBP24h at baseline (Day -1 to Day 0) 
Past disease and concomitant disease 
Past and concomitant diseases will be coded using MedDRA dictionary (version 19.1) and frequency 
distributions and percentages will be summarized by treatment group for the safety population by 
SOC and PT. 
Counts will be given for both SOC and PT by subject.  Subjects experiencing more than one past 
disease (or concomitant disease) event within a given SOC category will be counted only once within 
that SOC.  Similarly, subjects experiencing more than one past disease (or concomitant disease) event 
fitting a given PT will be counted only once for that PT. 
Previous, concomitant, posterior, and unclassified medications 
Medications will be coded using WHO-DD, September, 2016, using the following ATC codes: 
 
Anatomical Main Group (ATC 1st level code); 
 
Chemical subgroup (ATC 4th level code); 
 
Preferred name.  
Previous, concomitant, posterior, and unclassified medications (as defined in Section 1.3.16) will be 
summarized separately for the Safety population by anatomical main group, chemical subgroup and 
preferred name by treatment group. 
Subjects experiencing more than one previous (or concomitant or posterior or unclassified) 
medication within the same anatomical main group or chemical subgroup will be counted only once 
for that group.  Similarly, subjects experiencing more than one previous (or concomitant or posterior 
or unclassified) medication with the same preferred name will be counted only once for that preferred 
name. 
No formal (hypothesis testing) comparisons between treatments on baseline characteristics will be 
done. 
7.6. 
Treatment Compliance and Extent of Exposure 
Treatment compliance and extent of exposure as defined by the 7 parameters summarized in Section 5 
will be summarized using descriptive statistics by treatment group and overall for the Safety 
population. 
7.7. 
Primary Efficacy Analysis 
The primary efficacy analysis is to establish the non-inferiority of amlodipine tablets (10 mg) and 
celecoxib capsules (200 mg) given together (arm 1) with half the effect achieved with amlodipine 
tablets (10 mg) given alone (celecoxib placebo) (arm 2).  
Statistics are based on the change in BP from the baseline ABPM measurement (Day –1 to Day 0) to 
the post-dose ABPM measurement (Day 13 to Day 14 or if a LOCF is required Day 6 to Day 7), as 
this represents the efficacy of the treatment.  As indicated below, the change will be Day 13 to Day 14 
minus Baseline and so a reduction will be a negative number.  Sensitivity analysis will compare the 
results for the ITT population with those of the PP dataset and an MMRM analysis, if possible.  A 
sensitivity analysis will also compare the results with the mITT population. 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 42 of 190
 
 
The hypothesis test being conducted is as follows: 
H0: ∆SBPday,1 – 0.5(∆SBPday,2) ≥ 0 mmHg 
H1: ∆SBPday,1 – 0.5(∆SBPday,2) < 0 mmHg 
Where ∆SBPday,1 is the change, for subjects in arm 1, in the SBPday from the baseline ABPM 
measurement (SBPday,1,base) to the final ABPM measurement (SBPday,1,14). 
∆SBPday,1 = SBPday,1,14 – SBPday,1,base. 
∆SBPday,2 is the change, for subjects in arm 2, in SBPday from the baseline ABPM measurement 
(SBPday,2,0) to the final ABPM measurement (SBPday,2,14). 
∆SBPday,2 = SBPday,2,14 – SBPday,2,base.  
This makes the actual test statistic: 
δ = ∆SBPday,1 – 0.5(∆SBPday,2) 
A one-sided 97.5% CI for δ will be computed.  In addition, a two-sided non-inferiority t-test 
comparing δ to 0 will provide an appropriate p-value.  This p-value will be computing the probability 
of observing a value ≥ 0 from a normal distribution for δ. 
Refer to the protocol Appendix H for further details regarding the efficacy analysis, and in particular 
the non-inferiority margin. 
7.8. 
Secondary Efficacy Analysis 
Per the protocol, a serial gatekeeping strategy was to be used to evaluate the effect of amlodipine 
tablets (10 mg) and celecoxib capsules (200 mg) given together on the secondary efficacy endpoints.  
If and only if the statistical significance was achieved for the primary efficacy endpoint, the secondary 
hierarchical analysis was to be used to evaluate the secondary endpoints (i.e., body weight, SBP24h, 
DBP24h, and creatine clearance) and was only to proceed to the next endpoint in the list if the alpha is 
met for the prior analyses.  While defining success at the secondary efficacy level will remain based 
on the hierarchical approach, regardless of the outcome, all four secondary efficacy endpoints (body 
weight, SBP24h, DBP24h, and creatine clearance) will be analyzed for informational purposes and to 
allow comparisons to the trends and statistically significant differences observed in the prior trial 
(KIT-302-03-01).  
For all secondary efficacy endpoints, the mean change has been computed considering the difference 
between the value at endpoint (Day 13 to Day 14 for ABPM endpoints and Day 14 for body weight 
and creatinine clearance) and the value at baseline (Day -1 to Day 0 for ABPM endpoints and Day 0 
pre-dose for body weight and creatinine clearance) [Endpoint – Baseline].  
1. Analysis of Variance (ANOVA) will be used to compare the changes in body weight among 
the three treatment arms.  The omni-bus test will conclude if any differences exist with post-
hoc comparisons identifying specific differences between treatment arms.  Any statistically 
significant differences will be sufficient to pass this gate in the study-wide gate keeping 
strategy. 
H0: ∆BW1 = ∆BW2 = ∆BW3 
H1: At least one difference, ∆BWi - ∆BWj ≠ 0 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 43 of 190
 
