Celebrex Capsules

**(Celecoxib)**

# NDA 20-998/S-009 {#nda-20-998s-009 .unnumbered}

# Medical Officer Review {#medical-officer-review .unnumbered}

**Submission Date:** June 12, 2000

**Received Date:** June 14, 2000

**Review Date:** September 20, 2000

**Drug Name:** Celebrex

**Generic Name:** celecoxib

**Chemical Name:**
4-\[5-(4-methylphenyl)-3-trifluoromethyl)-1H-pyrazol-1-yl\]
benzenesulfonamide

**Applicant:** G.D. Searle & Co.

**Related Reviews:** Statistics, Cardio-Renal, Gastrointestinal
(HFD-550)

**Pharmacologic category:** COX-2 inhibitor

**Proposed Indication:** Label changes

-Warnings (Clinically Significant UGI Events)

**Dosage forms and route:** Oral capsule, 100 and 200 mg

**Submission type:** Supplemental NDA

**Materials Reviewed:** Primary-document N49-00-06-035_102

Orig NDA \# 20-998

HFD-550/Div File

HFD-550/PM/Kong

HFD-550/Pharm/Yang
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

HFD-550/Chem/Bhavnagri (James Witter, M.D., Ph.D. Medical Officer)

HFD-550/Biopharm/Bashaw

HFD-550/Statistics/Lin

HFD-550/MO/Witter/Goldkind

### **Celecoxib** {#celecoxib .unnumbered}

# NDA \# 20-998 /S-009

# Table of Contents

**Listing of sNDA Review
Tables.....................................................................................................3**

**Celecoxib Executive
Summary......................................................................................................**

**Background and
Overview....................................................................\.......................................5**

**Clinical (CLASS)
Study..............................................................................................................7**

**Study
Design.................................................................................................................8**

**Protocol...................................................................................................\.........9**

**Endpoints........................................................................................................14**

**Statistical
Considerations.....................................................................................19**

**Study
Results............................................................................................................\...23**

**Patient
Disposition.......................................................................................\.......23**

**Endpoint (CSUGIE)
results........................................................................\.........\...28**

**Censored Events/Informative
Censoring...............................................................\...35**

#########  Endpoint (CSUGIE/GDU) results...........................................................................41 {#endpoint-csugiegdu-results...41 .unnumbered}

**Summary of GI
results.................................................................................\........47**

**Arthritis Efficacy and
QOL..................................................................................50**

**Overview of
Safety..................................................................................................................54**

**Deaths.............................................\...............................................................54**

**Serious Adverse
Events/Withdrawal...........................\.............................................56**

**Adverse
Events.................................................................................................57**

**Clinical Laboratory
Evaluations............................................................................60**

**Gastrointestinal
Effects......................................................................................63**

**Renal
Effects................................................................................................\...66**

**Vascular
Effects..............................................................................................67**

**Hepatobiliary
Effects........................................................................................70**

**Dermatologic
Effects.........................................................................................71**

**Other
Effects...................................................................................................73**

**Discussion of
CLASS...............................................................................................................74**

**Conclusions...........................................................................................................................82**

**Labeling
Review.......................................................................................................................**

**Appendix..............................................................................................................................84**

**[Listing of Celecoxib sNDA (20-998) Review Tables]{.underline}**

**Table 1: Table 1: Schedule of Observations and
Procedures............................................................11**

**Table 2: Algorithm for Work-up of Suspected
CSUGIEs................................................................17**

Table 3: Patient Disposition-First Six Months and Entire Study
Period...............................................24

Table 4: Treatment Duration-First Six Months and Entire
Study......................................................25

**Table 5: Baseline demographic characteristics-ITT
cohort...............................................................27**

**Table 6: Distribution of CSUGIEs: Traditional Definitions -First Six
Months........................................29**

**Table 7: CSUGIEs (Traditional-ITT)-First 6 months (Crude &
Kaplan-Meier rates)..............................30**

**Table 8: CSUGIEs without ASA (Traditional-ITT)-First 6 months (Crude &
Kaplan-Meier rates............\...30**

**Table 9: Distribution of CSUGIEs: Traditional Definitions --Entire
Study Period.................................\...31**

**Table 10: CSUGIEs (Traditional-ITT)-Entire Study (Crude & Kaplan-Meier
rates).................................32**

######### Table 11: CSUGIEs without ASA (Traditional-ITT)-Entire Study (Crude & Kaplan-Meier rates.................33 

**Table 12: CSUGIEs: Alternate Definitions-Entire Study
Period..........................................................34**

**Table 13: Summary of CSUGIE Incidence (Traditional definition) - First
Six Months (ITT).....................\...34**

**Table 14: Summary of CSUGIE Incidence (Traditional definition) -
Entire Study Period (ITT)....................35**

**Table 15: Reasons for Censoring of CSUGIEs - Entire Study
Period.....................................................36**

**Table 16: Univariate Analysis of Risk Factors for CSUGIEs and
CSUGIEs/GDUs....................................37**

**Table 17: Multivariate Analysis of Risk Factors for
CSUGIEs/GDUs....................................................37**

**Table 18: Number of CSUGIEs or CSUGIE/GDU by Number of Risk
Factors........................................38**

**Table 19: Number of CSUGIEs or CSUGIE/GDU by Treatment and Risk
Factors...................................38**

**Table 20: Risk for CSUGIEs and CSUGIEs/GDUs in Patients With/Without
GI Symptoms.................,,,,,,,,,,39**

**Table 21: Adverse Events Causing Withdrawal with Incidence ≥1%: Entire
Study Period..........................39**

**Table 22: Incidence of Withdrawal for Moderate to Severe GI adverse
events.........................................40**

**Table 23: CSUGIE ± GDU rates and relative risks with/without 5 GI
symptoms......................................40**

**Table 24: Crude Incidence Rates for CSUGIEs ± GDUs Adjusted for GI
Withdrawals..............................41**

**Table 25: Distribution of CSUGIEs/GDU: Traditional Definitions --First
Six Months..............................\...42**

**Table 26: Summary of CSGUIE/GDU Incidence -- First Six
Months...................................................\...43**

**Table 27: CSUGIEs/GDU-First 6 months (Crude & Kaplan-Meier
rates................................................43**

**Table 28: CSUGIEs/GDU-First 6 months without ASA (Crude & Kaplan-Meier
rates-ITT).....................\...44**

**Table 29: Distribution of CSUGIEs/GDU: Traditional Definitions
--Entire Study.....................................45**

**Table 30: Summary of CSGUIE/GDU Incidence (Traditional Definitions) --
Entire Study........................\...46**

**Table 31: CSUGIEs/GDU-Entire Study-ITT (Crude & Kaplan-Meier
rates)...........................................46**

**Table 32: CSUGIEs/GDU-Entire Study without ASA-ITT (Crude &
Kaplan-Meier rates)..........................47**

**Table 33: Overall summary of log-rank p-values (CSUGIEs and
CSUGIES/GDU-ITT).............................49**

**Table 34: Summary of Patient's Global Assessment
Results...............................................................50**

**Table 35: Patient's Assessment of Arthritis Pain --
VAS.....................................................................51**

**Table 36: HAQ-Observed Means, Least Square Means and 95% Confidence
Intervals..............................52**

**Table 37: Summary of Results in Selected SF-36 Health Survey
Domains...............................................52**

**Table 38: Summary of Deaths-Entire Study or within 28 days of
Treatment...........................................54**

**Table 39: Summary of Deaths Occurring more than 28 days after
Treatment.......................................\...55**

**Table 40: Adverse Events Causing Withdrawal (Incidence \>1% ) in Any
Treatment Group-Entire Study......56**

**Table 41: Summary of Serious Adverse Events-Entire Study
Period.....................................................57**

**Table 42: Adverse Events with Incidence ≥3%- Entire Study
Period.....................................................58**

**Table 43: Adverse Events with ≥2% Incidence in Any Interval After the
First 90 days..............................59**

**Table 44: Mean Changes from Baseline to Final Visit in Laboratory
Values...........................................60**

**Table 45: Analysis of Extreme Laboratory Test Values: Entire Study
Period..........................................61**

**Table 46: Summary of Hemoglobin/Hematocrit Contingency Tables: Entire
Study Period..........................62**

**Table 47: Summary of Hepatobiliary and Renal Contingency Tables:
Entire Study..................................63**

**Table 48: Summary of GI Adverse Events by Time
Interval...............................................................64**

**Table 49: Summary of GI Adverse Events by Aspirin Use-Entire
Study.................................................65**

**Table 50: Selected Adverse Events Relating to Renal Function: Entire
Study Period.................................66**

**Table 51: Mean Changes from Baseline to Final Visit/Extreme Values in
Specific Renal Laboratory Values....67**

**Table 52: Incidences of Cardiac/Noncardiac Vascular Adverse Events:
Entire Study Period.....................\...67**

**Table 53: Incidences of Cardiac/Noncardiac Vascular Adverse Events
(Aspirin Use): Entire Study...............68**

**Table 54: Selected Cardiac Adverse Events Reported During CLASS
According to ASA Use......................69**

**Table 55: Serious Adverse Events per 100 Pt-Yrs Reported During CLASS
by ASA Use............................70**

**Table 56: Adverse Events and Laboratory Values Related to Hepatic
Function: Entire Study......................71**

**Table 57: Characteristics of Rash and Pruritus Among the Three
Treatment Groups................................72**

**[Clinical Background (Section 6):]{.underline}**

**Relevant Human Experience (Section 6.1):**

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat
chronic arthritic diseases such as osteoarthritis (OA) and rheumatoid
arthritis (RA). An important mechanism through which these agents are
thought to act is via inhibition of the enzyme cyclooxygenase (COX).
This enzyme is now known to exist in two isoforms: a mostly constitutive
form (COX-1) and a mostly inducible form (COX-2). However, it is now
appreciated that COX-2 can also be constitutively expressed in certain
areas in the body. COX-1 is thought to be widely distributed throughout
most body tissues and mediates synthesis of prostaglandins that have a
diverse array of homeostatic physiological functions. One of these
important functions is thought to include the maintenance of mucosal
integrity in the upper gastrointestinal (UGI) tract. In contrast, COX-2
in most areas of the body, is thought to be expressed in low levels in
tissues but is rapidly and highly induced at sites of inflammation.

Since "traditional" NSAIDs nonspecifically inhibit both COX isoforms, it
has been postulated that their anti-inflammatory and analgesic benefits
result from inhibition of COX-2 while the increased rate of UGI ulcers
and complications commonly associated with NSAIDs result from inhibition
of COX-1. The principal manifestations of ulcer complications are UGI
bleeding, perforation, and gastric outlet obstruction. The UGI toxicity
of NSAIDs has been well documented. For example, observational analysis
of the Arthritis, Rheumatism, and Aging Medical Information System
(ARAMIS) database suggests that in a large population receiving NSAIDs
over 10,600 patient-years, GI-related hospitalizations or deaths
occurred at a rate of 1.3% per year. Most studies in this area, such as
the one cited, have been observational cohort or retrospective
case-control studies. In the only large, randomized, prospective trial
of NSAID-related UGI ulcer complications (the MUCOSA trial), the
annualized incidence was approximately 1.9% in 8843 RA patients followed
for six months; the risk of UGI ulcer complications did not seem to
diminish with continuing exposure.

This risk of UGI complications noted for NSAIDs resulted in the
formation of a GI paragraph which has been included in the labeling of
approved NSAIDs. The current labeling for Celebrex is as follows:

***WARNINGS***

***Gastrointestinal (GI) Effects- Risk of GI Ulceration, Bleeding, and
Perforation:***

*Serious gastrointestinal toxicity such as bleeding, ulceration, and
perforation of the stomach, small intestine or large intestine, can
occur at any time, with or without warning symptoms, in patients treated
with nonsteroidal anti‑inflammatory drugs (NSAIDs). Minor upper
gastrointestinal problems, such as dyspepsia, are common and may also
occur at any time during NSAID therapy. Therefore, physicians and
patients should remain alert for ulceration and bleeding, even in the
absence of previous GI tract symptoms. Patients should be informed about
the signs and/or symptoms of serious GI toxicity and the steps to take
if they occur. The utility of periodic laboratory monitoring has not
been demonstrated, nor has it been adequately assessed. Only one in five
patients, who develop a serious upper GI adverse event on NSAID therapy,
is symptomatic. It has been demonstrated that upper GI ulcers, gross
bleeding or perforation, caused by NSAIDs, appear to occur in
approximately 1% of patients treated for 3-6 months, and in about 2-4%
of patients treated for one year. These trends continue thus, increasing
the likelihood of developing a serious GI event at some time during the
course of therapy. However, even short-term therapy is not without
risk.*

*It is unclear, at the present time, how the above rates apply to
CELEBREX. (See CLINICAL STUDIES-Special Studies.) Among 5285 patients
who received CELEBREX in studies of 1 to 6 months duration, at a daily
dose of 200 mg or more in controlled clinical trials, 2 (0.04%)
experienced significant upper GI bleeding at 14 and **22** days after
initiation of dosing. Approximately **40%** of these 5285 patients were
in studies that required them to be free of ulcers by endoscopy at study
entry. (Thus this study population may have been at lower risk for
significant gastrointestinal complications**.**) **Thus it is unclear if
this study is representative of the general population.** Prospective,
long-term studies required to compare the occurrence of serious
clinically significant upper GI adverse events in patients taking
CELEBREX vs. comparator NSAID products have not been performed.*

*NSAIDs should be prescribed with extreme caution in those with a prior
history of ulcer disease or gastrointestinal bleeding. Most spontaneous
reports of fatal GI events are in elderly or debilitated patients and
therefore special care should be taken in treating this population. **To
minimize the potential risk for an adverse GI event, the lowest
effective dose should be used for the shortest possible duration.** For
high risk patients, alternate therapies that do not involve NSAIDs
should be considered.*

*Studies have shown that patients with a prior history of peptic ulcer
disease and/or gastrointestinal bleeding and who use NSAIDs, have a
greater than 10-fold **higher** risk for developing a GI bleed than
patients with neither of these risk factors. In addition to a past
history of ulcer disease, pharmacoepidemiological studies have
identified several other co-therapies or co-morbid conditions that may
increase the risk for GI bleeding such as: treatment with oral
corticosteroids, treatment with anticoagulants, longer duration of NSAID
therapy, smoking, alcoholism, older age, and poor general health
status.*

An important hypothesis for development of selective inhibitors of COX-2
has been that they, by avoiding inhibition of COX-1, would spare the UGI
tract toxicity while maintaining analgesic and anti-inflammatory
efficacy. A corollary to this has been the impression that COX-2 agents
may also be safer, overall, as compared to traditional NSAIDs. The
original NDA for Celebrex included data on endoscopically-defined UGI
endpoints, but insufficient data on clinical UGI outcomes to allow for
any substantial modification of the GI Warning paragraph. **This sNDA,
which consists basically of two large safety studies (protocols
N49-98-02-035 and N49-98-02-102), seeks to address primarily the UGI
clinical outcomes of celecoxib, a COX-2 selective agent, as compared to
more traditional NSAIDs.** In particular, the incidence of clinically
significant UGI events (CSUGIEs) associated with celecoxib was compared
to that associated with ibuprofen or diclofenac during chronic
administration (at least six months) in patients with OA or RA. The term
"CSUGIE" represents a composite end point comprised of UGI bleeding,
perforation, or gastric outlet obstruction. It should be noted that
these companion protocols were prospectively designed with the intent to
combine the results into a single study, pooling the celecoxib patients
from both protocols into a single treatment group.

**[Clinical Studies (section 8):]{.underline}**

This sNDA consists of two trials, N49-98-02-035 and N49-98-02-102. Owing
to the similar nature of these trials, they will be described together
with any important differences noted.

These two trials were submitted as a combined document
(N49-00-06-035-102) entitled,

***"A multicenter, double-blind, parallel group study comparing the
incidence of clinically significant upper gastrointestinal events
between Celecoxib 400 mg BID and Ibuprofen 800 mg TID or Diclofenac 75
mg BID : The Celecoxib Long-Term Arthritis Safety Study (CLASS)"***

This study was conducted in compliance with **two protocols**:

(1) **Protocol N49-98-02-035**, entitled "A Multicenter, Double-Blind,
    Parallel Group Study Comparing the Incidence of Clinically
    Significant Upper Gastrointestinal Adverse Events Associated with
    SC-58635 400 mg BID to that of NSAID Treatment with Either
    Diclofenac 75 mg BID, Ibuprofen 800 mg TID or Naproxen 500 mg BID in
    Patients with Osteoarthritis or Rheumatoid Arthritis," dated 26
    January 1998

> \(2\) **Protocol N49-98-02-102**, entitled "A Multicenter,
> Double-Blind, Parallel Study       Comparing the Incidence of
> Clinically Significant Upper Gastrointestinal Adverse       Events
> Associated with SC-58635 400 mg BID to that of Diclofenac 75 mg BID
> and       Naproxen 500 mg BID in Patients with Osteoarthritis or
> Rheumatoid Arthritis,"       dated 24 August 1998.

There were a total of **eight amendments or administrative changes to
these two protocols**, described below. All of these changes were
implemented while all patients' treatment assignments remained blinded.