 
Where 
∆BW1 is the change, for subjects in arm 1, in body weight from the baseline 
measurement to the post-treatment measurement. 
∆BW2 is the change, for subjects in arm 2, in body weight from the baseline 
measurement to the post-treatment measurement.  
∆BW3 is the change, for subjects in arm 3, in body weight from the baseline 
measurement to the post-treatment measurement. 
2. A two-sample t-test for superiority will be used to test the one-sided hypothesis that treatment 
with amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together (arm 1) 
lowers SBP24h to a greater degree than amlodipine tablets (10 mg) given alone (with matched 
celecoxib placebo) (arm 2). 
H0: ∆SBP24h,1 – ∆SBP24h,2 =0 
H1: ∆SBP24h,1– ∆SBP24h,2 >0 
Where 
∆SBP24h,1 is the change, for subjects in arm 1, in SBP24h from the baseline ABPM 
measurement to the post-treatment ABPM measurement. 
∆SBP24h,2 is the change, for subjects in arm 2, in SBP24h from the baseline ABPM 
measurement to the post-treatment ABPM measurement. 
3. A two-sample t-test for superiority will be used to test the one-sided hypothesis that treatment 
with amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together (arm 1) 
lowers DBP24h to a greater degree than amlodipine tablets (10 mg) given alone (with matched 
celecoxib placebo) (arm 2). 
H0: ∆DBP24h,1 – ∆DBP24h,2 = 0 
H1: ∆DBP24h,1– ∆DBP24h,2 > 0 
Where 
∆DBP24h,1 is the change, for subjects in arm 1, in DBP24h from the baseline ABPM 
measurement to the post-treatment ABPM measurement. 
∆DBP24h,2 is the change, for subjects in arm 2, in DBP24h from the baseline ABPM 
measurement to the post-treatment ABPM measurement. 
4. A two-sample t-test for superiority will be used to test the one-sided hypothesis that treatment 
with amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together (arm 1) 
improves creatinine clearance to a greater degree than amlodipine tablets (10 mg) given alone 
(with matched celecoxib placebo) (arm 2). 
Note: an improvement in creatine clearance is assumed to be an increase in creatinine clearance; 
therefore, a positive difference is an indication of improvement as shown in the following 
hypotheses. 
H0: ∆CC1 – ∆CC2 = 0 
H1: ∆CC1– ∆CC2 > 0 
Where 
∆CC1 is the change, for subjects in arm 1, in creatinine clearance from the baseline 
creatinine clearance to the post-treatment creatinine clearance. 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 44 of 190
 
 
∆CC2 is the change, for subjects in arm 2, in creatinine clearance from the baseline 
creatinine clearance to the post-treatment creatinine clearance. 
7.9. 
Safety Analysis 
AEs 
PTAEs and TEAEs will be presented separately.   
All AE analyses will use the Safety population.  The AE listings will use the Randomized population. 
See section 6.4 for AE definitions.  Refer to Section 1.3.9, bullet d for further detail regarding how the 
PI assignments of expectedness differed from the protocol-specified definition and how this will be 
handled. 
A summary of TEAE categories [all TEAEs, treatment emergent SAEs, ADRs, oedema events, other 
PTs of interest, treatment emergent UAEs, TEAEs leading to discontinuation, and TEAEs leading to 
death] by number of events within the category and the number and percentage of patients 
experiencing an event in that category will be tabulated by treatment group.  Differences between 
groups will be evaluated using Chi-square test or Fisher’s exact test (if more than 20% of the cells in a 
contingency table have expected counts less than 5). 
AEs will be coded using the MedDRA dictionary (version 19.1).  The incidence of all TEAEs will be 
tabulated by SOC, PT, severity and patient identification.  The number of events and the number and 
percentage of patients with at least one event will be presented.  Subjects experiencing more than one 
TEAE within a given SOC category will be counted only once for that SOC.  Similarly, subjects 
experiencing more than one TEAE fitting a given PT will be counted only once for that PT.  If a PT is 
reported more than once for a given subject, the greatest severity will be presented in the summary 
table.   
The severity of AEs were graded as 1, 2, 3, or 4 according to WHO Toxicity Criteria (see Appendix C 
of protocol), or if the AEs were not included in this toxicity grading scale, they were categorized as 
mild, moderate, or severe per the definitions in Section 8.1.2 of the protocol.  To allow for tabular 
summaries of severity, AEs assigned as grade 1 or mild will be included under mild, AEs assigned as 
grade 2 or moderate will be included under moderate, and AEs assigned as grade 3 or 4 or severe will 
be included under severe.  Mild, moderate, and severe row headers will be presented under each PT, 
except in the case where there were no AEs across all treatment groups fitting a severity classification 
for that PT, in which case that severity classification will not be included as a row under that PT. 
Similar tabular summaries will be produced for each of the following:  treatment emergent SAEs, 
ADRs, oedema events, other PTs of interest, treatment emergent UAEs, TEAEs leading to 
discontinuation, PTAEs, PTAEs leading to discontinuation, and pre-treatment SAEs.  In the case of 
the latter two, the summaries will not be produced if there are no PTAEs leading to discontinuation or 
pre-treatment SAEs, respectively.  For the ADR summary, if an ADR is reported more than once for a 
given subject, the worst-case attribution will be presented in the summary table. 
A comparison of TEAE rates between the amlodipine + celecoxib and amlodipine + placebo arms will 
be performed using an exact logistic regression model with the TEAE (“1”=At least one TEAE 
occurred for the patient; “0”=otherwise) as dependent variable and treatment (amlodipine + celecoxib 
and amlodipine + placebo) as fixed effects.  The probability modeled will be TEAE=”1”.  The number 
of patients and the number of patients considered in the model will be provided.  The exact odds ratio 
of the fixed effects will be calculated (amlodipine + celecoxib and amlodipine + placebo) with the 
relative 95% CI and p-value.  


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 45 of 190
 
 
The same model will be repeated by considering treatment-emergent SAE (“1”=At least one 
treatment-emergent SAE occurred for the patient; “0”=otherwise) as dependent variable, with the 
caveat that if no treatment-emergent SAEs are reported the table will not be produced. 
The rates of oedema events between the amlodipine + celecoxib arm and the amlodipine + placebo 
arm will be compared using an exact logistic regression and reporting the odds ratio.  Oedema event 
(1 = at least one TEAE with PT of oedema, oedema peripheral, peripheral swelling, swelling, or joint 
swelling occurring for the subject; 0 = otherwise) will be the dependent variable, and treatment 
(amlodipine + celecoxib and amlodipine + placebo) will be the fixed effects. 
The Fisher’s exact test will be run to compare the number of oedema events that occurred while on 
treatment (Day 0 to Day 14+1) and post-treatment (>Day 14+1) between treatment arms 1 and 2 
(amlodipine + celecoxib and amlodipine + placebo). 
Comprehensive physical examination 
Each protocol-specified organ or body system for the comprehensive physical examination will be 
summarized for the Safety population by a shift table presenting the number and the percentage of 
patients in each bivariate category (Initial Screening Visit versus Day 14) with regards to 
Investigator’s interpretation (normal, abnormal NCS, abnormal CS, not done, and missing) by 
treatment group. 
The results of targeted physical examination will be only listed. 
Body weight 
Body weight will be summarized for the Safety population by treatment group at each applicable visit 
(Initial Screening Visit, Day 0, Day 7 and Day 14) by descriptive statistics (n, mean, SD, median, and 
range).  In addition, at each visit after baseline, change from baseline will be calculated and 
summarized by descriptive statistics (n, mean, SD, median, and range).  Baseline will be Day 0 if 
available, otherwise, the Initial Screening Visit assessment will be used. 
A comparison between treatment groups with an ANCOVA model, with change from baseline to 
Day 14 as dependent variable, treatment as fixed effect and baseline as covariate.  A LOCF method of 
imputation will be applied for missing values.  The number of patients and the number of patients 
considered in the model will be provided by treatment.  P-values of the fixed effects and covariates 
will also be presented.  The adjusted means for treatments and the relative 95% CIs will be presented.  
The difference between the adjusted means of the three treatment groups will be calculated with the 
relative 95% CI and p value. 
Vital signs other than BP 
Pulse rate (beats/min), respiration rate (breaths/min), and oral body temperature (degrees Celsius) will 
be summarized for the Safety population by treatment group at each applicable visit (Initial Screening 
Visit, Day 0, Day 7, Day 14, and Day 28) by descriptive statistics (n, mean, SD, median, and range).  
In addition, at each visit after baseline, change from baseline will be calculated and summarized by 
descriptive statistics (n, mean, SD, median, and range).  Baseline will be Day 0 if available, otherwise, 
the Initial Screening Visit assessment will be used. 
Vital signs - BP 
Clinic visit average resting SBP and DBP (mmHg) will be summarized for the Safety population by 
treatment group at each applicable visit (Initial Screening Visit, Day 0, Day 7, Day 14, and Day 28) 
by descriptive statistics (n, mean, SD, median, and range).  In addition, at each visit after baseline, 
change from baseline will be calculated and summarized by descriptive statistics (n, mean, SD, 
median, and range).  Baseline will be Day 0 if available, otherwise, the Initial Screening Visit 
assessment will be used.   