-   **Amendment No. 1 to N49-98-02-035, dated 16 July 1998, removed
    naproxen**

> **and diclofenac as NSAID comparators from the study; modified
> required**
>
> **laboratory testing; added a recommended algorithm for working up a
> suspected**
>
> **CSUGIE; and changed the clinical and medical monitors from Kenneth
> M.**
>
> **Verburg, PhD, and Richard C. Hubbard, MD, to David A. Callison, MS,
> and**
>
> **James B. Lefkowith, MD, respectively.**

-   **Amendment No. 2 to N49-98-02-035, dated 18 August 1998, reduced
    the**

> **sample size required for the study from 6000 patients to 4000
> patients, and**
>
> **specified that in the primary analysis, the celecoxib patients from
> the two**
>
> **companion studies would be pooled into a single treatment group.**

-   **Amendment No. 1 to N49-98-02-102, dated 26 October 1998, removed**

> **naproxen as an NSAID comparator from the study; added to the
> required**
>
> **laboratory testing; clarified the definition of UGI bleeding and the
> algorithm for**
>
> **working up a suspected CSUGIE; expanded the planned statistical
> analysis and**
>
> **interim analysis; and expanded the recording of alcohol and tobacco
> use.**

-   **Amendment No. 3 to N49-98-02-035, dated 9 November 1998, added to
    the**

> **required laboratory testing; clarified the definition of UGI
> bleeding and the**
>
> **algorithm for working up a suspected CSUGIE; expanded the planned
> statistical**
>
> **analysis and interim analysis; and expanded the recording of alcohol
> and**
>
> **tobacco use.**

-   **Amendment No. 4 to N49-98-02-035, dated 6 July 1999, lengthened
    the study**

> **period by up to an additional three months, in order to reach the
> target number**
>
> **of CSUGIEs; and amended the phrase "ulcer or erosion" to "ulcer or
> large**
>
> **erosion" in the traditional and alternate definitions of UGI
> bleeding.**

-   **Administrative Change No. 1 to N49-98-02-035, dated 4 August 1999,
    corrected one CRF.**

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-   **Administrative Change No. 1 to N49-98-02-102, dated 23 November
    1999,**

> **changed and clarified censoring rules for CSUGIEs; amended the
> phrase "ulcer**
>
> **or erosion" to "ulcer or large erosion" in the traditional and
> alternate definitions**
>
> **of UGI bleeding; and changed the clinical monitor from Mary Lonien,
> MS, to T.**
>
> **Kirsten Kätz, BA, and the statistician from Shawn Yu, PhD, to
> William Zhao, PhD.**

-   **Administrative Change No. 2 to N49-98-02-035, dated 24 November
    1999,**

> **changed and clarified the censoring rules for analysis of CSUGIEs.**

The two protocols were originally planned to continue until the
following criteria were fulfilled: (1) each patient had the opportunity
to remain in the study for at least 26 weeks, and (2) at least 20
CSUGIEs occurred in each protocol, or a maximum of 45 CSUGIEs occurred
in the two protocols combined. As of September 15, 1999, all patients
had had the opportunity to participate for at least 26 weeks. As of
November 24, 1999, a total of 40 CSUGIEs had been identified. Of these,
36 would be included in the analyses after application of the censoring
rules (17 in protocol N49-98-02-035 and 19 in protocol N49-98-02-102).
At that time, it was argued that the rate of CSUGIE development had
deviated considerably from the predicted rate of approximately one per
month. In protocol N49-98-02-035, no events had occurred in the previous
three months, and in protocol N49-98-02-102, only a single event had
occurred in the previous two months. It was considered unlikely that the
above criteria for study discontinuation would be met within the
following six months. Therefore, in consultation with the Executive
Committee, the GEC, and the Data Safety

Monitoring Board, as well as with FDA, the Sponsor decided to conclude
both protocols. All investigative sites were notified of this decision
on December 9,1999, and asked to schedule final visits for all remaining
patients to take place by January 7, 2000.

**The Sponsor's rationale for modifying the analyses of UGI safety
results by separately considering the first six months and the entire
study period** was as follows. Six months of exposure were felt to
represent a clinically meaningful exposure for a comparison of GI safety
end points and could be compared to available data from the only
prospective, controlled, published trial (i.e. MUCOSA) noted earlier.
Additionally, disproportionate withdrawal of patients with
NSAID-associated risk factors was observed over the first six months of
the study, and may have artificially decreased the observed rate of
clinically significant events in the NSAID groups after six months
(i.e., depletion of susceptible patients). The issue of unbalanced
withdrawal of patients with NSAID-associated risk factors prompted the
sponsor to discuss an adjustment for "informative censoring" for risk
factor analysis (see page 35 of section 8.1.1.4.2 for details regarding
informative censoring).

**Study Objective (Section 8.1.1.1):**

The Sponsor primarily is seeking modification of the GI Warning
paragraph.

**Study Design (Section 8.1.1.2):**

This combined study was a Phase 3B/4, randomized, controlled, parallel,
double-blind, multicenter (386 Investigators at 386 Study Sites in the
United States and Canada) study conducted from September 23, 1998 -
March 17, 2000.

**Protocol (Section 8.1.1.3):**

**Population, procedures (Section 8.1.1.3.1)**

Patients were randomly assigned to receive either celecoxib or the
comparator NSAID (ibuprofen 800 mg TID in protocol N49-98-02-035 or
diclofenac 75 mg BID in protocol N49-98-02-102) in a balanced
randomization that was stratified by OA/RA status. Patients for
inclusion or exclusion were selected according to the criteria noted
below. Total combined enrollment was planned to reach approximately 4000
patients receiving celecoxib and 2000 patients receiving each NSAID
comparator, for a total of 8000 patients.

###### **Inclusion Criteria:**

To qualify for study participation, candidates must have:

1\. Been of legal age of consent or older;

2\. For women of childbearing potential, had been using adequate
contraception

since last menses and agreed to continue to use adequate contraception
during

the study, not been lactating, and had a negative serum pregnancy test
within

seven days before receiving the first dose of study medication;

3\. Had a documented clinical diagnosis of OA or RA of at least three
months duration;

4\. Required chronic NSAID therapy in the Investigator's opinion;

5\. Been expected to be able to participate for the full duration of the
study; and

6\. Provided written informed consent.

###### **Exclusion Criteria:**

Candidates were excluded from participation if they satisfied any of the
following:

1.  Had an active malignancy of any type or history of malignancy.
    (Patients who

> had a history of basal cell carcinoma that had been treated were
> acceptable.

Patients with a history of other malignancies that had been surgically
removed

and who had no evidence of recurrence for at least five years before
study

enrollment were also acceptable.);

2\. Had been diagnosed as having or had received treatment for
esophageal, gastric,

pyloric channel, or duodenal ulceration within 30 days prior to
receiving the

first dose of study medication;

3\. Had active GI disease (e.g., inflammatory bowel disease);

4\. Had a history of gastric or duodenal surgery other than simple
oversew of an

ulcer or perforation;

5\. Had significant renal or hepatic dysfunction, or a significant
coagulation defect

considered by the Investigator to be clinically significant;

6\. Had abnormal Screening laboratory test values \>1.5 times the upper
limit of

normal (ULN) for either AST or ALT or any other laboratory abnormality
at

screening considered by the Investigator to be clinically significant;

7\. Had a positive screening fecal occult blood test result;

8\. Had a known hypersensitivity to COX-2 inhibitors, sulfonamides,
ibuprofen

(protocol-035) or diclofenac (protocol-102);

9\. Had received any investigational medication within 30 days before
the first dose

of study medication or was scheduled to receive an investigational drug
other

than celecoxib during the course of the study;

10\. Had previously been admitted to either of these protocols or a
prior study with

celecoxib.

**[Selection of Doses in the Study:]{.underline}**

For relief of the signs and symptoms of OA, the recommended, labeled
dose of celecoxib is

200 mg per day administered as a single dose or as 100 mg BID; for
relief of the signs and symptoms of RA in adults, the recommended dose
is 100 to 200 mg BID. The dose of celecoxib evaluated in this study, 400
mg BID, was therefore two to four times the maximum recommended doses
for RA and OA, respectively, and was chosen to ensure that the
ulcerogenic potential of celecoxib was rigorously assessed.

Ibuprofen and diclofenac are indicated for the treatment of RA and OA.
According to the prescribing information, the recommended dose of
ibuprofen is 1200-3200 mg/day for both OA and RA; the recommended doses
of diclofenac are 100-150 mg/day for OA and 150-200 mg/day for RA using
a BID or TID dosing regimen. On this basis, the ibuprofen dose of 800 mg
TID and the diclofenac dose of 75 mg BID were chosen for their
respective protocols. These represent the most commonly prescribed doses
of these two drugs for treating OA and RA.

Each protocol consisted of at least 26 weeks of treatment, with a
maximum potential treatment period of 52 weeks (study-102) or 65 weeks
(study-035). Patients underwent screening/baseline visits and follow-up
visits scheduled for 4, 13, 26, 39, and 52 weeks (and 65 weeks in
protocol -035 only) after the first dose of study medication. In
protocol-035, all patients were instructed to take two capsules from
bottle A (celecoxib 200 mg or placebo) and one tablet from bottle B
(ibuprofen or placebo) with their morning and evening meals, and one
tablet from bottle B only with their mid-day meal. In protocol-102, all
patients took two capsules from bottle A (celecoxib 200 mg or placebo)
and one tablet from bottle B (diclofenac 75 mg or placebo) with their
morning and evening meals. All patients and study personnel remained
blinded to each patient's treatment throughout the study.

The studies were planned to be conducted until at least 20 CSUGIEs
occurred in each protocol, or a maximum of 45 CSUGIEs occurred in the
two protocols combined. Minimum planned study participation for an
individual patient was 26 weeks. Occurrences of suspected CSUGIEs were
adjudicated and classified by an independent Gastrointestinal Events
Committee (GEC), all of the members of which were blinded to each
patient's study and treatment. The procedures performed in this combined
study are shown in **Table 1**.

Table 1: Schedule of Observations and Procedures

<table style="width:100%;">
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<col style="width: 24%" />
<col style="width: 9%" />
<col style="width: 10%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
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<tbody>
<tr class="odd">
<td></td>
<td colspan="2"><p><strong>Pretreatment Period</strong></p>
<p><strong>-7 to 0 Days</strong></p></td>
<td colspan="6"><p><strong>Treatment Period</strong></p>
<p><strong>Weeks ± Days</strong></p></td>
<td><p><strong>Final Visit</strong></p>
<p><strong>(b)</strong></p></td>
<td><p><strong>Early Term.</strong></p>
<p><strong>(c)</strong></p></td>
</tr>
<tr class="even">
<td></td>
<td>Screen</td>
<td>Baseline</td>
<td>4±5</td>
<td>13±5</td>
<td>26±5</td>
<td>39±5</td>
<td>52±5</td>
<td><p>65±5</p>
<p>(a)</p></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Informed Consent (d)</td>
<td><strong>X</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Medical History (L)</td>
<td><strong>X</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Physical Exam</td>
<td><strong>X</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
</tr>
<tr class="even">
<td>Clinical Lab Tests (e)</td>
<td><strong>X</strong></td>
<td></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
</tr>
<tr class="odd">
<td>Pregnancy Test (f)</td>
<td><strong>X</strong></td>
<td></td>
<td></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
</tr>
<tr class="even">
<td><p>Fecal Occult Blood</p>
<p>Testing (m)</p></td>
<td><strong>X</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
</tr>
<tr class="odd">
<td><p>D/C Current NSAID/</p>
<p>anti-ulcer drugs (g)</p></td>
<td></td>
<td><strong>X</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><p>Arthritis</p>
<p>Assessments (h)</p></td>
<td></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
</tr>
<tr class="odd">
<td>Signs and Symptoms</td>
<td></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
</tr>
<tr class="even">
<td><p>Indirect Cost</p>
<p>Assessment</p></td>
<td></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
</tr>
<tr class="odd">
<td><p>Patient Satisfaction</p>
<p>Questionnaire</p></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
</tr>
<tr class="even">
<td>QOL Assessments (i)</td>
<td></td>
<td><strong>X</strong></td>
<td></td>
<td></td>
<td><strong>X</strong></td>
<td></td>
<td></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
</tr>
<tr class="odd">
<td><p>Health Status</p>
<p>Assessments (j)</p></td>
<td></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td></td>
<td><strong>X</strong></td>
<td></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
</tr>
<tr class="even">
<td>Dispense Study Med</td>
<td></td>
<td><strong>X</strong></td>
<td><strong>X (k)</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X (a)</strong></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><p>Dispense Concurrent</p>
<p>Meds Diary Card</p></td>
<td></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X (a)</strong></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><p>Retrieve Concurrent</p>
<p>Meds Diary Card</p></td>
<td></td>
<td></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
</tr>
<tr class="odd">
<td><p>Retrieve and Count</p>
<p>Study Med</p></td>
<td></td>
<td></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
<td><strong>X</strong></td>
</tr>
</tbody>
</table>

\(a\) Protocol 035 only.

\(b\) The Final Treatment Visit coincided with the Week 65 visit in
protocol 035 or the Week 52 visit in protocol 102, or may have occurred
at any time when the study officially concluded.

\(c\) Patients terminating early were contacted monthly for two months
following their withdrawal or until the study officially concluded,
whichever occurred first.

\(d\) Informed consent was obtained before any study-related procedures
were performed.

\(e\) Clinical laboratory tests included: Hematology (WBC, hemoglobin,
hematocrit, platelet count, MCV, MCHC, ferritin, iron, iron binding
capacity; the latter five were performed after Screening only in the
event of new-onset anemia), and Biochemistry (BUN, creatinine, total
bilirubin, alkaline phosphatase, AST (SGOT), ALT (SGPT), creatine kinase
(CK), sodium, potassium, chloride, phosphorus, bicarbonate). At
Screening, serum FlexSure HP test for H. pylori status was also
performed.

\(f\) For females of childbearing potential only.

\(g\) Current NSAID and any anti-ulcer drugs were discontinued at or
before the Baseline Visit.

\(h\) Patient's Global Assessment of Arthritis and Patient\'s Assessment
of Arthritis Pain-VAS.

\(i\) Protocol 035 only. Consisted of SF-36 Health Survey and Health
Assessment Questionnaire (HAQ).

\(j\) Protocol 102 only. Consisted of Severity of Dyspepsia Assessment
(SODA).

\(k\) At the Week 4 visit, patients brought back the kit dispensed at
Baseline. Compliance was checked and the remaining medication from the
Baseline kit redispensed.

\(L\) The information gathered in the medical history included date of
birth, duration of OA or RA, duration of NSAID therapy, GI-related NSAID
intolerance (defined as any history of NSAID-induced gastroduodenal
ulcers, NSAID-induced erosive gastritis, or NSAID-induced UGI symptoms
of sufficient severity to discontinue NSAID use), history of UGI
bleeding, history of gastroduodenal ulcer disease (defined as a
diagnosis by UGI barium x-ray or endoscopy or treatment by a physician
for an ulcer diagnosed by

clinical judgment and based on reliable patient history), history of
cardiovascular disease, corticosteroid use, anticoagulant use, tobacco
use, and alcohol use.

\(m\) All patients were tested for *H. pylori* antibodies using FlexSure
HP serological testing.

At the end of the baseline visit, site personnel called the Interactive
Voice-activated Response System (IVRS) utilized to randomize the patient
into the study and receive the study medication allocation assignment.
Study medication and a diary card were then dispensed to the patient.
Patients returned to the study site at Weeks 4, 13, 26, 39, and 52 (and
Week 65 in protocol 035 only) after the first dose of study medication.
Study medication and concurrent medications diary cards were dispensed
at all visits except the final visit, and previously dispensed study
medication and completed diary cards were returned at each visit.
Patients were queried about their alcohol and tobacco use at the week 26
and final (or early termination) visits.

At the final (or early termination) visit, patients underwent a complete
physical examination, including weight and vital signs, and completed a
patient satisfaction questionnaire. This questionnaire incorporates four
questions regarding the patient's overall satisfaction with the efficacy
and tolerability of their study medication.

**[Other Endpoints:]{.underline}**

As noted in Table 1, the **arthritis assessments** consisted of a
patient's global assessment of arthritis and a patient\'s assessment of
arthritis pain. For the **patient's global assessment** of arthritis,
patients answered the question: "Considering all the ways your arthritis
affects you, how are you doing today?" Patients rated their condition
using the following 5-point scale:

> **1 Very Good - Asymptomatic and no limitation of normal activities**
>
> **2 Good - Mild symptoms and no limitation of normal activities**

####### 3 Fair - Moderate symptoms and limitation of some normal activities

> **4 Poor - Severe symptoms and inability to carry out most normal
> activities**
>
> **5 Very Poor - Very severe symptoms which are intolerable and
> inability to**
>
> **carry out all normal activities**

For the **patient's assessment of arthritis pain**, patients were asked
to rate their arthritis pain on a 100-mm visual analog scale (VAS)
between 0 (no pain) and 100 (most severe pain).

In protocol 035, Quality of Life (QOL) assessments consisted of the
**SF-36** health survey and the Health Assessment Questionnaire
Functional Disability Index **(HAQ**); both of these indices are widely
used in arthritis clinical trials. These two assessments were completed
before patients saw the investigator for arthritis assessments. The
SF-36 Health Survey is a generic QOL instrument incorporating 36 items
within eight domains: physical functioning, role-physical, bodily pain,
general health, vitality, social functioning, role-emotional, and mental
health. The HAQ assesses eight areas of daily function, each with two to
three activities. Patients indicated their ability to perform these
activities on a scale of 0 to 3, as follows: without any difficulty,
with some difficulty, with much difficulty, or unable to do,
respectively, including whether or not help from another person or use
of a device is required to perform these activities.

In protocol 102, patients completed the Severity of Dyspepsia Assessment
(**SODA**) questionnaire. This questionnaire was developed for
characterizing abdominal discomfort in a dyspepsia population, but is as
yet unvalidated in an arthritis population. Patients also completed an
**Indirect Cost Assessment** questionnaire at the baseline visit. This
instrument contains a series of questions about how arthritis or the
treatment of arthritis affects the patient's ability to work or carry
out daily activities.

For the QOL, SODA, and Indirect Cost measures, after the patient
completed the questionnaire, site personnel checked it for completeness.
If an answer to any question was missing, the patient was asked to
complete or clarify it.

Patients answered the following question during the visit: "**Do you
currently have any symptoms that are not associated with your
arthritis?**" (The information collected was used in the analyses of
adverse events.) In addition, patients were asked to list any medication
they had taken in the previous 30 days.

###### **Removal of Patients from Therapy or Assessment**

Patients who took study medication for the full scheduled treatment
period or were continuing to take study medication when the trial
officially concluded were considered to have completed the study.
Patients terminating study participation before completing the full
treatment period and before the trial officially concluded were
considered to have withdrawn. Reasons for withdrawal were classified as
follows:

· Lost to follow-up

· Preexisting violation of entry criteria

· Protocol noncompliance (failure to comply with the requirements of the

> protocol, e.g., failure to take at least 70% of the study medication
> in any 13-week dispensing interval)

· Treatment failure (arthritis signs and symptoms were not controlled)

· Adverse sign or symptom (including an ulcer found at an endoscopy).