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 46 of 190
 
 
For each variable (average resting SBP and DBP) a comparison between treatment groups will be 
performed with an ANCOVA model with change from baseline to Day 14 as dependent variable, 
treatment as fixed effect and baseline as covariate.  A LOCF method of imputation will be applied for 
missing values.  In the event there is no Day 14 measurement, the Day 7 measurement will be carried 
forward.  Baseline measurement is Day 0 (prior to study drug administration); however, in the event 
the Day 0 measurement is missing, the Initial Screening Visit measurement will be carried forward.  
The number of patients and the number of patients considered in the model will be provided by 
treatment.  The adjusted means for treatments and the relative 95% CIs and p values will be presented.  
The difference between the adjusted means of the three treatment groups will be calculated with the 
relative 95% CI and p-value. 
Continuous monitoring of BP 
SBPday, SBPnight, SBP24h, DBPday, DBPnight, and DBP24h (mmHg) will be summarized for the Safety 
population by treatment group at each applicable visit (Day -1 to Day 0, Day 6 to Day 7, and Day 13 
to Day 14) by descriptive statistics (n, mean, SD, median, and range).  In addition, at each visit after 
baseline, change from baseline will be calculated and summarized by descriptive statistics (n, mean, 
SD, median, and range).  Baseline will be Day -1 to Day 0. 
Orthostatic hypotension evaluation 
The orthostatic hypotension evaluation BP values will be summarized for the Safety population by 
treatment group at each applicable visit (Day 0, Day 7, and Day 14) by descriptive statistics (n, mean, 
SD, median, and range).  In addition, at each visit after baseline, change from baseline will be calculated 
and summarized by descriptive statistics (n, mean, SD, median, and range).  Baseline will be Day 0.  
The above analysis will be performed for each of the following: 
1. Average BP after 5 minutes rest in supine position (average of 3 recordings) 
a. SBP 
b. DBP 
2. BP 1 minute after standing 
a. SBP 
b. DBP 
3. BP 3 minutes after standing 
a. SBP 
b. DBP 
4. Difference between average BP after 5 minutes rest supine and BP 1 minute after standing 
a. SBP 
b. DBP 
5. Difference between average BP after 5 minutes rest supine and BP 3 minutes after standing 
a. SBP 
b. DBP 
Comparisons of the orthostatic hypotension BP measurements among treatment arms using ANCOVA 
will be presented for each of the above 5 parameters.  The change from baseline to Day 14 will be 
considered. 
The number and the percentage of patients with evidence of Orthostatic Hypotension (Yes, No, 
Missing) will be presented at each visit (Day 0, Day 7, and Day 14) by treatment group.  The Chi-
Squared/Fisher’s Exact test will be provided to test differences between arms. 
Laboratory parameters 
Hematology, chemistry and urinalysis (including urine microscopy) parameters will be summarized 
for the Safety population by treatment group at each applicable visit (Initial Screening Visit, Day 0*, 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 47 of 190
 