Patients found to have a gastric or duodenal ulcer were required to be
withdrawn from the study and treated according to the clinical judgment
of the Investigator. Patients terminating early from the study were
contacted by telephone monthly for two months or until the official
conclusion of the study, whichever occurred first, to gather
pharmacoeconomic information as well as to determine if a CSUGIE had
occurred. What the sponsor considered reasonable attempts were made to
contact each patient.

**[Prior and Concomitant Therapy:]{.underline}**

No medications were prohibited prior to entering the study except the
use of any

investigational drug within 30 days prior to receiving the first dose.
Patients were instructed to avoid the use of any medication other than
the drugs provided, if at all possible, during the treatment period. The
following drugs were specifically

excluded:

-   NSAIDs, either prescription or nonprescription. (Patients taking ≤
    325 mg

> aspirin per day for reasons other than arthritis, for at least 30 days
> before the
>
> first dose of study medication, were allowed to continue the same dose
> regimen
>
> for the duration of the study.);

-   Anti-ulcer drugs (including H2 antagonists, proton pump inhibitors,
    sucralfate,

> and misoprostol), either prescription or nonprescription. Short-term
> use of
>
> antacids (up to seven days of more than one dose per day each month)
> and daily
>
> use of calcium-containing antacids as a calcium supplement (e.g., for
>
> osteoporosis) was permitted;

-   Antibiotics (i.e., amoxicillin, clarithromycin, azithromycin,
    tetracycline,

> metronidazole, or bismuth) used alone or combined with omeprazole,
>
> lansoprazole, or ranitidine specifically as treatment for *H. pylori*
> infection; and

-   Antineoplastics (other than methotrexate ≤ 25 mg/wk or azathioprine
    as

> treatment for RA).

Acetaminophen ≤ 2 g/day, alone or in combination with propoxyphene
hydrochloride or napsalate, hydromorphone hydrochloride, oxycodone
hydrochloride, or codeine phosphate) was permitted as necessary
throughout the study. Oral, intramuscular, and intra-articular
corticosteroids were also allowed.

Patients were instructed to record the drug name, dosage, regimen,
reason for therapy, and therapy dates of any concomitant therapy on the
concurrent medications diary card. The diary was reviewed with the
patient at each visit and the information transcribed onto the
appropriate CRF. Compliance was monitored by counting the number of
unused tablets or capsules.

At each follow-up visit, patients answered the following question:
"Since your last visit, have you experienced or do you currently have
any symptoms that are not associated with your arthritis?" If any sign
or symptom was suggestive, in the Investigator's opinion, of a CSUGIE
(i.e., bleeding, perforation, or gastric outlet obstruction, see section
8.1.1.3.2), the investigator called the CRO safety specialist
immediately and initiated work-up of the potential event according to
the algorithm (see section 8.1.1.3.2). Potentially suggestive signs or
symptoms included, but were not limited to, abdominal pain, protracted
nausea and vomiting, hematemesis, melena, and decreased hemoglobin or
hematocrit.

**Endpoints (Section 8.1.1.3.2)**

The **primary objective of the study** was to compare the incidence of
CSUGIEs (UGI bleeding, perforation, or gastric outlet obstruction) and
CSUGIEs combined with gastroduodenal ulcers (CSUGIEs/GDUs) associated
with celecoxib 400 mg BID to that associated with ibuprofen 800 mg TID
(protocol 035) or diclofenac 75 mg BID (protocol 102) in patients with
OA or RA.

The **secondary objectives of the study** were to:

1.  Compare the chronic overall safety and tolerability of celecoxib
    versus

> ibuprofen and diclofenac;

2.  Compare the effect of celecoxib versus ibuprofen and diclofenac on
    quality of

> life and patient satisfaction;

3.  Compare the effect of celecoxib versus ibuprofen and diclofenac on
    direct and

> indirect costs;

4.  Compare the chronic arthritis efficacy of celecoxib to that of
    ibuprofen and diclofenac;

5.  Evaluate potential risk factors (e.g., age, gender, *Helicobacter
    pylori \[H.*

> *pylor*i\] infection, type of arthritis, cardiovascular disease,
> concurrent use of
>
> oral corticosteroids, history of peptic ulcer and/or gastrointestinal
> bleeding,
>
> alcohol, tobacco, and aspirin use) for their impact on the effect of
> treatment on outcome.

# [UGI SAFETY EVALUATION]{.underline} {#ugi-safety-evaluation .unnumbered}

For the two end points of primary interest, namely **CSUGIEs**
(traditional definition) and CSUGIEs combined with gastroduodenal ulcers
(**CSUGIEs/GDUs**).

***Definitions of CSUGIEs***

Two differing sets of definitions of CSUGIEs were employed and used in
co-primary analyses; these are referred as "Traditional" and "Alternate"
definitions. Both sets of definitions were prospectively devised.

***Traditional Definitions***

The traditional definitions listed below were based on those used in the
MUCOSA trial and in the celecoxib NDA.

**UGI Bleeding** **(Category 1)**

Upper GI bleeding was categorized as one of the following seven
traditional clinical presentations:

-   Hematemesis with a gastric or duodenal ulcer or large erosion proven
    by

> endoscopy or a UGI barium x-ray **(category 1A)**;

-   A gastric or duodenal ulcer or large erosion proven by endoscopy
    with evidence

> of active bleeding or stigmata of a recent hemorrhage (visible vessel
> or attached
>
> clot to base of an ulcer) **(category 1B)**;

-   Melena with a gastric or duodenal ulcer or large erosion proven by
    endoscopy or

> barium UGI x-ray **(category 1C**);

-   Hemoccult-positive stools with a gastric or duodenal ulcer or large
    erosion

> proven by endoscopy or barium UGI x-ray and with bleeding as evidenced
> by a
>
> fall in hematocrit ≥5 percentage points or a reduction of hemoglobin
> of more
>
> than 1.5 g/dL from Baseline **(category 1D-1)**;

-   Hemoccult-positive stools with a gastric or duodenal ulcer or large
    erosion

> proven by endoscopy or barium UGI x-ray and with bleeding as evidenced
> both
>
> orthostasis (changes to postural vital signs: increase in pulse rate
> of ≥20
>
> beats/min and/or a decrease in systolic blood pressure of ³20 mm Hg
> and/or
>
> diastolic blood pressure of ≥10 mm Hg) **(category 1D-2**);

-   Hemoccult-positive stools with a gastric or duodenal ulcer or large
    erosion

> proven by endoscopy or barium UGI x-ray and with bleeding as evidenced
> by a
>
> need for blood transfusion of two or more units **(category 1D-3)**;
> or

-   Hemoccult-positive stools with a gastric or duodenal ulcer or large
    erosion

> proven by endoscopy or barium UGI x-ray and with bleeding as evidenced
> by
>
> blood in the stomach as determined by endoscopy or nasogastric
> aspiration
>
> **(category 1D-4)**.

UGI Perforation (Category 2)

Upper GI perforation was defined as an opening in the wall of the
stomach or duodenum requiring surgery, or laparoscopic repair but only
if the evidence is unequivocal (free air, peritoneal irritation signs,
etc.).

Gastric Outlet Obstruction (Category 3)

Occurrence of a gastric outlet obstruction was based on the opinion of
the clinician with endoscopic or UGI barium x-ray documentation.
Endoscopic evidence would include a tight edematous pylorus with an
ulcer in the pyloric channel, inability to pass the endoscope tip into
the duodenal bulb or descending duodenum, or retained fluid/food in the
stomach. UGI barium x-ray evidence of obstruction would include:

-   a dilated stomach;

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```
-   a slowly emptying stomach in a patient with clinical evidence of
    outlet

-   obstruction and in some instances with an ulcer in the channel or
    duodenal bulb; or

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-   severe narrowing and edema obstructing the outlet of the stomach.

***Alternate Definitions of Bleeding Events***

In the alternate set of definitions, the seven categories of UGI
bleeding events were redefined into four categories that incorporated
specific hemoglobin results and hypotension, as follows:

-   **Category 1E**: hematemesis with a gastric or duodenal ulcer or
    large erosion proven by endoscopy or a UGI barium x-ray, and

> -a drop in hemoglobin \>2 g/dL with adequate hydration or if urgent
> transfusion required, final hemoglobin (approximately 12-24 hours
> after the last urgent transfusion) pre-bleed hemoglobin (within
> assay variability) or
>
> -hypotension (defined as less than 90/60 mm Hg) or orthostatic
> hypotension;

-   **Category 1F**: a gastric or duodenal ulcer or large erosion proven
    by endoscopy with evidence of active

> bleeding or stigmata of a recent hemorrhage (visible vessel or
> attached clot to base of an ulcer) and
>
> -a drop in hemoglobin \>2 g/dL with adequate hydration or if urgent
> transfusion required, final hemoglobin (approximately 12-24 hours
> after the last urgent transfusion) pre-bleed hemoglobin (within
> assay variability) or
>
> -hypotension (defined as less than 90/60 mm Hg) or orthostatic
> hypotension;

-   **Category 1G**: melena with a gastric or duodenal ulcer or large
    erosion proven by endoscopy or barium UGI x-ray and

> -a drop in hemoglobin \>2 g/dL with adequate hydration or if urgent
> transfusion required, final hemoglobin (approximately 12-24 hours
> after the last urgent transfusion) pre-bleed hemoglobin (within
> assay variability) or
>
> -hypotension (defined as less than 90/60 mm Hg) or orthostatic
> hypotension;

-   **Category 1H**: Hemoccult positive stools with a gastric or
    duodenal ulcer or large erosion proven by endoscopy or UGI barium
    x-ray and

> -a drop in hemoglobin \>2 g/dL with adequate hydration or if urgent
> transfusion required, final hemoglobin (approximately 12-24 hours
> after the last urgent transfusion) pre-bleed hemoglobin (within
> assay variability) or
>
> -hypotension (defined as less than 90/60 mm Hg) or orthostatic
> hypotension.

Potential CSUGIEs, according to either set of definitions, were reviewed
and adjudicated by an independent Gastrointestinal Events Committee
(GEC) consisting of four expert gastroenterologists. In all of their
activities related to reviewing and adjudicating potential CSUGIEs, all
GEC members were blinded to all patients' study and treatment
assignments.

As noted before, if during a visit, there were any signs or symptoms
suggestive (in the investigator's opinion) of a CSUGIE, a work-up of the
potential event was initiated according to the algorithm shown in
**Table 2**. **Potentially suggestive signs or symptoms included (but
were not limited to) abdominal pain, protracted nausea and vomiting,
hematemesis, melena, and decreased hemoglobin or hematocrit**. Study
personnel were instructed that clinical judgment and the administration
of standard medical care should take precedence over the algorithm in
the evaluation and treatment of any patient in the study.