 
Day 7*, and Day 14) by descriptive statistics as appropriate (i.e., n, mean, SD, median, and range for 
continuous data and frequency for categorical data).  In addition, at each visit after baseline, change 
from baseline will be calculated and summarized for continuous data by descriptive statistics (n, 
mean, SD, median, and range).  Baseline will be Day 0 if available, otherwise, the Initial Screening 
Visit assessment will be used. 
*The laboratory parameters on Day 0 and Day 7 were limited to serum chemistry tests (i.e., no 
hematology or urinalysis), and further, the serum chemistry tests at Day 7 were limited to creatinine 
(and calculation of creatinine clearance) and electrolytes (sodium, bicarbonate, calcium, chloride, 
phosphorous, and potassium).     
Shift tables presenting the number and the percentage of patients in each bivariate category (Baseline 
versus Day 14) with regards to reference range (Low, Normal, High, missing) will be provided for all 
laboratory parameters by treatment group.  Baseline will be Day 0 if available, otherwise, the Initial 
Screening Visit assessment will be used.   
The laboratory reference range for assigning low “L” flags to the creatinine clearance results differed 
for the Celerion, Belfast laboratory (>90 mL/min) versus the centralized laboratory used for the 
remaining sites (ACM Global Central Laboratories; ≥ 60 mL/min).  The serum chemistry shift table 
analysis will be based on the laboratory assigned flags (i.e., no reassignment of the Celerion, Belfast 
laboratory flags based on the ACM laboratory reference range will be made).  The main body of the 
clinical study report will note the difference in the creatinine clearance reference range for the two 
laboratories and will note by treatment group any cases where a Celerion, Belfast low creatinine 
clearance value would be reassigned as Normal if the ≥ 60 mL/min criterion was used. 
For serum creatinine and BUN, comparisons between treatment groups will be performed with an 
ANCOVA model with change from baseline to Day 14 as dependent variable, treatment as fixed effect 
and baseline as covariate.  The number of patients and the number of patients considered in the model 
will be provided by treatment.  P-values of the fixed effects and covariates will also be presented.  The 
adjusted means for treatments and the relative 95% CIs will be presented.  The difference between the 
adjusted means of the three treatment groups will be calculated with the relative 95% CI and p-value. 
The primary comparison will be treatment group 1 compared to treatment group 2, and the key 
secondary comparison will be treatment group 1 compared to treatment group 3.  In these analyses, the 
null hypothesis will be that there is no statistically significant difference in the change in the measured 
blood parameter (serum creatinine or BUN) from baseline to the end of treatment between the two 
treatment groups.  Baseline will be Day 0 if available, otherwise, the Initial Screening Visit assessment 
will be used. 
The listings and summary tables will use the clinical laboratory test names as they appear in the Study 
Data Tabulation Model dataset files (i.e., the Clinical Data Interchange Standards Consortium 
compliant clinical laboratory test names).  Refer to “Note to File - Differences in Laboratory Test Names 
Between Testing Laboratory and Study Data Tabulation Model (SDTM) Files”, a copy of which is 
available in the Trial Master File. 
12-Lead ECG 
The 12-Lead ECG diagnoses will be summarized for the Safety population by a shift table presenting 
the number and the percentage of patients in each bivariate category (Initial Screening Visit versus 
Day 14) with regards to Investigator’s interpretation (Normal, Abnormal NCS, Abnormal CS, Not 
done) will be provided by treatment group. 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 48 of 190
 
 
7.10. 
Additional Analyses 
A set of additional analyses will be performed, which will include testing of pharmacokinetics, BP at 
peak and trough amlodipine concentrations, sensitivity analyses, exploratory and other efficacy 
analyses, and Investigational Site-specific analyses. 
Pharmacokinetics  
For the individual patient data listing of amlodipine plasma concentrations, all values below the 
LLOQ will be reported as BLQ, as in the bioanalytical report.  
Non-transformed amlodipine plasma concentration values at Day 14 will be summarized for the PK 
population by treatment group by descriptive statistics (n, mean, SD, median, and range).  A t-test will 
compare the non-transformed amlodipine plasma concentration values in those subjects who receive 
amlodipine tablets (10 mg) given alone (with matched celecoxib placebo) (arm 2) with those who 
receive amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together (arm 1).  A box 
plot of the non-transformed amlodipine plasma concentrations at Day 14 by treatment arm will be 
produced.  For these analyses, BLQ values will be treated as 0, and only treatment arms that included 
amlodipine will be included (i.e., the placebo + placebo arm will not be included). 
Log-transformed amlodipine plasma concentration values at Day 14 will be summarized for the PK 
population by treatment group by descriptive statistics (n, mean, SD, median, and range).  A t-test will 
compare the log-transformed amlodipine plasma concentration values in those subjects who receive 
amlodipine tablets (10 mg) given alone (with matched celecoxib placebo) (arm 2) with those who 
receive amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together (arm 1).  For these 
analyses, only treatment arms that included amlodipine will be included (i.e., the placebo + placebo 
arm will not be included). Further, all BLQ values will be treated as 0.04 ng/mL rather than 0.  Zero 
cannot be log-transformed.  Assignment of the BLQ values to a nonzero number will allow 
computation of the log transformation.  The selection of 0.04 ng/mL as the nonzero number for BLQ 
assignment was based on the LLOQ of the validated bioanalytical method (i.e., 0.05 ng/mL) and 
selecting the next lowest number at the hundredth decimal place. 
Peak and trough 
SBP and DBP at the expected peak and trough amlodipine concentrations will be summarized for the 
ITT population by treatment group at Day 6 and Day 13 by descriptive statistics (n, mean, SD, 
median, and range).  Additionally, the difference between Day 6 and Day 13 will be calculated and 
summarized by descriptive statistics (n, mean, SD, median, and range).   
For each variable (SBP peak, SBP trough, DBP peak, and DBP trough) a comparison between 
treatment groups will be performed with a two-sample t-test of the change from Day 6 to Day 13.  A 
LOCF method of imputation will not be applied for missing values. The p-value will be evaluated on 
a two-sided t-test.  
The trough BP (SBP and DBP) is the ambulatory BP measurement taken closest to the time of study 
drug administration on Study Day 6 or Day 13, respectively, that is also before the time of study drug 
administration that day.  If there is no ambulatory measurement prior to administration of study drug 
on Study Day 6 or Day 13, the first ambulatory measurement after study drug administration that day 
will be used as trough. 
The peak BP (SBP and DBP) is the ambulatory BP measurement taken closest to the time point 9 
hours after study drug is administered on Study Day 6 or Day 13, respectively, that is also before the 
time point 9 hours after the study drug is administered that day.  Based on the approved labeling for 
amlodipine besylate tablets, the expected peak time for amlodipine is 6 to 12 hours after the 
medication is administered, and thus the midway point (9 hours) was selected for this analysis. 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 49 of 190
 
 
Sensitivity analyses 
A sensitivity analysis will be conducted to insure the change in definition of the ITT population (see 
Section 1.3.2) does not impact the study conclusions.  A mITT population will be based on the 
definition originally presented as the ITT population in the protocol (valid Baseline and at least one 
valid follow-up ABPM measurement) and a second set of analyses will be conducted purely to 
demonstrate the definition does not have an impact on the primary and secondary efficacy analyses.  
The following analyses will be conducted: 
1. mITT for SBPday 
2. mITT for SBP24h 
3. mITT for DBP24h 
The impact of defining valid ABPM measurements based on valid daytime measurements for the 
efficacy analyses (see Section 1.3.1 for further detail) is that the analyses of the secondary ABPM 
efficacy parameters (SBP24h and DBP24h) and exploratory ABPM efficacy parameters (SBPnight and 
DBPnight) may include invalid measurements with respect to the 24-hour period (i.e., may not meet 
criterion d or e in Section 1.3.1) or night-time period (i.e., may not meet criterion d in Section 1.3.1), 
respectively.  It is anticipated that this will be a very small number of cases and will not impact the 
secondary and exploratory ABPM efficacy conclusions drawn.  Sensitivity analyses will be conducted 
to verify this point.  The following analyses will be conducted: 
1. ITT for SBP24h excluding SBP24h values that had an entry of valid for day validity and an 
entry of invalid for night or 24h validity (i.e., did not meet criterion d or e, respectively) 
2. ITT for DBP24h excluding DBP24h values that had an entry of valid for day validity and an 
entry of invalid for night or 24h validity (i.e., did not meet criterion d or e, respectively) 
3. ITT for SBPnight excluding SBPnight values that had an entry of valid for day validity and an 
entry of invalid for night validity (i.e., did not meet criterion d) 
4. ITT for DBPnight excluding DBPnight values that had an entry of valid for day validity and an 
entry of invalid for night validity (i.e., did not meet criterion d) 
To assess the impact of baseline, a further sensitivity analysis will be conducted on the primary 
endpoint (mean change of SBPday) using a regression model adjusted from Baseline on ITT, mITT, 
and PP populations. 
Exploratory efficacy analyses 
Exploratory efficacy analyses will include two-sample t-tests to test one-side hypotheses of 
superiority for pairwise comparisons between treatment arms 1 and 2, 1 and 3, and 2 and 3 for 
DBPday, SBPnight and DBPnight.   
Further, two-sample t-tests to test one-side hypotheses of superiority for pairwise comparisons 
between treatment arms 1 and 3 and 2 and 3 will be performed for SBPday, SBP24h, and DBP24h (the 
comparison of treatment arms 1 and 2 for these endpoints are covered separately under the respective 
primary and secondary efficacy analyses).   
All exploratory efficacy comparisons will be based on the mean reduction in BP from the baseline 
(Day -1 to Day 0) ABPM measurement to the Day 13 to Day 14 ABPM measurement (or if a LOCF 
was required, the Day 6 to Day 7 ABPM measurement).  The analyses will use the ITT data set 
including LOCF (and MMRM if possible) for subjects who were withdrawn from treatment early.  
Sensitivity analyses will be used to compare these results to those of the PP data set.   
Investigational Site-specific analyses 
An Investigational Site-specific summary tabulation for the Safety Population, including demographic 
characteristics (age, sex and race), Initial Screening Visit characteristics (height, weight, BMI, pulse 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 50 of 190
 