**Table 2: Algorithm for Work-up of Suspected CSUGIEs**

+-----------------+----+----------------+-----+-----------------------+
| *               |    | **Initial      |     | **Work-up**           |
| *Presentation** |    | Evaluation**   |     |                       |
+-----------------+----+----------------+-----+-----------------------+
| ##              |    |                |     |                       |
|                 |    |                |     |                       |
| #               |    |                |     |                       |
| # Clinical situ |    |                |     |                       |
| ations requirin |    |                |     |                       |
| g emergent or U |    |                |     |                       |
| RGENT attention |    |                |     |                       |
|                 |    |                |     |                       |
| **For all       |    |                |     |                       |
| patients with   |    |                |     |                       |
| the following   |    |                |     |                       |
| p               |    |                |     |                       |
| resentations:** |    |                |     |                       |
|                 |    |                |     |                       |
| -   **Obtain    |    |                |     |                       |
|     base data   |    |                |     |                       |
|                 |    |                |     |                       |
|    (hematocrit, |    |                |     |                       |
|     stool heme  |    |                |     |                       |
|     x3, and     |    |                |     |                       |
|     postural    |    |                |     |                       |
|     vital       |    |                |     |                       |
|     signs) as   |    |                |     |                       |
|     part of     |    |                |     |                       |
|     initial     |    |                |     |                       |
|                 |    |                |     |                       |
|   evaluation.** |    |                |     |                       |
|                 |    |                |     |                       |
| ```{=html}      |    |                |     |                       |
| <!-- -->        |    |                |     |                       |
| ```             |    |                |     |                       |
| -   **Test      |    |                |     |                       |
|     for H.      |    |                |     |                       |
|     pylori      |    |                |     |                       |
|     infection   |    |                |     |                       |
|     as part of  |    |                |     |                       |
|     work-up     |    |                |     |                       |
|     (Meretek    |    |                |     |                       |
|     UBT,        |    |                |     |                       |
|     CLOtest or  |    |                |     |                       |
|     H&E).**     |    |                |     |                       |
|                 |    |                |     |                       |
| ```{=html}      |    |                |     |                       |
| <!-- -->        |    |                |     |                       |
| ```             |    |                |     |                       |
| -   **Notify    |    |                |     |                       |
|     Searle      |    |                |     |                       |
|     medical     |    |                |     |                       |
|     monitor and |    |                |     |                       |
|     Kendle      |    |                |     |                       |
|     Safety      |    |                |     |                       |
|     Specialist  |    |                |     |                       |
|                 |    |                |     |                       |
|    immediately. |    |                |     |                       |
|     Provide     |    |                |     |                       |
|     contact     |    |                |     |                       |
|                 |    |                |     |                       |
|  information.** |    |                |     |                       |
|                 |    |                |     |                       |
| ```{=html}      |    |                |     |                       |
| <!-- -->        |    |                |     |                       |
| ```             |    |                |     |                       |
| -   **Complete  |    |                |     |                       |
|     GI event    |    |                |     |                       |
|     case report |    |                |     |                       |
|     forms       |    |                |     |                       |
|     (CRFs).**   |    |                |     |                       |
+-----------------+----+----------------+-----+-----------------------+
| Severe acute    | E  |                | -D  |                       |
| abdominal       | ME |                | ocu |                       |
|                 | RG |                | men |                       |
| pain/acute      | EN |                | tat |                       |
| abdomen         | T: |                | ion |                       |
|                 |    |                | of  |                       |
|                 | -  |                | pe  |                       |
|                 | Ev |                | rfo |                       |
|                 | al |                | rat |                       |
|                 | ua |                | ion |                       |
|                 | ti |                | by  |                       |
|                 | on |                | s   |                       |
|                 | f  |                | urg |                       |
|                 | or |                | ery |                       |
|                 | p  |                | or  |                       |
|                 | er |                | by  |                       |
|                 | fo |                | la  |                       |
|                 | ra |                | par |                       |
|                 | ti |                | osc |                       |
|                 | ng |                | opy |                       |
|                 | u  |                | w   |                       |
|                 | lc |                | ith |                       |
|                 | er |                | rad |                       |
|                 |    |                | iog |                       |
|                 | i  |                | rap |                       |
|                 | nc |                | hic |                       |
|                 | lu |                | ev  |                       |
|                 | di |                | ide |                       |
|                 | ng |                | nce |                       |
|                 | ba |                | of  |                       |
|                 | se |                | f   |                       |
|                 | da |                | ree |                       |
|                 | ta |                | air |                       |
|                 |    |                | in  |                       |
|                 |    |                | a   |                       |
|                 |    |                | bdo |                       |
|                 |    |                | men |                       |
|                 |    |                |     |                       |
|                 |    |                | \-  |                       |
|                 |    |                | T   |                       |
|                 |    |                | est |                       |
|                 |    |                | for |                       |
|                 |    |                | H.  |                       |
|                 |    |                | pyl |                       |
|                 |    |                | ori |                       |
|                 |    |                | inf |                       |
|                 |    |                | ect |                       |
|                 |    |                | ion |                       |
+-----------------+----+----------------+-----+-----------------------+
| Intractable     | E  |                | \-  |                       |
| abdominal pain  | ME |                | D   |                       |
| with            | RG |                | ocu |                       |
|                 | EN |                | men |                       |
| nausea/vomiting | T: |                | tat |                       |
|                 |    |                | ion |                       |
|                 | -  |                | of  |                       |
|                 | Ev |                | g   |                       |
|                 | al |                | ast |                       |
|                 | ua |                | ric |                       |
|                 | ti |                | out |                       |
|                 | on |                | let |                       |
|                 | f  |                | ob  |                       |
|                 | or |                | str |                       |
|                 | g  |                | uct |                       |
|                 | as |                | ion |                       |
|                 | tr |                | w   |                       |
|                 | ic |                | ith |                       |
|                 | ou |                | UGI |                       |
|                 | tl |                | st  |                       |
|                 | et |                | udy |                       |
|                 | o  |                | (   |                       |
|                 | bs |                | rad |                       |
|                 | tr |                | iog |                       |
|                 | uc |                | rap |                       |
|                 | ti |                | hic |                       |
|                 | on |                | or  |                       |
|                 | i  |                | en  |                       |
|                 | nc |                | dos |                       |
|                 | lu |                | cop |                       |
|                 | di |                | ic) |                       |
|                 | ng |                |     |                       |
|                 | ba |                | \-  |                       |
|                 | se |                | T   |                       |
|                 | da |                | est |                       |
|                 | ta |                | for |                       |
|                 |    |                | H.  |                       |
|                 |    |                | pyl |                       |
|                 |    |                | ori |                       |
|                 |    |                | inf |                       |
|                 |    |                | ect |                       |
|                 |    |                | ion |                       |
+-----------------+----+----------------+-----+-----------------------+
| Hematemesis or  | E  |                | \-  |                       |
| melena          | ME |                | D   |                       |
|                 | RG |                | ocu |                       |
|                 | EN |                | men |                       |
|                 | T: |                | tat |                       |
|                 |    |                | ion |                       |
|                 | -  |                | of  |                       |
|                 | Ev |                | bl  |                       |
|                 | al |                | eed |                       |
|                 | ua |                | ing |                       |
|                 | ti |                | sou |                       |
|                 | on |                | rce |                       |
|                 | f  |                | by  |                       |
|                 | or |                | UGI |                       |
|                 | GI |                | end |                       |
|                 | bl |                | osc |                       |
|                 | ee |                | opy |                       |
|                 | di |                | (t  |                       |
|                 | ng |                | est |                       |
|                 | so |                | for |                       |
|                 | ur |                | H.  |                       |
|                 | ce |                | pyl |                       |
|                 |    |                | ori |                       |
|                 | i  |                | i   |                       |
|                 | nc |                | nfe |                       |
|                 | lu |                | cti |                       |
|                 | di |                | on) |                       |
|                 | ng |                |     |                       |
|                 | ba |                | \-  |                       |
|                 | se |                | Lo  |                       |
|                 | da |                | wer |                       |
|                 | ta |                | GI  |                       |
|                 |    |                | w   |                       |
|                 |    |                | ork |                       |
|                 |    |                | -up |                       |
|                 |    |                | if  |                       |
|                 |    |                | bl  |                       |
|                 |    |                | eed |                       |
|                 |    |                | ing |                       |
|                 |    |                | sou |                       |
|                 |    |                | rce |                       |
|                 |    |                | unc |                       |
|                 |    |                | ert |                       |
|                 |    |                | ain |                       |
+-----------------+----+----------------+-----+-----------------------+
| Acute           | E  |                | \-  |                       |
| hypovole        | ME |                | If  |                       |
| mia/hypotension | RG |                | GI  |                       |
|                 | EN |                | e   |                       |
|                 | T: |                | val |                       |
|                 |    |                | uat |                       |
|                 | \- |                | ion |                       |
|                 | Ev |                | po  |                       |
|                 | al |                | sit |                       |
|                 | ua |                | ive |                       |
|                 | ti |                | (e. |                       |
|                 | on |                | g., |                       |
|                 | f  |                | bl  |                       |
|                 | or |                | ood |                       |
|                 | a  |                | in  |                       |
|                 | cu |                | na  |                       |
|                 | te |                | sog |                       |
|                 | GI |                | ast |                       |
|                 | b  |                | ric |                       |
|                 | lo |                | asp |                       |
|                 | od |                | ira |                       |
|                 | lo |                | te, |                       |
|                 | ss |                | h   |                       |
|                 | i  |                | eme |                       |
|                 | nc |                | po  |                       |
|                 | lu |                | sit |                       |
|                 | di |                | ive |                       |
|                 | ng |                | sto |                       |
|                 | ba |                | ol, |                       |
|                 | se |                | or  |                       |
|                 | da |                | h   |                       |
|                 | ta |                | ema |                       |
|                 |    |                | toc |                       |
|                 |    |                | rit |                       |
|                 |    |                | dec |                       |
|                 |    |                | rea |                       |
|                 |    |                | sed |                       |
|                 |    |                | by  |                       |
|                 |    |                | 5%  |                       |
|                 |    |                | or  |                       |
|                 |    |                |     |                       |
|                 |    |                | m   |                       |
|                 |    |                | ore |                       |
|                 |    |                | \   |                       |
|                 |    |                | [ab |                       |
|                 |    |                | sol |                       |
|                 |    |                | ute |                       |
|                 |    |                | c   |                       |
|                 |    |                | han |                       |
|                 |    |                | ge\ |                       |
|                 |    |                | ]), |                       |
|                 |    |                | in  |                       |
|                 |    |                | ves |                       |
|                 |    |                | tig |                       |
|                 |    |                | ate |                       |
|                 |    |                | sou |                       |
|                 |    |                | rce |                       |
|                 |    |                | w   |                       |
|                 |    |                | ith |                       |
|                 |    |                | UGI |                       |
|                 |    |                | end |                       |
|                 |    |                | osc |                       |
|                 |    |                | opy |                       |
|                 |    |                | (t  |                       |
|                 |    |                | est |                       |
|                 |    |                | for |                       |
|                 |    |                | H.  |                       |
|                 |    |                | pyl |                       |
|                 |    |                | ori |                       |
|                 |    |                | i   |                       |
|                 |    |                | nfe |                       |
|                 |    |                | cti |                       |
|                 |    |                | on) |                       |
|                 |    |                |     |                       |
|                 |    |                | \-  |                       |
|                 |    |                | Lo  |                       |
|                 |    |                | wer |                       |
|                 |    |                | GI  |                       |
|                 |    |                | w   |                       |
|                 |    |                | ork |                       |
|                 |    |                | -up |                       |
|                 |    |                | if  |                       |
|                 |    |                | bl  |                       |
|                 |    |                | eed |                       |
|                 |    |                | ing |                       |
|                 |    |                | sou |                       |
|                 |    |                | rce |                       |
|                 |    |                | unc |                       |
|                 |    |                | ert |                       |
|                 |    |                | ain |                       |
+-----------------+----+----------------+-----+-----------------------+
| Current/recent  | IM |                | -If |                       |
| (\<14 days)     | ME |                | any |                       |
|                 | DI |                | com |                       |
| history of:     | AT |                | pon |                       |
|                 | E: |                | ent |                       |
| \- melena       |    |                | of  |                       |
| (black tarry    | -  |                | w   |                       |
| stool) or       | Ob |                | ork |                       |
|                 | ta |                | -up |                       |
| \- black stool  | in |                | po  |                       |
| which is a      | ba |                | sit |                       |
|                 | se |                | ive |                       |
| change in       | da |                | (st |                       |
| normal pattern  | ta |                | ool |                       |
|                 |    |                | h   |                       |
|                 |    |                | eme |                       |
|                 |    |                | pos |                       |
|                 |    |                | iti |                       |
|                 |    |                | ve, |                       |
|                 |    |                | h   |                       |
|                 |    |                | ema |                       |
|                 |    |                | toc |                       |
|                 |    |                | rit |                       |
|                 |    |                | dec |                       |
|                 |    |                | rea |                       |
|                 |    |                | sed |                       |
|                 |    |                | by  |                       |
|                 |    |                | 5%  |                       |
|                 |    |                | or  |                       |
|                 |    |                | m   |                       |
|                 |    |                | ore |                       |
|                 |    |                | \   |                       |
|                 |    |                | [ab |                       |
|                 |    |                | sol |                       |
|                 |    |                | ute |                       |
|                 |    |                | cha |                       |
|                 |    |                | nge |                       |
|                 |    |                | \], |                       |
|                 |    |                | or  |                       |
|                 |    |                | p   |                       |
|                 |    |                | ati |                       |
|                 |    |                | ent |                       |
|                 |    |                | o   |                       |
|                 |    |                | rth |                       |
|                 |    |                | ost |                       |
|                 |    |                | ati |                       |
|                 |    |                | c), |                       |
|                 |    |                | p   |                       |
|                 |    |                | erf |                       |
|                 |    |                | orm |                       |
|                 |    |                | UGI |                       |
|                 |    |                | end |                       |
|                 |    |                | osc |                       |
|                 |    |                | opy |                       |
|                 |    |                | (t  |                       |
|                 |    |                | est |                       |
|                 |    |                | for |                       |
|                 |    |                | H.  |                       |
|                 |    |                | pyl |                       |
|                 |    |                | ori |                       |
|                 |    |                | I   |                       |
|                 |    |                | nfe |                       |
|                 |    |                | cti |                       |
|                 |    |                | on) |                       |
|                 |    |                |     |                       |
|                 |    |                | \-  |                       |
|                 |    |                | Lo  |                       |
|                 |    |                | wer |                       |
|                 |    |                | GI  |                       |
|                 |    |                | w   |                       |
|                 |    |                | ork |                       |
|                 |    |                | -up |                       |
|                 |    |                | if  |                       |
|                 |    |                | bl  |                       |
|                 |    |                | eed |                       |
|                 |    |                | ing |                       |
|                 |    |                | sou |                       |
|                 |    |                | rce |                       |
|                 |    |                | unc |                       |
|                 |    |                | ert |                       |
|                 |    |                | ain |                       |
|                 |    |                |     |                       |
|                 |    |                | -If |                       |
|                 |    |                | w   |                       |
|                 |    |                | ork |                       |
|                 |    |                | -up |                       |
|                 |    |                | neg |                       |
|                 |    |                | ati |                       |
|                 |    |                | ve, |                       |
|                 |    |                | ret |                       |
|                 |    |                | est |                       |
|                 |    |                | st  |                       |
|                 |    |                | ool |                       |
|                 |    |                | for |                       |
|                 |    |                | he  |                       |
|                 |    |                | me; |                       |
|                 |    |                | rep |                       |
|                 |    |                | eat |                       |
|                 |    |                | h   |                       |
|                 |    |                | ema |                       |
|                 |    |                | toc |                       |
|                 |    |                | rit |                       |
|                 |    |                | in  |                       |
|                 |    |                | 1-2 |                       |
|                 |    |                | we  |                       |
|                 |    |                | eks |                       |
+-----------------+----+----------------+-----+-----------------------+
| Development of: | IM |                | \-  |                       |
|                 | ME |                | If  |                       |
| -postural       | DI |                | GI  |                       |
| dizziness or    | AT |                | e   |                       |
| lightheadedness | E: |                | val |                       |
|                 |    |                | uat |                       |
| -syncope        | \- |                | ion |                       |
|                 | Ob |                | po  |                       |
|                 | ta |                | sit |                       |
|                 | in |                | ive |                       |
|                 | ba |                | (e. |                       |
|                 | se |                | g., |                       |
|                 | da |                | bl  |                       |
|                 | ta |                | ood |                       |
|                 |    |                | in  |                       |
|                 | \- |                | na  |                       |
|                 | If |                | sog |                       |
|                 | p  |                | ast |                       |
|                 | at |                | ric |                       |
|                 | ie |                | asp |                       |
|                 | nt |                | ira |                       |
|                 | or |                | te, |                       |
|                 | th |                | h   |                       |
|                 | os |                | eme |                       |
|                 | ta |                | po  |                       |
|                 | ti |                | sit |                       |
|                 | c, |                | ive |                       |
|                 | ev |                | sto |                       |
|                 | al |                | ol, |                       |
|                 | ua |                | or  |                       |
|                 | te |                | h   |                       |
|                 | f  |                | ema |                       |
|                 | or |                | toc |                       |
|                 | a  |                | rit |                       |
|                 | cu |                | dec |                       |
|                 | te |                | rea |                       |
|                 | GI |                | sed |                       |
|                 | b  |                | by  |                       |
|                 | lo |                | 5%  |                       |
|                 | od |                | or  |                       |
|                 | lo |                |     |                       |
|                 | ss |                | m   |                       |
|                 |    |                | ore |                       |
|                 |    |                | \   |                       |
|                 |    |                | [ab |                       |
|                 |    |                | sol |                       |
|                 |    |                | ute |                       |
|                 |    |                | c   |                       |
|                 |    |                | han |                       |
|                 |    |                | ge\ |                       |
|                 |    |                | ]), |                       |
|                 |    |                | in  |                       |
|                 |    |                | ves |                       |
|                 |    |                | tig |                       |
|                 |    |                | ate |                       |
|                 |    |                | sou |                       |
|                 |    |                | rce |                       |
|                 |    |                | w   |                       |
|                 |    |                | ith |                       |
|                 |    |                | UGI |                       |
|                 |    |                | end |                       |
|                 |    |                | osc |                       |
|                 |    |                | opy |                       |
|                 |    |                | (t  |                       |
|                 |    |                | est |                       |
|                 |    |                | for |                       |
|                 |    |                | H.  |                       |
|                 |    |                | pyl |                       |
|                 |    |                | ori |                       |
|                 |    |                | i   |                       |
|                 |    |                | nfe |                       |
|                 |    |                | cti |                       |
|                 |    |                | on) |                       |
|                 |    |                |     |                       |
|                 |    |                | \-  |                       |
|                 |    |                | Lo  |                       |
|                 |    |                | wer |                       |
|                 |    |                | GI  |                       |
|                 |    |                | w   |                       |
|                 |    |                | ork |                       |
|                 |    |                | -up |                       |
|                 |    |                | if  |                       |
|                 |    |                | bl  |                       |
|                 |    |                | eed |                       |
|                 |    |                | ing |                       |
|                 |    |                | sou |                       |
|                 |    |                | rce |                       |
|                 |    |                | unc |                       |
|                 |    |                | ert |                       |
|                 |    |                | ain |                       |
+-----------------+----+----------------+-----+-----------------------+
| Development of: | IM |                | \-  |                       |
|                 | ME |                | If  |                       |
| -postural       | DI |                | GI  |                       |
| dizziness or    | AT |                | e   |                       |
|                 | E: |                | val |                       |
| lightheadedness |    |                | uat |                       |
|                 | \- |                | ion |                       |
| -syncope        | Ob |                | po  |                       |
|                 | ta |                | sit |                       |
|                 | in |                | ive |                       |
|                 | ba |                | (e. |                       |
|                 | se |                | g., |                       |
|                 | da |                | bl  |                       |
|                 | ta |                | ood |                       |
|                 |    |                | in  |                       |
|                 | \- |                | na  |                       |
|                 | If |                | sog |                       |
|                 | p  |                | ast |                       |
|                 | at |                | ric |                       |
|                 | ie |                | asp |                       |
|                 | nt |                | ira |                       |
|                 | or |                | te, |                       |
|                 | th |                | h   |                       |
|                 | os |                | eme |                       |
|                 | ta |                | po  |                       |
|                 | ti |                | sit |                       |
|                 | c, |                | ive |                       |
|                 | ev |                | sto |                       |
|                 | al |                | ol, |                       |
|                 | ua |                | or  |                       |
|                 | te |                | h   |                       |
|                 | f  |                | ema |                       |
|                 | or |                | toc |                       |
|                 |    |                | rit |                       |
|                 | a  |                | dec |                       |
|                 | cu |                | rea |                       |
|                 | te |                | sed |                       |
|                 | GI |                | by  |                       |
|                 | b  |                | 5%  |                       |
|                 | lo |                | or  |                       |
|                 | od |                |     |                       |
|                 | lo |                | m   |                       |
|                 | ss |                | ore |                       |
|                 |    |                | \   |                       |
|                 |    |                | [ab |                       |
|                 |    |                | sol |                       |
|                 |    |                | ute |                       |
|                 |    |                | c   |                       |
|                 |    |                | han |                       |
|                 |    |                | ge\ |                       |
|                 |    |                | ]), |                       |
|                 |    |                | in  |                       |
|                 |    |                | ves |                       |
|                 |    |                | tig |                       |
|                 |    |                | ate |                       |
|                 |    |                | sou |                       |
|                 |    |                | rce |                       |
|                 |    |                | w   |                       |
|                 |    |                | ith |                       |
|                 |    |                | UGI |                       |
|                 |    |                | end |                       |
|                 |    |                | osc |                       |
|                 |    |                | opy |                       |
|                 |    |                | (t  |                       |
|                 |    |                | est |                       |
|                 |    |                | for |                       |
|                 |    |                | H.  |                       |
|                 |    |                | pyl |                       |
|                 |    |                | ori |                       |
|                 |    |                | i   |                       |
|                 |    |                | nfe |                       |
|                 |    |                | cti |                       |
|                 |    |                | on) |                       |
|                 |    |                |     |                       |
|                 |    |                | -Lo |                       |
|                 |    |                | wer |                       |
|                 |    |                | GI  |                       |
|                 |    |                | w   |                       |
|                 |    |                | ork |                       |
|                 |    |                | -up |                       |
|                 |    |                | if  |                       |
|                 |    |                | bl  |                       |
|                 |    |                | eed |                       |
|                 |    |                | ing |                       |
|                 |    |                | sou |                       |
|                 |    |                | rce |                       |
|                 |    |                | unc |                       |
|                 |    |                | ert |                       |
|                 |    |                | ain |                       |
+-----------------+----+----------------+-----+-----------------------+
| ##              |    |                |     |                       |
|                 |    |                |     |                       |
| ## C            |    |                |     |                       |
| linical situati |    |                |     |                       |
| ons requiring P |    |                |     |                       |
| ROMPT attention |    |                |     |                       |
|                 |    |                |     |                       |
| **For all       |    |                |     |                       |
| patients with   |    |                |     |                       |
| the following   |    |                |     |                       |
| p               |    |                |     |                       |
| resentations:** |    |                |     |                       |
|                 |    |                |     |                       |
| \- **Obtain     |    |                |     |                       |
| base data       |    |                |     |                       |
| (hematocrit,    |    |                |     |                       |
| stool heme x3,  |    |                |     |                       |
| and postural    |    |                |     |                       |
| vital signs) as |    |                |     |                       |
| soon as         |    |                |     |                       |
| possible.**     |    |                |     |                       |
|                 |    |                |     |                       |
| \- **Test for   |    |                |     |                       |
| H. pylori       |    |                |     |                       |
| infection as    |    |                |     |                       |
| part of work up |    |                |     |                       |
| (Meretek UBT,   |    |                |     |                       |
| CLOtest or      |    |                |     |                       |
| H&E)**          |    |                |     |                       |
|                 |    |                |     |                       |
| \- **Notify     |    |                |     |                       |
| Kendle Safety   |    |                |     |                       |
| Specialist as   |    |                |     |                       |
| soon as         |    |                |     |                       |
| possible.**     |    |                |     |                       |
|                 |    |                |     |                       |
| \- **Complete   |    |                |     |                       |
| GI event        |    |                |     |                       |
| CRFs.**         |    |                |     |                       |
+-----------------+----+----------------+-----+-----------------------+
| History of dark |    | ASAP:          |     | \- If any component   |
| stool:          |    |                |     | of work-up positive   |
|                 |    | -n Obtain base |     |                       |
| \- \>14 days    |    | data           |     | (stool heme positive, |
| previously, or  |    |                |     | hematocrit decreased  |
|                 |    |                |     | by 5% or more         |
| \- vaguely      |    |                |     | \[absolute change\],  |
| characterized,  |    |                |     | or patient            |
| or              |    |                |     | orthostatic), perform |
|                 |    |                |     | UGI endoscopy (test   |
| \- with         |    |                |     | for H. pylori         |
| concurrent      |    |                |     | infection)            |
| iron/bismuth    |    |                |     |                       |
|                 |    |                |     | \- Lower GI work-up   |
| ingestion       |    |                |     | if bleeding source    |
|                 |    |                |     | uncertain             |
+-----------------+----+----------------+-----+-----------------------+
| History of :    |    | ASAP:          |     | \- Perform            |
|                 |    |                |     | colonoscopy           |
| \-              |    | \- Obtain base |     |                       |
| hematochezia,   |    | data           |     | \- UGI endoscopy at   |
| or              |    |                |     | Investigator's        |
|                 |    |                |     |                       |
| \- anal/rectal  |    |                |     | discretion (test for  |
| bleeding after  |    |                |     | H. pylori infection)  |
|                 |    |                |     |                       |
| elimination     |    |                |     |                       |
+-----------------+----+----------------+-----+-----------------------+
| Development of: |    | ASAP:          |     | -If stools heme       |
|                 |    |                |     | positive or studies   |
| \- New anemia,  |    | -Obtain base   |     | indicate iron         |
| or              |    | data including |     | deficiency, perform   |
|                 |    | ferritin,      |     | UGI endoscopy (test   |
| \- Drop in      |    |                |     | for H. pylori         |
| hematocrit of   |    | iron, iron     |     | infection)            |
| 5% or more      |    | binding        |     |                       |
| (absolute       |    | capacity, MCV, |     | \- Lower GI work-up   |
| change)         |    | MCHC           |     | if bleeding source    |
|                 |    |                |     | uncertain             |
+-----------------+----+----------------+-----+-----------------------+
| Development of: |    | ASAP:          |     | \- If any component   |
|                 |    |                |     | of work-up positive   |
| \- Dyspepsia,   |    | \- Obtain base |     |                       |
| or              |    | data           |     | (stool heme positive, |
|                 |    |                |     | hematocrit decreased  |
| \- Abdominal    |    |                |     | by 5% or more         |
| pain, or        |    |                |     | \[absolute change\],  |
|                 |    |                |     | or patient            |
| \-              |    |                |     | orthostatic), perform |
| Nausea/vomiting |    |                |     | UGI endoscopy (test   |
|                 |    |                |     | for H. pylori         |
|                 |    |                |     | infection)            |
|                 |    |                |     |                       |
|                 |    |                |     | \- Additional studies |
|                 |    |                |     | as indicated by       |
|                 |    |                |     |                       |
|                 |    |                |     | \"ordinary care\"     |
+-----------------+----+----------------+-----+-----------------------+
| Development of: |    | ASAP:          |     | -Perform UGI          |
|                 |    |                |     | endoscopy (test for   |
| -Heme-positive  |    | -Obtain base   |     | H. pylori infection)  |
| stools          |    | data           |     |                       |
|                 |    |                |     | \- Lower GI work-up   |
|                 |    | uncertain      |     | if bleeding source    |
+-----------------+----+----------------+-----+-----------------------+

If none of the base data (including the GI event CRFs and any source
documentation) suggested a CSUGIE, then the case (information forwarded
by Sponsor) was reviewed in a blinded fashion by a single member of the
GEC (these cases were usually assigned to GEC members alphabetically by
the patient's initials). The GEC member either confirmed that there was
no evidence of a CSUGIE and the case was classified as a negative event,
or chose (based upon potential evidence of a CSUGIE) to send the case
material to the full GEC for adjudication.