 
rate, respiration rate, oral body temperature, SBP left arm, SBP right arm, DPB left arm, DBP right 
arm, and ECG), and Baseline Day 0 characteristics (weight, SBP, and DBP) by treatment arm and 
overall will be presented.  The Day 0 SBP and DBP to be included in this table will be for the arm 
with the higher average resting SBP determined as part of the manual vital signs at the Initial 
Screening Visit.  Descriptive statistics will be generated as appropriate (i.e., n, mean, SD, median and 
range for continuous data and number and percentage of patients for categorical data). 
An Investigational Site-specific summary tabulation for the Safety Population, including SBPday, 
SBPnight, SBP24h, DBPday, DBPnight and DBP24h at baseline (Day -1 to Day 0) by treatment arm and 
overall will be presented.  The table will include pooled values (i.e., for all sites) as well.  Descriptive 
statistics will be generated (i.e., n, mean, SD, median and range).  
A summary tabulation for the ITT population, including the mean ± SD SBPday at baseline, end of 
study, and the change from baseline to end of study for the patients at Sites 301 (Queen Mary School 
of Medicine & Dentistry), 302 (Celerion, Belfast), 303 (Rowden Surgery), and 304 (Medicines 
Evaluation Unit), the four largest recruiting sites, and the patients at all remaining sites (pooled) by 
treatment arm will be presented as a means of evaluating the comparability of the primary efficacy 
endpoint across sites.  Pooling of data for 4 of the 8 sites (that randomized patients) will be done due 
to the small numbers of patients per treatment arm per Investigational Site.  The table will also 
include a row that includes the summary statistics for the whole ITT population (i.e., including all 
sites) for comparison. 
8. General Considerations 
8.1. 
Software to be used 
All statistical analyses and data processing will be performed using SAS version 9.4 or higher. 
8.2. 
Programs and Tables Quality Control 
The following procedures will be implemented as quality control measures: 
 
Double-blind programming, ensuring that the code gives the required output and the 
programming is in compliance with any applicable specifications from the analysis plan 
 
Check for errors and warning messages 
 
Check of the layout of the listings and tables 
 
Additionally, in the course of data collection eCRF data will be reviewed and queries raised if needed. 
9. Data Storage 
Relevant study documentation will be stored in the “Buncro” – private StatisticaMedica cloud hosted 
by Radix Technologies, in Kitov 302-03-02/Programming for the scripts and Kitov 302-03-02/Reports 
for the delivered documentation, in the corresponding subfolders for the SAP, TFLs and CSR.


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 51 of 190
 
 
Appendices 
Appendix A. ABPM Measurement Specifics 
ABPM Measurement Weighting 
Each measurement shall be weighted according to half the duration to the preceding measurement and 
half the duration to the succeeding measurement up to maxima of half the expected intervals as follows: 
Time of Day (in minutes) 
Max Preceding Weight 
Max Succeeding Weight 
09:00 to 09:20 (540 to 560) 
15 min 
10 min 
09:21 to 21:39 (550 to 1299) 
10 min 
10 min 
21:40 to 21:59 (1300 to 1319) 
10 min 
15 min 
22:00 to 08:59 (0 to 539 and 1320 to 1439) 
15 min 
15 min 
All statistics shall be based on weighted measurements. For daytime and night-time statistics, weights 
for the first measurements within the respective periods shall be truncated at the start of the period and 
weights for the last measurements within the respective periods shall be truncated at the end of the 
period. 
Hourly mean pressures shall be based on the weights of measurements occurring within the hour. Each 
hour shall be defined by “m \ 60”, where m is the number of minutes from midnight on the day the 
monitor is fitted and \ represents the quotient of the Euclidian division. (m ≡ (m \ 60) × 60 + m mod 60) 
ABPM Study Measurements 
A measurement shall be regarded as valid if it contains values for systolic blood pressure (SBP), 
diastolic blood pressure (DBP) and heart rate (HR) and 
SBP is between 50 mmHg and 300 mmHg. 
DBP is between 40 mmHg and 150 mmHg. 
Pulse pressure is between 10 mmHg and 150 mmHg. 
HR is between 40 bpm and 150 bpm. 
The first study measurement shall be  
The nearest valid measurement to the drug intake time on the day the monitor is fitted that is both a) 
between 07:00 and 10:00 and b) within 15 minutes of the drug intake time. 
If there is no valid measurement within this period, a 1-hour grace period is permitted. It is, therefore, 
the nearest valid measurement to the drug intake time on the day the monitor is fitted that is both a) 
between 06:00 and 11:00 and b) within 75 minutes of the drug intake time.  
If there is no valid measurement within this period, or if no drug intake time is recorded (e.g., Day-1), 
the first valid measurement recorded between 07:00 and 10:00.  
If there is no valid measurement within this period, the first valid measurement recorded between 06:00 
and 11:00. 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 52 of 190
 