If any base data or work-up results were suggestive of a CSUGIE, a
narrative summary of the case was written by CRO personnel and forwarded
to the Sponsor with other relevant documentation. All material on the
case was then reviewed by all members of the GEC and discussed in a
teleconference. The decision whether the case met the definition of a
CSUGIE was reached by consensus. Those events that were adjudicated and
considered by consensus not to meet the predetermined criteria are
referred to as non-CSUGIEs. At any point during the review and
adjudication process, the Investigator may have been **contacted to
request further information or follow-up.**

***Definitions of CSUGIEs/GDUs:***

Symptomatic ulcer cases were those cases in which criteria for a CSUGIE
were not met but in which a gastroduodenal ulcer was found by either
endoscopy or upper gastrointestinal series, performed as a result of
symptoms or signs. The combined category of these ulcers with the
CSUGIEs was referred to as "**CSUGIEs/GDUs."** Of note, any patient with
either a gastric or duodenal ulcer, or both, is counted as having a
gastroduodenal ulcer.

Upper GI ulcers documented by endoscopy or UGI barium x-ray with no
evidence of perforation, bleeding, or obstruction were categorized
separately. Data on GI complaints and other GI adverse events, such as
esophageal, small bowel, colonic, or rectal pathology, were also
collected.

All analyses of GI safety/endpoints were carried out on the
Intent-to-Treat Cohort, defined as all randomized patients who received
at least one dose of study medication. For the two GI safety end points
of interest, namely (1) CSUGIEs and (2) CSUGIEs combined with
gastroduodenal ulcers (termed "CSUGIEs/GDUs" as noted above), the
analyses were performed as follows:

· First Six Months of Treatment

> a\. All Patients
>
> b\. Patients not Taking Aspirin
>
> c\. Patients Taking Aspirin

· Entire Study Period

> a\. All Patients
>
> b\. Patients not Taking Aspirin
>
> c\. Patients Taking Aspirin

The rationale for separately considering the first six months and the
entire study period has been discussed. The subgroup analyses of
patients not taking aspirin and those taking aspirin were performed
because of the confounding effect of aspirin (aspirin use at \<325
mg/day was allowed during the study). The idea that aspirin has a
confounding effect on assessment of UGI endpoints is supported by
studies in the literature, as well as by the present study which
included analysis of low-dose aspirin as an independent cause of CSUGIEs
and ulcers among patients receiving celecoxib.

**Statistical considerations (Section 8.1.1.3.3)**

The two trials described in this sNDA were prospectively designed with
the intent to combine the data into a pooled analysis. Therefore, except
where otherwise noted, were performed on a single, combined data set in
which celecoxib patients from both protocols were pooled into a single
treatment group for comparison with the diclofenac 75 mg BID and
ibuprofen 800 mg TID (i.e. NSAID) treatment groups. In most analyses the
two NSAID groups are considered separately, but pooling was done for
certain analyses.

#### Determination of Sample Size

The sample sizes for the combined protocols were determined based on the
assumption that the probability of experiencing a CSUGIE is 0.3% per
year with celecoxib and 1.2% per year with each of the NSAIDs. Assuming
a withdrawal rate of 35%, a sample size of 4,000 patients (combining the
two protocols) for the celecoxib group and 2,000 patients for each of
the NSAID groups would be needed to detect this difference with
approximately 85% power at a 5% significance level (two-sided). With the
above assumptions and an enrollment period of approximately three
months, it would be expected that a total of 40 CSUGIEs would occur in
the combined study (eight in the combined celecoxib group and 16 in each
NSAID group).

**End point analyses**

**The primary end point in the GI safety analyses was the development of
a CSUGIE** (i.e., UGI bleeding, perforation, or obstruction). The **null
hypothesis** being tested was that there is no difference between the
incidence of **CSUGIEs** associated with celecoxib and that associated
with either of the NSAID groups. Because of the association of
development of an ulcer with an increased risk of experiencing a CSUGIE,
all analyses of CSUGIEs in this study were repeated for patients who
experienced either a CSUGIE or symptomatic gastroduodenal ulcer
**(CSUGIE/GDU).**

The main analyses of baseline data were performed on the
**Intent-to-Treat Cohort**, defined as all randomized patients who
received at least one dose of study medication. However, analyses were
also carried out on the cohort of all randomized patients. For
consistency with the GI safety analyses, certain analyses of termination
reasons, patient disposition, and baseline data were also analyzed for
just the first six months of study participation, as well as being
analyzed for the subgroups of patients taking and not taking
**aspirin.** The reasons for these analyses are described elsewhere.

In the analyses of both CSUGIEs and CSUGIEs/GDUs, the events of interest
were counted within each treatment group by time intervals. The event
rates were summarized by time intervals (1, 4, 13, 26, 39, and 52
weeks), and **the log-rank test** was used to compare the time-to-event
curves between celecoxib and the two NSAIDs combined, as well as between
celecoxib and each of the NSAIDs separately as a stepwise procedure.
Each test was performed at the alpha level of 0.05 (two-sided).

In this analysis, patients completing the study without the event of
interest were **censored** at the final visit, and patients who withdrew
from the study for reasons other than occurrence of an event were
censored at the time of withdrawal. Analyses of CSUGIEs based on the
alternate definitions were also performed, both with and without the use
of censoring as described elsewhere. Because patients receiving
celecoxib from both protocols were pooled into a single group, the
celecoxib results from the two protocols were also compared
(numerically) to ensure homogeneity.

The numbers of patients randomized at each site, and the numbers of
patients completing study participation or withdrawing for any reason,
were summarized numerically by treatment group. Treatment duration was
calculated for all completed patients, all withdrawn patients, and all
patients in the Intent-to-Treat Cohort. Numbers of patients were
summarized within each treatment group by the following intervals of
treatment duration: 0 to 1 month, \>1 to 3 months, \>3 to 6 months, \>6
to 9 months, \>9 to 12 months, \>12 to 15 months, and \>15 months. In
addition, mean duration of treatment as well as total patient-years of
treatment were calculated.

Descriptive statistics for demographics and other baseline
characteristics (height, weight, vital signs, GI risk factors, alcohol
and tobacco use, and arthritis history) were calculated for all
treatment groups. Categorical variables were summarized with frequency
distributions and percentages. For continuous variables, mean values,
standard deviations, median values, and ranges (minimum to maximum) were
reported. The treatment groups were compared using Pearson's chi-square
test for categorical variables and two-way analysis of variance (ANOVA)
with treatment and study site as factors for continuous variables.

Because of the potential for certain medications to influence the risk
of experiencing a CSUGIE, concurrent use of corticosteroids,
anticoagulant agents, and aspirin during the study was compared among
treatment groups using Pearson's chi-square test.

Baseline results on patient's global assessment of arthritis and
patient\'s assessment of arthritis pain-VAS were summarized and compared
among treatment groups using the Cochran-Mantel-Haenszel test stratified
by center and two-way ANOVA with treatment and study site as factors,
respectively.

Potential risk factors for the development of a CSUGIE were identified
prior to analysis. These included demographic and disease
characteristics (age, gender, disease type and duration, and baseline
disease severity), GI history (positive Flexsure test for *H. pylori,*
or history of UGI bleeding, gastroduodenal ulcer, or NSAID intolerance),
concomitant medication use (including aspirin use), alcohol use, and
tobacco use. For each of these factors, factor effect and
treatment-by-factor interaction, as well as within-group effects, were
assessed based on time to event with a COX proportional hazards model.
All of these risk factor analyses were performed with the NSAID groups
examined separately as well as with pooling of the two NSAID groups.

***Efficacy and QOL Analysis***

All efficacy (patient global, patient pain-VAS, and withdrawal due to
lack of efficacy) and QOL analyses were carried out on the ITT cohort
with missing values imputed by carrying forward the last observed value.
For patient's global assessment and patient's assessment of arthritis
pain-VAS, mean values with SD at each scheduled visit were summarized by
treatment group. Least-squares means and 95% confidence intervals were
created by visit, using ANCOVA with study site and treatment as factors
and baseline score as the covariate. In addition, patient's global
assessment scores were categorized based on changes from baseline as
improved (reduction of at least one grade from baseline), unchanged, or
worsened (increase of at least one grade from baseline). Percentages of
patients in each category (and 95% confidence intervals) were calculated
by scheduled visit and treatment group.

Incidences of withdrawal due to lack of arthritis efficacy were analyzed
using the chi-square test. Times to withdrawal due to lack of arthritis
efficacy were analyzed using the log-rank test. For the purpose of this
analysis, patients who withdrew for other reasons were censored at the
time of withdrawal; those who did not withdraw at any time were censored
at the final scheduled visit. Similar analyses were performed for
withdrawal due either to lack of arthritis efficacy or to an adverse
event.

Quality of Life assessments were performed in protocol 035, and
consisted of the HAQ and SF-36 health survey. For both of these
instruments, mean values and SD at each scheduled visit were summarized
by treatment group. Least-squares means and 95% confidence intervals
were created by visit, using ANCOVA with study site and treatment as
factors and baseline score as the covariate. Results on the patient
satisfaction questionnaires and the SODA questionnaires were analyzed
similarly. For the patient satisfaction questionnaires, least-squares
means and 95% confidence intervals were created, using ANOVA with study
site and treatment as factors. For the SODA, least-squares means, 95%
confidence intervals, and p values were created by visit, using ANCOVA
with study site and treatment as factors and baseline values as the
covariate.

To verify homogeneity between the celecoxib groups in the two protocols,
all of the summaries and analyses of patient disposition, reasons for
termination, and baseline variables were repeated with the two celecoxib
treatment groups from the two protocols analyzed separately. The same
statistical tests were used as those described above.

***Safety evaluation***:

All patients who took at least one dose of study medication were
included in all safety analyses. Adverse events (AE) were coded using
W.H.O.a.r.t. terminology. The incidences of treatment-emergent adverse
events were tabulated by treatment group and body system, and compared
pairwise between treatment groups using Fisher's Exact test. Events
occurring more than 28 days after the last dose of study medication were
excluded from all analyses.

Adverse events causing withdrawal were similarly analyzed. Serious
adverse events were tabulated by treatment group and body system, but no
statistical analysis was performed. The incidences of treatment-emergent
adverse events were also tabulated by severity and by the Investigator's
attribution of the cause of the event.

Because of the long treatment period in this study, a separate analysis
was performed in which adverse events were summarized by 90-day
intervals (1 to 90 days, 91 to 180 days, 181 to 270 days, 271 to 360
days, 361 to 450 days, and 451 to 540 days). In this analysis,
incidences and prevalences were summarized separately for each adverse
event. Within each interval, events were counted under prevalence if
they were new in that interval or continued from a previous interval,
whereas incidence values included only events that were new within that
interval.

For selected GI adverse events, time-to-event analyses were performed to
assess the rates of the events by pre-specified time intervals (1, 4,
13, 26, 39, 52, and 65 weeks). The log-rank test was used to compare the
time-to-event curves between celecoxib 400 mg BID and the two NSAIDs
combined, as well as between celecoxib and each of the NSAIDs
separately. Each test was performed at the alpha level of 0.05.

Times to withdrawal due to adverse events were analyzed using the
log-rank test. In this analysis, patients who withdrew for other reasons
were censored at the time of withdrawal; those who did not withdraw at
any time were censored at the final scheduled visit.

Changes from baseline in clinical laboratory values at weeks 4, 13, 26,
39, 52, and the final visit were summarized as means and standard
deviations (SD). The changes were compared among treatment groups by
ANCOVA using pairwise treatment contrasts with baseline value as the
covariate.

Incidences of extreme laboratory (and vital signs) values during the
study were summarized by treatment group and compared among groups using
Fisher's exact test. The values representing upper and lower extremes
for each laboratory test were determined before the initiation of study
conduct through discussions with external safety consultants, and were
listed (Table 6.d, N49-00-06-035-102, p. 52/24295) and were utilized to
construct shift tables. Contingency tables were also prepared showing
numbers of patients whose post-treatment laboratory results met certain
criteria for combinations of values or changes in values that might
indicate hematologic, hepatobiliary, or renal effects. These criteria
represented: decreases in both hemoglobin and hematocrit; increases in
both creatinine and BUN; increases in both AST and ALT; increases in
both alkaline phosphatase and total bilirubin; increases in both ALT and
alkaline phosphatase; and increases in both ALT and total bilirubin.
These tables showed numbers of patients shifting among various
categories of increases and decreases according to predetermined cutoff
values.

[Results (Section 8.1.1.4):]{.underline}

Patient Disposition, comparability (Section 8.1.1.4.1)

As seen in **Table 3**, a total of **8059 patients were randomized** at
386 centers in the two protocols **4031 to the celecoxib** group, **2019
to the diclofenac** group, and **2009 to the ibuprofen** group.
Ninety-one patients were determined never to have taken any study
medication; those who did represent the Intent-to-Treat **(ITT) cohort**
(i.e. patients who took at least one dose of study medication). Of these
91 subjects, the majority were randomized but were never entered into
the study or dispensed study medication. Across the three treatment
groups, 98 patients were found to have violated one or more entry
criteria. These included 47 patients in the celecoxib group, 22 patients
in the diclofenac group, and 29 patients in the ibuprofen group. These
**violations** (Table 7.a, N49-00-06-035-102, p. 60) were mostly for
past or active GI disease (including positive occult fecal blood), liver
function test abnormalities, or hypersensitivity to the study
medications (41 patients for celecoxib, 18 patients for diclofenac, 23
patients for ibuprofen). The seven patients entered into the study with
violations of the inclusion/exclusion criteria were approved by the
sponsor either prior to entry or upon discovery of the violation.
Approval was given only if a review of the violation indicated that the
patient could safely participate in the study and the violation was
unlikely to affect the results of the study. Across the study, 50
patients were **withdrawn** for pre-existing protocol violations: 27
celecoxib patients, 11 diclofenac patients, and 12 ibuprofen patients.

The reasons for termination from the study within the first six months
are shown in Table 3. A total of **4573 patients completed six months**
(182 days or more): 2376 (60%) receiving celecoxib, 1148 (58%) receiving
diclofenac, and 1049 (53%) receiving ibuprofen. A total of **3409
patients completed the study**: 1779 (45%) receiving celecoxib, 939
(47%) receiving diclofenac, and 691 (35%) receiving ibuprofen. The
**majority of withdrawals in all treatment groups were due to protocol
noncompliance, treatment failure, or an adverse event. No patients were
lost to follow-up in any treatment group during the entire study.**

Across the entire study, **1147 patients were withdrawn** from the study
for protocol noncompliance: 585 celecoxib patients, 197 diclofenac
patients, and 365 ibuprofen patients (Table 3). These withdrawals
occurred despite the study's objective to mimic standard medical
practice so that minor protocol violations did not invariably lead to
withdrawal during the study. Some examples of such violations included
missing a protocol-required procedure (e.g., obtaining a blood sample
for laboratory tests); missing the visit window established in the
protocol and/or missing a visit altogether; intermittent use of proton
pump inhibitors,H~2~- antagonists, or NSAIDs; throwing out empty
medication bottles; and misallocation of study medication by the site.
However, prolonged use of non-study medications; compliance below 70% on
more than one consecutive visit or sustained failure to comply with the
required visit schedule; pregnancy; or receiving a treatment other than
that assigned necessitated immediate withdrawal from the study.

In one case, a patient's treatment assignment was **unblinded** at the
investigational site (the patient experienced a diverticular bleed). In
two cases the treatment assignment was unblinded through the IVRS
randomization system by telephone. None of these three patients
experienced a CSUGIE or ulcer, and in no instance was the patient's
assigned treatment made known to sponsor or any members of the oversight
committees.

**^Table\ 3:\ Patient\ Disposition-First\ Six\ Months\ and\ Entire\ Study\ Period^**1

+----------------+------+--------------+--------------+---------------+
| **Patients     | *    | **Celebrex   | **Diclofenac | **Ibuprofen   |
| (%)**          | *Tot | 400 mg BID** | 75 mg BID**  | 800 mg TID**  |
|                | al** |              |              |               |
+----------------+------+--------------+--------------+---------------+
| **Randomized** | 8059 | 4031         | 2019         | 2009          |
+----------------+------+--------------+--------------+---------------+
| **Took         | 7968 | 3987         | 1996         | 1985          |
| medication     |      |              |              |               |
| (ITT)**        |      |              |              |               |
+----------------+------+--------------+--------------+---------------+
| **Completed 6  | 4573 | 2376 (59.6)  | 1148 (57.5)  | 1049 (52.8)   |
| months**       |      |              |              |               |
+----------------+------+--------------+--------------+---------------+
| **Completed    | 3409 | 1779 (44.6)  | 939 (47.0)   | 691 (34.8)    |
| Study^2^**     |      |              |              |               |
+----------------+------+--------------+--------------+---------------+
| **6 months**   | 3395 | 1611 (40.4)  | 848 (42.5)   | 936 (47.2)    |
|                |      |              |              |               |
| **Withdrawn**  | 0    | 0 (0)        | 0 (0)        | 0 (0)         |
|                |      |              |              |               |
| **Lost to      | 46   | 25 (0.6)     | 10 (0.5)     | 11 (0.6)      |
| follow-up**    |      |              |              |               |
|                | 703  | 351 (8.8)    | 142 (7.1)    | 210 (10.6)    |
| **Preexisting  |      |              |              |               |
| violation**    | 1092 | 503 (12.6)   | 253 (12.7)   | 336 (16.9)    |
|                |      |              |              |               |
| **N            | 1554 | 732 (18.4)   | 443 (22.2)   | 379 (19.1)    |
| oncompliance** |      |              |              |               |
|                |      |              |              |               |
| **Treatment    |      |              |              |               |
| failure**      |      |              |              |               |
|                |      |              |              |               |
| **Adverse      |      |              |              |               |
| event**        |      |              |              |               |
+----------------+------+--------------+--------------+---------------+
| **Entire       | 4559 | 2208 (55.4)  | 1057 (53.0)  | 1294 (65.2)   |
| Study**        |      |              |              |               |
|                | 0    | 0 (0)        | 0 (0)        | 0 (0)         |
| **Withdrawn**  |      |              |              |               |
|                | 50   | 27 (0.7)     | 11 (0.6)     | 12 (0.6)      |
| **Lost to      |      |              |              |               |
| follow-up**    | 1147 | 585 (14.7)   | 197 (9.9)    | 365 (18.4)    |
|                |      |              |              |               |
| **Preexisting  | 1456 | 691 (17.3)   | 309 (15.5)   | 456 (23.0)    |
| violation**    |      |              |              |               |
|                | 1906 | 905 (22.7)   | 540 (27.1)   | 461 (23.2)    |
| **N            |      |              |              |               |
| oncompliance** |      |              |              |               |
|                |      |              |              |               |
| **Treatment    |      |              |              |               |
| failure**      |      |              |              |               |
|                |      |              |              |               |
| **Adverse      |      |              |              |               |
| event**        |      |              |              |               |
+----------------+------+--------------+--------------+---------------+

1.  From Figure 7.a and b (p. 57 and 59) and Table T2.1 and T2.3 (p. 247
    and 250); N49-00-06-035-102.

2.  Completed patients are those who completed the full scheduled
    treatment period or remained in the study at the time of study
    closure.

Reviewer's comment: Considering the argument of disproportionate
withdrawal of patients (i.e. informative censoring), during the first 6
months a higher proportion (compared to celecoxib) of patients in the
diclofenac withdrew due to an adverse event while more patients in the
ibuprofen group withdrew for noncompliance or treatment failure. This
same general trend occurred in the entire study. Also, reasons for study
termination (first 6 months) in patients taking ASA did not appear to
differ substantially (Appendix 2.6.1, p. 2096/24295) in any treatment
group from those noted in the table above. Total withdrawal, whether
during the first 6 months or the entire study, was highest in the
ibuprofen group.

The duration of exposure to treatment in each group (all ITT patients,
patients with aspirin) is shown for both the first six months and the
entire study in **Table 4**. As can be seen, proportions of patients
with at least three months of exposure to treatment ranged from 64% to
70% whereas for the entire study period, approximately 45% to 51% of
patients in all treatment groups had at least nine months of exposure to
treatment. Essentially all patients who completed the study had at least
9 months of exposure to treatment. **Exposure to medication for the
entire study was estimated to be 2320 patient-years for celecoxib, 1081
patient-years for diclofenac, and 1122 patient-years for ibuprofen
800.**

**^Table\ 4:\ Treatment\ Duration-First\ Six\ Months\ and\ Entire\ Study^**1

+-----------------+-----------------+-----------------+-----------------+
| **Treatment     | **Celecoxib**   | **Diclofenac**  | **Ibuprofen**   |
| Duration^2^**   |                 |                 |                 |
|                 | **(N = 3987)**  | **(N = 1996)**  | **(N = 1985)**  |
+-----------------+-----------------+-----------------+-----------------+
| **First 6       |                 |                 |                 |
| months**        |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| ITT-(Total)     | 656 (16%)       | 328 (16%)       | 364 (18%)       |
|                 |                 |                 |                 |
| 0 - 1 months    | 546 (14%)       | 293 (15%)       | 351 (18%)       |
|                 |                 |                 |                 |
| 1.1 - 3 months  | 2785 (70%)      | 1375 (69%)      | 1270 (64%)      |
|                 |                 |                 |                 |
| 3.1 - 6         | 1441.07         | 710.29          | 673.52          |
| months^3^       |                 |                 |                 |
|                 |                 |                 |                 |
| Patient yrs.    |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| ITT-(non-ASA)   | (n=3154)        | (n=1567)        | (n=1602)        |
|                 |                 |                 |                 |
| 0 - 1 months    | 527 (17%)       | 262 (17%)       | 309 (19%)       |
|                 |                 |                 |                 |
| 1.1 - 3 months  | 419 (13%)       | 222 (14%)       | 267 (17%)       |
|                 |                 |                 |                 |
| 3.1 - 6 months  | 2208 (70%)      | 1083 (69%)      | 1026 (64%)      |
|                 |                 |                 |                 |
| Patient yrs.    | 1143.05         | 559.21          | 541.48          |
+-----------------+-----------------+-----------------+-----------------+
| ITT-(ASA)       | (n=833)         | (n=429)         | (n=383)         |
|                 |                 |                 |                 |
| 0 - 1 months    | 129 (15%)       | 66 (15%)        | 55 (14%)        |
|                 |                 |                 |                 |
| 1.1 - 3 months  | 127 (15%)       | 71 (17%)        | 84 (22%)        |
|                 |                 |                 |                 |
| 3.1 - 6 months  | 577 (69%)       | 292 (68%)       | 244 (64%)       |
|                 |                 |                 |                 |
| Patient yrs.    | 298.02          | 151.07          | 132.04          |
+-----------------+-----------------+-----------------+-----------------+
| ## Entire Study |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| ITT-(Total)     | 656 (16%)       | 328 (16%)       | 364 (18%)       |
|                 |                 |                 |                 |
| 0 - 1 months    | 546 (14%)       | 293 (15%)       | 351 (18%)       |
|                 |                 |                 |                 |
| 1.1 - 3 months  | 467 (12%)       | 262 (13%)       | 246 (12%)       |
|                 |                 |                 |                 |
| 3.1 - 6 months  | 291 (7%)        | 136 (7%)        | 130 (7%)        |
|                 |                 |                 |                 |
| 6.1-9 months    | 1442 (36%)      | 913 (46%)       | 415 (21%)       |
|                 |                 |                 |                 |
| 9.1-12 months   | 585 (15%)       | 64 (3%)         | 477 (24%)       |
|                 |                 |                 |                 |
| 12.1-15 months  | 0 (0%)          | 0 (0%)          | 2 (0%)          |
|                 |                 |                 |                 |
| \>15 months     | 2320.44         | 1080.55         | 1122.48         |
|                 |                 |                 |                 |
| Patient yrs.    |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| ITT-(non-ASA)   | (n=3105)        | (n=1551)        | (n=1573)        |
|                 |                 |                 |                 |
| 0 - 1 months    | 527 (17%)       | 262 (17%)       | 309 (20%)       |
|                 |                 |                 |                 |
| 1.1 - 3 months  | 419 (13%)       | 222 (14%)       | 267 (17%)       |
|                 |                 |                 |                 |
| 3.1 - 6 months  | 357 (11%)       | 203 (13%)       | 206 (13%)       |
|                 |                 |                 |                 |
| 6.1-9 months    | 229 (7%)        | 97 (6%)         | 100 (6%)        |
|                 |                 |                 |                 |
| 9.1-12 months   | 1114 (36%)      | 717 (46%)       | 330 (21%)       |
|                 |                 |                 |                 |
| 12.1-15 months  | 459 (15%)       | 50 (3%)         | 359 (23%)       |
|                 |                 |                 |                 |
| \>15 months     | 0 (0%)          | 0 (0%)          | 2 (0%)          |
|                 |                 |                 |                 |
| Patient yrs.    | 1803.46         | 841.16          | 873.80          |
+-----------------+-----------------+-----------------+-----------------+
| ITT-(ASA)       | (n=882)         | (n=445)         | (n=412)         |
|                 |                 |                 |                 |
| 0 - 1 months    | 129 (15%)       | 66 (15%)        | 55 (13%)        |
|                 |                 |                 |                 |
| 1.1 - 3 months  | 127 (14%)       | 71 (16%)        | 84 (20%)        |
|                 |                 |                 |                 |
| 3.1 - 6 months  | 110 (12%)       | 59 (13%)        | 40 (10%)        |
|                 |                 |                 |                 |
| 6.1-9 months    | 62 (7%)         | 39 (9%)         | 30 (7%)         |
|                 |                 |                 |                 |
| 9.1-12 months   | 328 (37%)       | 196 (44%)       | 85 (21%)        |
|                 |                 |                 |                 |
| 12.1-15 months  | 126 (14%)       | 14 (3%)         | 118 (29%)       |
|                 |                 |                 |                 |
| \>15 months     | 0 (0%)          | 0 (0%)          | 0 (0%)          |
|                 |                 |                 |                 |
| Patient yrs.    | 516.98          | 239.39          | 248..68         |
+-----------------+-----------------+-----------------+-----------------+
| ## Comple       |                 |                 |                 |
| ted and Withdra |                 |                 |                 |
| wn-Entire Study |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
|                 | N=1779          | N=939           | N=691           |
+-----------------+-----------------+-----------------+-----------------+
| Completed^4^    | 0 (0%)          | 0 (0%)          | 0 (0%)          |
|                 |                 |                 |                 |
| 0 - 1 months    | 0 (0%)          | 0 (0%)          | 0 (0%)          |
|                 |                 |                 |                 |
| 1.1 - 3 months  | 0 (0%)          | 1 (0%)          | 0 (0%)          |
|                 |                 |                 |                 |
| 3.1 - 6 months  | 10 (1%)         | 6 (1%)          | 0 (0%)          |
|                 |                 |                 |                 |
| 6.1-9 months    | 1282 (72%)      | 868 (92%)       | 297 (43%)       |
|                 |                 |                 |                 |
| 9.1-12 months   | 487 (27%)       | 64 (7%)         | 392 (57%)       |
|                 |                 |                 |                 |
| 12.1-15 months  | 0 (0%)          | 0 (0%)          | 2 (0%)          |
|                 |                 |                 |                 |
| \>15 months     | 1640.68         | 812.87          | 698.69          |
|                 |                 |                 |                 |
| Patient yrs.    |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
|                 | N=2208          | N=1057          | N=1294          |
+-----------------+-----------------+-----------------+-----------------+
| Withdrawn       | 656 (30%)       | 328 (31%)       | 364 (28%)       |
|                 |                 |                 |                 |
| 0 - 1 months    | 546 (25%)       | 293 (28%)       | 351 (27%)       |
|                 |                 |                 |                 |
| 1.1 - 3 months  | 467 (21%)       | 261 (25%)       | 246 (19%)       |
|                 |                 |                 |                 |
| 3.1 - 6 months  | 281 (13%)       | 130 (12%)       | 130 (10%)       |
|                 |                 |                 |                 |
| 6.1-9 months    | 160 (7%)        | 45 (4%)         | 118 (9%)        |
|                 |                 |                 |                 |
| 9.1-12 months   | 98 (4%)         | 0 (0%)          | 85 (7%)         |
|                 |                 |                 |                 |
| 12.1-15 months  | 0 (0%)          | 0 (0%)          | 0 (0%)          |
|                 |                 |                 |                 |
| \>15 months     | 679.76          | 267.68          | 423.79          |
|                 |                 |                 |                 |
| Patient yrs.    |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

1.  From Table T2.2.1-3 and Table T2.4.1-3, N49-00-06-035-102, p.
    247-253/24295; Appendix Table 2.3.1-.2, p2058-9.

2.  Treatment duration is the time between first dose date and last dose
    date or last available visit date (if last dose date is not
    available).

3.  Includes patients who withdrew during this interval or continued
    beyond 182 days.

4.  Completed patients are those who completed the full scheduled
    treatment period or remained in the study at the time of study
    closure.

Reviewer's comment: Within treatment groups, either for the first six
months or the entire study, use of ASA did not seem to substantially
shorten treatment durations.

Baseline demographic characteristics are summarized in Table 5.
Differences among the groups

in mean age (p=0.017) and in distribution of race (p\<0.001) were found
to be statistically significant; these differences are of unclear
clinical significance. Most patients enrolled in this study had OA and
were elderly, white and female.

As seen in **Table 5**, fewer than 2% of patients in each treatment
group had a history of UGI bleeding (p=0.705). History of gastroduodenal
ulcers were not statistically significantly different among treatment
groups (p=0.543), however, NSAID intolerance was different (p\<0.001).
Positive results on FlexSure testing for *H. pylori* was also similar
among the groups (p=0.989).

The difference among treatment groups in self-reported alcohol use
(Table 5) was statistically significant: 30.9% of celecoxib patients
(when combined), 40.7% of diclofenac patients, and 19.4% of ibuprofen
patients reported some alcohol use (p\<0.001). Reported tobacco use was
similar among the treatment groups (p=0.455).

> ***Reviewer's comment: As can be seen in Table 5, the rates of
> self-reported alcohol use differed between protocol 035 and 102:***

The duration of arthritis (Table 5) was similar between OA and RA, at
approximately 10 to 11 years in all treatment groups. Regarding severity
of arthritis symptoms, patients generally gave a global assessment of
arthritis of fair, poor, or very poor (mean scores from 2.9-3.0) with
mean VAS pain scores ranging from 50.3 to 51.7 on the 100-mm scale. The
differences among the groups in these measures were not statistically
significant (p≥0.956 and 0.355 for global and pain, respectively).

As instructed, the majority of patients refrained from concurrent
medication use, although these medications were not specifically
prohibited by the protocols. The differences among the groups in any of
the categories of use were not statistically significant. However, a
noteworthy proportion of patients used aspirin during the trial; the
incidence of aspirin use was approximately 21% among the three groups
(Table 5).

The baseline demographic and concurrent medication data suggest that the
two celecoxib protocols were essentially homogeneous with respect to
these characteristics. The isolated statistically significant
differences noted do not suggest any consistent pattern of disparity
between the groups.