 
If there is no valid measurement within this period, the nearest valid measurement to the drug intake 
time on the day the monitor is fitted, if that is recorded, or first valid measurement otherwise. 
Measurements recorded during the first hour, from the first study measurement, shall be regarded as 
white-coat window measurements. The period covered by these measurements defines the white-coat 
window. 
The last study measurements shall be  
The earliest valid measurement that is a) at least 25 h after the first study measurement b) at least 25 h 
after the drug intake time on the day the monitor is fitted and c) less than 25 h after the end of the white-
coat window  
If there is no valid measurement within this period, a 1-hour grace period is permitted. It is, therefore, 
the earliest valid measurement that is a) at least 24 h after the first study measurement b) at least 24 h 
after the drug intake time on the day the monitor is fitted and c) less than 26 h after the end of the white-
coat window 
If there is no valid measurement within this period, the latest measurement that is less than 26 h after 
the end of the white-coat window. 
Measurements before the first study measurement and measurements after the last study measurement 
shall be disregarded. 
Invalid measurements and measurements that result in an error shall not be regarded as study 
measurements. 
Measurements recorded during the white-coat window are not included in daytime, night-time and 24 h 
statistics. 
ABPM Validity 
An ABPM measurement shall be defined as valid overall if the data comply with the following criteria: 
The time of the first study measurement is between 07:00 and 10:00. 
The duration, from the first study measurement to the last study measurement, is at least 25 h 
(1500 min). 
There are at least 21 study measurements recorded during the standard daytime period (09:00 to 21:00) 
There are at least 8 study measurements recorded during the standard night-time period (01:00 to 06:00) 
There are at least 35 study measurements recorded after the white-coat window 
There are no more than 3 hours with a total measurement weight of less than 20 min and no more than 
2 consecutive hours with total measurement weights each of less than 20 min. 
For the purpose of defining the ITT, mITT, and PP populations, a visit measurement will be valid if the 
Daytime measurement is valid.   
 


Statistical Analysis Plan 
CONFIDENTIAL 
Date 20th April 2018 
KIT-302-03-02 
 
 
Draft4.0 
 
Page 53 of 190
 
 
An ABPM measurement shall be defined as valid within tolerance if the data comply with the following 
criteria: 
The time, of the first study measurement is between 06:00 and 11:00. 
The duration, from the first study measurement to the last study measurement, is at least 24 h 
(1440 min). 
There are at least 20 study measurements recorded during the standard daytime period (09:00 to 21:00) 
There are at least 7 study measurements recorded during the standard night-time period (01:00 to 06:00) 
There are at least 34 study measurements recorded after the white-coat window 
There are no more than 3 hours with a total measurement weight of less than 20 min and no more than 
2 consecutive hours with total measurement weights each of less than 20 min. 
An ABPM measurement shall be defined as invalid if it is not valid within tolerance. 
ABPM Statistics 
Average 24-hour, daytime and night-time pressures are calculated as 
,
,
,
,
LSM
r i
p i
i FSM
p r
LSM
p i
i FSM
v w
v
w





 
where 
r 
is SBP or DBP 
p 
is 24-hour, daytime or night-time 
vr,i 
is the SBP or DBP for measurement i 
wp,i 
is the weight of the measurement for period p, zero if the measurement does not belong to that 
period 
FSM 
is the first study measurement 
LSM 
is the last study measurement 
2) 
The SDs are calculated as 
2
2
,
,
,
,
,
,
1
LSM
LSM
r i
p i
p r
p i
i FSM
i FSM
p r
LSM
p
p i
p
i FSM
v w
v
w
s
M
w
M









 
where Mp 
is the number of non-zero weighted measurements in period p