**^Table\ 5:\ Baseline\ demographic\ characteristics-ITT\ cohort^**1

+----------------------+-------+---------+----------+-------+-------+
| **Characteristic**   | **C   |         | **Dicl   | **I   | *     |
|                      | eleco |         | ofenac** | bupro | *p-va |
|                      | xib** |         |          | fen** | lue** |
|                      |       |         | **(n     |       |       |
|                      | **    |         | =1996)** | **    |       |
|                      | (n=39 |         |          | (n=19 |       |
|                      | 87)** |         |          | 85)** |       |
+----------------------+-------+---------+----------+-------+-------+
|                      | **    | **Study |          |       |       |
|                      | Study | 102**   |          |       |       |
|                      | 035** |         |          |       |       |
|                      |       | **(n=   |          |       |       |
|                      | **    | 1997)** |          |       |       |
|                      | (n=19 |         |          |       |       |
|                      | 90)** |         |          |       |       |
+----------------------+-------+---------+----------+-------+-------+
| Age (yrs)            | 60.2  | 60.9    | 60.1     | 59.5  | 0.0   |
|                      |       |         |          |       | 17^4^ |
| Mean                 | 61.0  | 61.0    | 61.0     | 60.0  |       |
|                      |       |         |          |       |       |
| Median               | 1226  | 1202    | 1234     | 1261  |       |
|                      | (     | (60.2)  | (61.8)   | (     |       |
| Range (%)            | 61.6) |         |          | 63.5) |       |
|                      |       | 562     | 526      |       |       |
| ≤64                  | 510   | (28.1)  | (26.4)   | 507   |       |
|                      | (     |         |          | (     |       |
| 65-74                | 25.6) | 233     | 236      | 25.5) |       |
|                      |       | (11.7)  | (11.8)   |       |       |
| ≥75                  | 254   |         |          | 217   |       |
|                      | (     |         |          | (     |       |
|                      | 12.8) |         |          | 10.9) |       |
+----------------------+-------+---------+----------+-------+-------+
| Gender (%)           | 637   | 618     | 650      | 580   | 0.1   |
|                      | (     | (30.9)  | (32.6)   | (     | 10^5^ |
| Male                 | 32.0) |         |          | 29.2) |       |
|                      |       | 1379    | 1346     |       |       |
| Female               | 1353  | (69.1)  | (67.4)   | 1405  |       |
|                      | (     |         |          | (     |       |
|                      | 68.0) |         |          | 70.8) |       |
+----------------------+-------+---------+----------+-------+-------+
| Race/Ethnic Origin   | 1730  | 1798    | 1784     | 1713  | \<0.0 |
| (%)                  | (     | (90.0)  | (89.4)   | (     | 01^5^ |
|                      | 86.9) |         |          | 86.3) |       |
| White                |       | 146     | 151      |       |       |
|                      | 155   | (7.3)   | (7.6)    | 172   |       |
| Black                | (7.8) |         |          | (8.7) |       |
|                      |       | 15      | 19 (1.0) |       |       |
| Asian                | 14    | (0.8)   |          | 9     |       |
|                      | (0.7) |         | 36 (1.8) | (0.5) |       |
| Hispanic             |       | 29      |          |       |       |
|                      | 78    | (1.5)   | 6 (0.3)  | 75    |       |
| Other                | (3.9) |         |          | (3.8) |       |
|                      |       | 9 (0.5) |          |       |       |
|                      | 13    |         |          | 16    |       |
|                      | (0.7) |         |          | (0.8) |       |
+----------------------+-------+---------+----------+-------+-------+
| Rheumatoid Arthritis | 548   | 523     | 536      | 542   |       |
| (%)                  | (     | (26.6)  | (27.0)   | (     |       |
|                      | 27.7) |         |          | 27.6) |       |
+----------------------+-------+---------+----------+-------+-------+
| Duration of Disease, | 10.07 | 10.43   | 10.35    | 9.94  | 0.7   |
| mean (SD)            | (9.6) | (9.8)   | (10.33)  | (9.5) | 34^4^ |
|                      |       |         |          |       |       |
| OA                   | 11.20 | 11.26   | 10.51    | 10.94 | 0.4   |
|                      | (9.7) | (10.03) | (9.4)    | (9.8) | 65^4^ |
| RA                   |       |         |          |       |       |
+----------------------+-------+---------+----------+-------+-------+
| Potential Risk       | 31    | 37      | 30 (1.5) | 28    | 0.7   |
| Factor (%)           | (1.6) | (1.9)   |          | (1.4) | 05^5^ |
|                      |       |         | 170      |       |       |
| History GI bleed     | 159   | 175     | (8.5)    | 151   | 0.5   |
|                      | (8.0) | (8.8)   |          | (7.6) | 43^5^ |
| History              |       |         | 202      |       |       |
| gastroduodenal ulcer | 138   | 209     | (10.1)   | 165   | \<0.0 |
|                      | (6.9) | (10.5)  |          | (8.3) | 01^5^ |
| GI-related NSAID     |       |         | 805      |       |       |
| intolerance^2^       | 795   | 807     | (40.3)   | 794   | 0.9   |
|                      | (     | (40.4)  |          | (     | 89^5^ |
| Cardiovascular       | 39.9) |         |          | 40.0) |       |
| disease              |       |         |          |       |       |
+----------------------+-------+---------+----------+-------+-------+
| H. pylori-Flexsure   | 780   | 756     | 752      | 769   | 0.7   |
| positive (%)         | (     | (37.9)  | (37.7)   | (     | 22^5^ |
|                      | 39.2) |         |          | 38.7) |       |
+----------------------+-------+---------+----------+-------+-------+
| Tobacco use (%)      | 320   | 309     | 311      | 284   | 0.4   |
|                      | (     | (15.5)  | (15.6)   | (     | 55^5^ |
|                      | 16.1) |         |          | 14.3) |       |
+----------------------+-------+---------+----------+-------+-------+
| Alcohol use (%)      | 380   | 852     | 812      | 386   | \<0.0 |
|                      | (     | (42.7)  | (40.7)   | (     | 01^5^ |
|                      | 19.1) |         |          | 19.4) |       |
+----------------------+-------+---------+----------+-------+-------+
| Pt global            | 2.9   | 3.0     | 3.0      | 2.9   | 0.9   |
| assessment, mean     | (     | (0.76)  | (0.74)   | (     | 65^6^ |
| (SD)                 | 0.69) |         |          | 0.70) |       |
+----------------------+-------+---------+----------+-------+-------+
| Pt pain-(0-100mm),   | 51.7  | 50.3    | 50.3     | 51.7  | 0.3   |
| mean (SD)            | (     | (25.1)  | (25.2)   | (     | 55^4^ |
|                      | 23.1) |         |          | 23.6) |       |
+----------------------+-------+---------+----------+-------+-------+
| Concurrent           | 410   | 423     | 429      | 383   | 0.3   |
| medications (%)      | (     | (21.2)  | (21.5)   | (     | 29^5^ |
|                      | 20.6) |         |          | 19.3) |       |
| #########            |       | 606     | 568      |       | 0.6   |
|   ASA (≤325 mg/d)^3^ | 613   | (30.3)  | (28.5)   | 607   | 01^5^ |
|                      | (     |         |          | (     |       |
| Corticosteroids      | 30.8) | 24      | 24 (1.2) | 30.6) | 0.5   |
| (any)                |       | (1.2)   |          |       | 02^5^ |
|                      | 18    |         |          | 20    |       |
| Anticoagulants (any) | (0.9) |         |          | (1.0) |       |
+----------------------+-------+---------+----------+-------+-------+

1.  From Appendix 2.2.3-2.2.10, N49-00-06-035-102, p. 2040-2047/24295;
    Table T6, p. 257/24295.

2.  Defined as a history of NSAID-induced gastroduodenal ulcers,
    NSAID-induced erosive gastritis or NSAID-induced upper GI symptoms
    of sufficient severity to cause discontinuation of NSAID use.

3.  Defined as **any** aspirin use during the first 6 months.

4.  P-value from Two-Way Analysis of Variance with treatment group and
    center as factors.

5.  P-value from Pearson's Chi-square test.

6.  P-value from Cochran-Mantel-Haenszel (Row Mean Scores Differ) test
    stratified by center.

**[Efficacy endpoint outcomes (Section 8.1.1.4.2)]{.underline}**

**Endpoint of CSUGIE:**

**CSUGIEs-first 6 months**:

A total of 1214 potential CSUGIEs (representing 1163 patients, not
mutually exclusive across classifications), occurred within the **first
six months** (182 days) of study participation and were worked up at the
investigational sites with referral to one or all members of the GI
events committee (GEC) for evaluation. The results (from Figure 8a, p.
66 of N49-00-06-035_102) can be summarized as follows:

-   **Total potential CSUGIE 1214 (1163 patients)**

-   **Reviewed by single GEC member 955**

-   **Negative events 954 (912 patients)**

-   **Potential CSUGIE (forwarded) 1**

-   **Reviewed by all GEC members 260**

-   **Non-CSUGIE 225 (224 patients)**

-   **CSUGIE 35 (35 patients)**

All of these cases were eventually classified as **negative event**s,
**non-CSUGIE**s, or **CSUGIEs** (see section 8.1.1.3.2). It should be
noted that the numbers of events exceeds the number of patients since
some patients experienced more than one potential CSUGIE. However, **any
patient who experienced a CSUGIE was withdrawn from the study**;
therefore, no patient experienced more than one actual CSUGIE. The
reported potential events classified as **negative cases** represented
nonspecific GI symptoms (e.g., nausea, abdominal pain/cramping, etc.),
decreases in hematocrit of unknown cause, non-GI symptoms (e.g.,
dizziness), non-localized minor GI bleeding episodes, and miscellaneous
laboratory abnormalities without corresponding clinical events. The
reported potential events classified as **non-CSUGIEs** included all of
the ulcers (i.e. gastroduodenal), as well as esophageal disease,
gastroduodenitis, small bowel/colonic/anorectal pathology, non-ulcer GI
bleeding, anemia, and miscellaneous GI symptoms and findings.

The 35 CSUGIEs (traditional definition) found within the first six
months are shown in **Table 6**. Thirteen (13) events occurred on
celecoxib treatment, nine (9) events on diclofenac treatment, and
thirteen (13) events on ibuprofen treatment. Four events (two in the
celecoxib group and two in the ibuprofen group) were censored owing to
the timing of their occurrence. All but one of the events (a gastric
outlet obstruction in the celecoxib group) represented bleeding events
in which an ulcer or large erosion was associated with either visual
evidence of bleeding, melena, or hemoccult-positive stools and a
decrease in hematocrit or hemoglobin. There were no UGI perforations**.
A narrative summary of each event can be found in the Appendix .**
Analyses and summaries of these events are shown in tables that follow.

**^Table\ 6:\ Distribution\ of\ CSUGIEs:\ Traditional\ Definitions\ -First\ Six\ Months1^**

+-------------------------------------------+--------+--------+-------+
| # Eve                                     | *      | **     | **I   |
| nt Category {#event-category .unnumbered} | *Celec | Diclof | bupro |
|                                           | oxib** | enac** | fen** |
|                                           |        |        |       |
|                                           | **(n=3 | **(n=1 | **    |
|                                           | 987)** | 996)** | (n=19 |
|                                           |        |        | 85)** |
+-------------------------------------------+--------+--------+-------+
| **UGI Bleeding (Category 1)**             | **-**  | **-**  | **-** |
|                                           |        |        |       |
| 1A: Hematemesis with ulcer/large erosion  | **7**  | **4**  | **7** |
|                                           |        |        |       |
| 1B: Ulcer/large erosion with evidence of  | **     | **4**  | **3   |
| bleeding                                  | 3^2^** |        | ^3^** |
|                                           |        | **1**  |       |
| 1C: Melena with ulcer/large erosion       | **     |        | **3** |
|                                           | 2^2^** | **-**  |       |
| [Hemoccult (+) stool with ulcer/large     |        |        | **-** |
| erosion and:]{.underline}                 | **-**  | **-**  |       |
|                                           |        |        | **-** |
| 1D-1: Hematocrit/Hemoglobin drop          | **-**  | **-**  |       |
|                                           |        |        | **-** |
| 1D-2: orthostasis                         | **-**  |        |       |
|                                           |        |        |       |
| 1D-3: transfusion                         |        |        |       |
|                                           |        |        |       |
| 1D-4: blood in stomach                    |        |        |       |
+-------------------------------------------+--------+--------+-------+
| **UGI Perforation (Category 2)**          | **-**  | **-**  | **-** |
+-------------------------------------------+--------+--------+-------+
| **Gastric Outlet Obstruction (Category    | **1**  | **-**  | **-** |
| 3)**                                      |        |        |       |
+-------------------------------------------+--------+--------+-------+
| ######### Total                           | **13** | **9**  | *     |
|                                           |        |        | *13** |
+-------------------------------------------+--------+--------+-------+
| **Total Uncensored**                      | **11** | **9**  | *     |
|                                           |        |        | *11** |
+-------------------------------------------+--------+--------+-------+

1.  From Table 8b (p.67), Table T13 (p. 270), appendix 2.6.1 (p. 2123);
    N49-00-06-035-102.

2.  One of these events censored from primary analysis.

3.  Two of these events censored from primary analysis

**Table 7** shows the rates (both crude and Kaplan-Meier) by time
interval of all CSUGIEs that occurred within the 182-day period. These
rates are in the entire ITT cohort. When all patients were included in
the analysis, regardless of aspirin status, the uncensored events were
shown to accrue in the ibuprofen group at a steady rate throughout the
first six months. For celecoxib, seven of the 11 uncensored events
occurred in the first three months. In the diclofenac group, all nine
events occurred in the first 100 days, with a cluster of five events
within the first 15 days and four more events occurring sporadically
through approximately day 85. The cumulative event rates were lower at
all time points (Weeks 1, 4, 13, and 26) for celecoxib than for either
of the NSAID comparators. The p-values comparisons, as noted in the
footnote of the table, are not statistically significantly different
between celecoxib and either NSAID, or when they were pooled.

**^Table\ 7:\ CSUGIEs\ (Traditional-ITT)-First\ 6\ months\ (Crude\ &\ Kaplan-Meier\ rates)^**1,2

+-------------+--------+--------+---------+---------+--------+-------+
|             | Cel    |        | Dic     |         | Ibu    |       |
|             | ecoxib |        | lofenac |         | profen |       |
|             |        |        |         |         |        |       |
|             | (n     |        | (       |         | (n     |       |
|             | =3987) |        | n=1996) |         | =1985) |       |
+-------------+--------+--------+---------+---------+--------+-------+
| Rates       | \+     | \-     | \+      | \-      | \+     | \-    |
|             | cen    | cen    | ce      | ce      | cen    | cens  |
|             | soring | soring | nsoring | nsoring | soring | oring |
+-------------+--------+--------+---------+---------+--------+-------+
| Crude       | 0.00%  | 0.03%  | 0.10%   | 0.10%   | 0.10%  | 0.15% |
|             |        |        |         |         |        |       |
| Week 1      | 0.03%  | 0.05%  | 0.25%   | 0.25%   | 0.20%  | 0.25% |
| (1-7)       |        |        |         |         |        |       |
|             | 0.18%  | 0.23%  | 0.40%   | 0.40%   | 0.30%  | 0.40% |
| Week 4      |        |        |         |         |        |       |
| (8-28)      | 0.28%  | 0.33%  | 0.45%   | 0.45%   | 0.55%  | 0.65% |
|             |        |        |         |         |        |       |
| Week 13     |        |        |         |         |        |       |
| (29-91)     |        |        |         |         |        |       |
|             |        |        |         |         |        |       |
| Week 26     |        |        |         |         |        |       |
| (92-182)    |        |        |         |         |        |       |
+-------------+--------+--------+---------+---------+--------+-------+
| K           | 0.01%  | 0.03%  | 0.10%   | 0.10%   | 0.12%  | 0.17% |
| aplan-Meier |        |        |         |         |        |       |
|             | 0.05%  | 0.07%  | 0.28%   | 0.28%   | 0.25%  | 0.31% |
| Week 1      |        |        |         |         |        |       |
| (1-7)       | 0.24%  | 0.30%  | 0.51%   | 0.51%   | 0.47%  | 0.58% |
|             |        |        |         |         |        |       |
| Week 4      | 0.37%  | 0.42%  | 0.52%   | 0.52%   | 0.75%  | 0.86% |
| (8-28)      |        |        |         |         |        |       |
|             |        |        |         |         |        |       |
| Week 13     |        |        |         |         |        |       |
| (29-91)     |        |        |         |         |        |       |
|             |        |        |         |         |        |       |
| Week 26     |        |        |         |         |        |       |
| (92-182)    |        |        |         |         |        |       |
+-------------+--------+--------+---------+---------+--------+-------+

1\. From Table T11.2 (p. 263); N49-00-06-035-102. Kaplan-Meier rates are
based on the highest Kaplan-Meier estimates within that time interval.
Uncensored events were defined as those meeting either of the following
two conditions: 1. Occurred after 48 hours past midnight of the first
dosing day and before 48 hours following midnight of the last dosing
day. 2. Occurred after 48 hours past midnight of the last dosing day and
before 2 weeks following midnight of the last dosing day and were
determined to be causally related to study drug by the GI events
committee. Events were censored if they failed to meet either of these
two conditions. For **censored events, log rank P-values** (Table T11.3,
p. 264) of celecoxib vs. NSAIDs = 0.092, celecoxib vs. diclofenac =
0.264, celecoxib vs. ibuprofen = 0.073. **For uncensored events, log
rank P-values** (Table T11.4, p. 265) of celecoxib vs. NSAIDs = 0.112,
celecoxib vs. diclofenac = 0.445, celecoxib vs. ibuprofen = 0.053.

**Table 8** shows the rates (both crude and Kaplan-Meier) by time
interval of all CSUGIEs that occurred within the 182-day period in **the
non-aspirin (ASA)** using ITT cohort. The p-values comparisons, as noted
in the footnote of the table, suggest statistically significant
differences between celecoxib and NSAIDs (p = 0.037 and 0.047 for
censored and uncensored respectively) and celecoxib and ibuprofen (with
or without censoring, p=0.005) but not between celecoxib and diclofenac.

**^Table\ 8:\ CSUGIEs\ without\ ASA\ (Traditional-ITT)-First\ 6\ months\ (Crude\ &\ Kaplan-Meier\ rates)^**1,2

+-------------+--------+--------+---------+---------+--------+-------+
|             | *      |        | **Diclo |         | *      |       |
|             | *Celec |        | fenac** |         | *Ibupr |       |
|             | oxib** |        |         |         | ofen** |       |
|             |        |        | **(n=   |         |        |       |
|             | **(n=3 |        | 1567)** |         | **(n=1 |       |
|             | 154)** |        |         |         | 602)** |       |
+-------------+--------+--------+---------+---------+--------+-------+
| Rates       | \+     | \-     | \+      | \-      | \+     | \-    |
|             | cen    | cen    | ce      | ce      | cen    | cens  |
|             | soring | soring | nsoring | nsoring | soring | oring |
+-------------+--------+--------+---------+---------+--------+-------+
| Crude       | 0.00%  | 0.03%  | 0.06%   | 0.06%   | 0.12%  | 0.12% |
|             |        |        |         |         |        |       |
| Week 1      | 0.00%  | 0.03%  | 0.19%   | 0.19%   | 0.25%  | 0.25% |
| (1-7)       |        |        |         |         |        |       |
|             | 0.13%  | 0.16%  | 0.26%   | 0.26%   | 0.37%  | 0.44% |
| Week 4      |        |        |         |         |        |       |
| (8-28)      | 0.16%  | 0.19%  | 0.26%   | 0.26%   | 0.62%  | 0.69% |
|             |        |        |         |         |        |       |
| Week 13     |        |        |         |         |        |       |
| (29-91)     |        |        |         |         |        |       |
|             |        |        |         |         |        |       |
| Week 26     |        |        |         |         |        |       |
| (92-182)    |        |        |         |         |        |       |
+-------------+--------+--------+---------+---------+--------+-------+
| K           | 0.01%  | 0.04%  | 0.10%   | 0.10%   | 0.14%  | 0.14% |
| aplan-Meier |        |        |         |         |        |       |
|             | 0.03%  | 0.06%  | 0.22%   | 0.22%   | 0.32%  | 0.32% |
| Week 1      |        |        |         |         |        |       |
| (1-7)       | 0.19%  | 0.23%  | 0.28%   | 0.28%   | 0.58%  | 0.65% |
|             |        |        |         |         |        |       |
| Week 4      | 0.20%  | 0.23%  | \-      | \-      | 0.81%  | 0.89% |
| (8-28)      |        |        |         |         |        |       |
|             |        |        |         |         |        |       |
| Week 13     |        |        |         |         |        |       |
| (29-91)     |        |        |         |         |        |       |
|             |        |        |         |         |        |       |
| Week 26     |        |        |         |         |        |       |
| (92-182)    |        |        |         |         |        |       |
+-------------+--------+--------+---------+---------+--------+-------+

1\. From Table T12.2 (p. 267); N49-00-06-035-102. Kaplan-Meier rates are
based on the highest Kaplan-Meier estimates within that time interval.
Uncensored and censored events as defined (Table 7 above).

2.For **censored events, log Rank P-values** (Table T12.3, p. 268) of
celecoxib vs. NSAIDs = 0.037, celecoxib vs. diclofenac = 0.476,
celecoxib vs. ibuprofen = 0.005. **For uncensored events, log Rank
P-values** (Table T12.4, p. 269) of celecoxib vs. NSAIDs = 0.047,
celecoxib vs. diclofenac = 0.651, celecoxib vs. ibuprofen = 0.005.

***Reviewer's comment: Subset analysis looking at ASA status was not a
prospectively defined endpoint in this trial.***

###### **CSUGIEs-Entire Study:**

A total of 1670 potential CSUGIEs (representing 1527 patients, not
mutually exclusive across classifications), occurred throughout the
**full length of the study** participation and were worked up at the
investigational sites with referral to one or all members of the GI
events committee (GEC) for evaluation. The results (figure 8b, p. 71
N49-00-06-035-102), can be summarized as follows:

-   **Total potential CSUGIE 1670 (1527 patients)**

-   **Reviewed by single GEC member 1287**

-   **Negative events 1286 (1186 patients)**

-   **Potential CSUGIE (forwarded) 1**

-   **Reviewed by all GEC members 384**

-   **Non-CSUGIE 340 (337 patients)**

-   **CSUGIE 44 (44 patients)**

All of these cases were eventually classified as **negative event**s,
**non-CSUGIE**s, or **CSUGIEs** (see section 8.1.1.3.2). It should be
noted that the numbers of events exceeds the number of patients since
some patients experienced more than one potential CSUGIE. However, any
patient who experienced a CSUGIE was withdrawn from the study;
therefore, no patient experienced more than one actual CSUGIE.

The 44 events found to represent CSUGIEs through the entire study period
are shown by treatment group and category in Table 9. Twenty events
occurred on celecoxib treatment, 11 on diclofenac, and 13 on ibuprofen.
This table includes all CSUGIEs that met the traditional definition,
including those that were censored from the primary analysis owing to
the timing of their occurrence (three in the celecoxib group, one in the
diclofenac group, and 2 in the ibuprofen group). All events were
classified into the same categories as those that occurred in the first
six months, with the following exceptions: one bleeding event in the
celecoxib group represented category 1A, and two UGI perforations
occurred, one in the celecoxib group and one in the diclofenac group.

^**Table\ 9:**\ **Distribution\ of\ CSUGIEs:\ Traditional\ Definitions\ --Entire\ Study\ Period1**^

+-------------------------------------------+--------+--------+-------+
| # Event                                   | *      | **     | **I   |
|  Category {#event-category-1 .unnumbered} | *Celec | Diclof | bupro |
|                                           | oxib** | enac** | fen** |
|                                           |        |        |       |
|                                           | **(n=3 | **(n=1 | **    |
|                                           | 987)** | 996)** | (n=19 |
|                                           |        |        | 85)** |
+-------------------------------------------+--------+--------+-------+
| **UGI Bleeding (Category 1)**             | **1**  | **-**  | **-** |
|                                           |        |        |       |
| 1A: Hematemesis with ulcer/large erosion  | **8**  | **4**  | **7** |
|                                           |        |        |       |
| 1B: Ulcer/large erosion with evidence of  | **     | **4**  | **3   |
| bleeding                                  | 5^3^** |        | ^3^** |
|                                           |        | **2**  |       |
| 1C: Melena with ulcer/large erosion       | **     |        | **3** |
|                                           | 3^2^** | **-**  |       |
| [Hemoccult (+) stool with ulcer/large     |        |        | **-** |
| erosion and:]{.underline}                 | **-**  | **-**  |       |
|                                           |        |        | **-** |
| 1D-1: Hematocrit/Hemoglobin drop          | **-**  | **-**  |       |
|                                           |        |        | **-** |
| 1D-2: orthostasis                         | **-**  |        |       |
|                                           |        |        |       |
| 1D-3: transfusion                         |        |        |       |
|                                           |        |        |       |
| 1D-4: blood in stomach                    |        |        |       |
+-------------------------------------------+--------+--------+-------+
| **UGI Perforation (Category 2)**          | **1**  | **     | **-** |
|                                           |        | 1^2^** |       |
+-------------------------------------------+--------+--------+-------+
| **Gastric Outlet Obstruction (Category    | **2**  | **-**  | **-** |
| 3)**                                      |        |        |       |
+-------------------------------------------+--------+--------+-------+
| ######### Total                           | **20** | **11** | *     |
|                                           |        |        | *13** |
+-------------------------------------------+--------+--------+-------+
| **Total Uncensored**                      | **17** | **10** | *     |
|                                           |        |        | *11** |
+-------------------------------------------+--------+--------+-------+

1.  From Table 8e (p.72), Table T1 (p. 279), appendix 2.6.1 (p. 2123);
    N49-00-06-035-102.

2.  One of these events censored from primary analysis.

3.  Two of these events censored from primary analysis

**Table 10** shows the rates (both crude and Kaplan-Meier) by time
interval of all CSUGIEs that occurred within the entire study. These
rates are in the entire ITT cohort. **When all patients were included in
the analysis, regardless of aspirin status, the uncensored events were
shown to continue to accrue in the celecoxib group at a generally steady
rate from six months through the end of the study. In contrast, only one
uncensored event occurred in the diclofenac group after 182 days, and
none occurred in the ibuprofen group.** The curves for the two NSAIDs
therefore become essentially flat in the second half of the study, with
the result that the end points of the three curves are similar at the
end of the study. As argued by the Sponsor, the decrease in accrual of
events in patients taking NSAIDs suggests the possibility of depletion
of patients at risk (depletion of susceptible patients, or informative
censoring; see below). **The p-values comparisons, as noted in the
footnote of the table, are not statistically significantly different
between celecoxib and either NSAID, or when they were pooled.**

**^Table\ 10:\ CSUGIEs\ (Traditional-ITT)-Entire\ Study\ (Crude\ &\ Kaplan-Meier\ rates)^**1,2

+---------------+--------+-------+---------+-------+--------+-------+
|               | *      |       | **Diclo |       | *      |       |
|               | *Celec |       | fenac** |       | *Ibupr |       |
|               | oxib** |       |         |       | ofen** |       |
|               |        |       | **(n=   |       |        |       |
|               | **(n=3 |       | 1996)** |       | **(n=1 |       |
|               | 987)** |       |         |       | 985)** |       |
+---------------+--------+-------+---------+-------+--------+-------+
| Rates         | \+     | \-    | \+      | \-    | \+     | \-    |
|               | cen    | cens  | ce      | cens  | cen    | cens  |
|               | soring | oring | nsoring | oring | soring | oring |
+---------------+--------+-------+---------+-------+--------+-------+
| Crude         | 0.00%  | 0.03% | 0.10%   | 0.10% | 0.10%  | 0.15% |
|               |        |       |         |       |        |       |
| Week 1 (1-7)  | 0.03%  | 0.05% | 0.25%   | 0.25% | 0.20%  | 0.25% |
|               |        |       |         |       |        |       |
| Week 4 (8-28) | 0.18%  | 0.23% | 0.40%   | 0.40% | 0.30%  | 0.40% |
|               |        |       |         |       |        |       |
| Week 13       | 0.28%  | 0.33% | 0.45%   | 0.45% | 0.55%  | 0.65% |
| (29-91)       |        |       |         |       |        |       |
|               | 0.35%  | 0.43% | 0.50%   | 0.50% | 0.55%  | 0.65% |
| Week 26       |        |       |         |       |        |       |
| (92-182)      | 0.43%  | 0.50% | 0.50%   | 0.55% | 0.55%  | 0.65% |
|               |        |       |         |       |        |       |
| Week 39       |        |       |         |       |        |       |
| (183-273)     |        |       |         |       |        |       |
|               |        |       |         |       |        |       |
| Week 52       |        |       |         |       |        |       |
| (274-364)     |        |       |         |       |        |       |
+---------------+--------+-------+---------+-------+--------+-------+
| Kaplan-Meier  | 0.01%  | 0.03% | 0.10%   | 0.10% | 0.12%  | 0.17% |
|               |        |       |         |       |        |       |
| Week 1 (1-7)  | 0.05%  | 0.07% | 0.28%   | 0.28% | 0.25%  | 0.31% |
|               |        |       |         |       |        |       |
| Week 4 (8-28) | 0.24%  | 0.30% | 0.51%   | 0.51% | 0.47%  | 0.58% |
|               |        |       |         |       |        |       |
| Week 13       | 0.40%  | 0.45% | 0.58%   | 0.58% | 0.75%  | 0.86% |
| (29-91)       |        |       |         |       |        |       |
|               | 0.54%  | 0.65% | 0.62%   | 0.71% | \-     | \-    |
| Week 26       |        |       |         |       |        |       |
| (92-182)      | 0.68%  | 0.78% | \-      | 0.73% | \-     | \-    |
|               |        |       |         |       |        |       |
| Week 39       |        |       |         |       |        |       |
| (183-273)     |        |       |         |       |        |       |
|               |        |       |         |       |        |       |
| Week 52       |        |       |         |       |        |       |
| (274-364)     |        |       |         |       |        |       |
+---------------+--------+-------+---------+-------+--------+-------+

1\. From Table T12.2 (p. 267); N49-00-06-035-102. Kaplan-Meier rates are
based on the highest Kaplan-Meier estimates within that time interval.
Uncensored and censored events were previously defined (Table 7 above).

2.For **censored events, log Rank P-values** (Table T14.3, p. 273) of
celecoxib vs. NSAIDs = 0.450, celecoxib vs. diclofenac = 0.640,
celecoxib vs. ibuprofen = 0.414. **For uncensored events, log Rank
P-values** (Table T14.4, p. 274) of celecoxib vs. NSAIDs = 0.474,
celecoxib vs. diclofenac = 0.752, celecoxib vs. ibuprofen = 0.372.

**Table 11** shows the rates (both crude and Kaplan-Meier) by time
interval of all CSUGIEs that occurred during the entire study. These
rates are in the non-aspirin (ASA) using ITT cohort. The p-values
comparisons, as noted in the footnote of the table **do not suggest
statistically significantly difference between celecoxib and NSAIDs
(both censored and uncensored results) nor between celecoxib and
diclofenac (with or without censoring) but do between celecoxib and
ibuprofen (p = 0.037 and 0.033 with and without censoring,
respectively).**

**^Table\ 11:\ CSUGIEs\ without\ ASA\ (Traditional-ITT)-Entire\ Study\ (Crude\ &\ Kaplan-Meier\ rates)^**1,2

+---------------+--------+-------+---------+-------+--------+-------+
|               | Cel    |       | Dic     |       | Ibu    |       |
|               | ecoxib |       | lofenac |       | profen |       |
|               |        |       |         |       |        |       |
|               | (n     |       | (       |       | (n     |       |
|               | =3105) |       | n=1551) |       | =1573) |       |
+---------------+--------+-------+---------+-------+--------+-------+
| Rates         | \+     | \-    | \+      | \-    | \+     | \-    |
|               | cen    | cens  | ce      | cens  | cen    | cens  |
|               | soring | oring | nsoring | oring | soring | oring |
+---------------+--------+-------+---------+-------+--------+-------+
| Crude         | 0.00%  | 0.03% | 0.06%   | 0.06% | 0.13%  | 0.13% |
|               |        |       |         |       |        |       |
| Week 1 (1-7)  | 0.00%  | 0.03% | 0.19%   | 0.19% | 0.25%  | 0.25% |
|               |        |       |         |       |        |       |
| Week 4 (8-28) | 0.13%  | 0.16% | 0.26%   | 0.26% | 0.38%  | 0.45% |
|               |        |       |         |       |        |       |
| Week 13       | 0.16%  | 0.19% | 0.26%   | 0.26% | 0.64%  | 0.70% |
| (29-91)       |        |       |         |       |        |       |
|               | 0.23%  | 0.26% | 0.26%   | 0.26% | 0.64%  | 0.70% |
| Week 26       |        |       |         |       |        |       |
| (92-182)      | 0.26%  | 0.29% | 0.26%   | 0.26% | 0.64%  | 0.70% |
|               |        |       |         |       |        |       |
| Week 39       |        |       |         |       |        |       |
| (183-273)     |        |       |         |       |        |       |
|               |        |       |         |       |        |       |
| Week 52       |        |       |         |       |        |       |
| (274-364)     |        |       |         |       |        |       |
+---------------+--------+-------+---------+-------+--------+-------+
| Kaplan-Meier  | 0.01%  | 0.04% | 0.10%   | 0.10% | 0.15%  | 0.15% |
|               |        |       |         |       |        |       |
| Week 1 (1-7)  | 0.03%  | 0.06% | 0.23%   | 0.23% | 0.32%  | 0.32% |
|               |        |       |         |       |        |       |
| Week 4 (8-28) | 0.20%  | 0.23% | 0.28%   | 0.28% | 0.59%  | 0.67% |
|               |        |       |         |       |        |       |
| Week 13       | 0.25%  | 0.29% | \-      | \-    | 0.83%  | 0.91% |
| (29-91)       |        |       |         |       |        |       |
|               | 0.35%  | 0.38% | \-      | \-    | \-     | \-    |
| Week 26       |        |       |         |       |        |       |
| (92-182)      | 0.41%  | 0.44% | \-      | \-    | \-     | \-    |
|               |        |       |         |       |        |       |
| Week 39       |        |       |         |       |        |       |
| (183-273)     |        |       |         |       |        |       |
|               |        |       |         |       |        |       |
| Week 52       |        |       |         |       |        |       |
| (274-364)     |        |       |         |       |        |       |
+---------------+--------+-------+---------+-------+--------+-------+

1\. From Table T15.2 (p. 276); N49-00-06-035-102. Kaplan-Meier rates are
based on the highest Kaplan-Meier estimates within that time interval.
Uncensored and censored events were previously defined (Table 7 above).

2\. For **censored events, log Rank P-values** (Table T15.3, p. 277) of
celecoxib vs. NSAIDs = 0.185, celecoxib vs. diclofenac = 0.972,
celecoxib vs. ibuprofen = 0.037. **For uncensored events, log Rank
P-values** (Table T15.4, p. 278) of celecoxib vs. NSAIDs = 0.204,
celecoxib vs. diclofenac = 0.870, celecoxib vs. ibuprofen = 0.033.

**[CSUGIEs (Alternate Definition) Entire Study]{.underline}:**

As shown above, 40 of the 44 CSUGIEs that occurred during the entire
study period were UGI

bleeding events according to the traditional definition. Of these 40, 31
met one of the more restrictive alternate definitions of UGI bleeding
(see section 8.1.1.3.2). These 31 uncensored events, along with the
perforations and gastric outlet obstructions, are shown by category in
Table 12. **No statistical analysis of the data were performed**. The
profile of the events, however, is similar to that for CSUGIEs according
to the traditional definition. The event rates were generally similar
between the groups for the first six months of the study. Thereafter,
events continued to accrue in the celecoxib group but not in the two
NSAID groups. The difference between celecoxib and the NSAIDs was
augmented by the fact that all of the uncensored traditional CSUGIEs in
the celecoxib group met one of the alternate definitions, whereas this
was true for only half of the events in the diclofenac group and nine of
the 11 events in the ibuprofen group.

**^Table\ 12:\ CSUGIEs:\ Alternate\ Definitions-Entire\ Study\ Period^**1

+-------------------------------------------+--------+-------+--------+
| Event Category                            | Cel    | Diclo | Ibu    |
|                                           | ecoxib | fenac | profen |
|                                           |        |       |        |
|                                           | (n     | (n=   | (n     |
|                                           | =3987) | 1996) | =1985) |
+-------------------------------------------+--------+-------+--------+
| **UGI Bleeding (Category 1)**             | 1      | \-    | \-     |
|                                           |        |       |        |
| 1E: Hematemesis with ulcer/large erosion  | 8      | 2     | 6      |
| and either                                |        |       |        |
|                                           | 5^2^   | 2     | 2^3^   |
| hemoglobin drop or hypotension            |        |       |        |
|                                           | 2      | 1     | 2      |
| 1F: Ulcer/large erosion with evidence of  |        |       |        |
| bleeding and either                       |        |       |        |
|                                           |        |       |        |
| hemoglobin drop or hypotension            |        |       |        |
|                                           |        |       |        |
| 1G: Melena with ulcer/large erosion and   |        |       |        |
| either hemoglobin drop or hypotension     |        |       |        |
|                                           |        |       |        |
| 1H: Hemoccult-positive stool with         |        |       |        |
| ulcer/large erosion and either            |        |       |        |
|                                           |        |       |        |
| hemoglobin drop or hypotension.           |        |       |        |
+-------------------------------------------+--------+-------+--------+
| **UGI Perforation (Category 2)**          | 1      | 1^3^  | \-     |
+-------------------------------------------+--------+-------+--------+
| **Gastric Outlet Obstruction (Category    | 2      | \-    | \-     |
| 3)**                                      |        |       |        |
+-------------------------------------------+--------+-------+--------+
| #### Total                                | 19     | 6     | 10     |
+-------------------------------------------+--------+-------+--------+
| **Total Uncensored**                      | 17     | 5     | 9      |
+-------------------------------------------+--------+-------+--------+
| **Week 52 crude rate (censoring rule      | 0.43%  | 0.25% | 0.45%  |
| applied)**                                |        |       |        |
+-------------------------------------------+--------+-------+--------+

1.  From Table 8u (p. 157) and 8v (p. 158); N49-00-06-035-102.

2.  Two of these events censored from primary analysis.

3.  One of these events censored from primary analysis.

**[Summary-CSUGIEs for 6 months and entire study:]{.underline}**

Table 13 summarizes the incidence of CSUGIEs and the results during the
first six months in the ITT population. The p-value comparisons are for
uncensored events.

^Table\ 13:\ Summary\ of\ CSUGIE\ Incidence\ (Traditional\ definition)\ -\ First\ Six\ Months\ (ITT)1^

+-------------+--------+---------+-----------+-------+--------+-------+
|             | Cel    | Dic     | Ibuprofen | Log   |        |       |
|             | ecoxib | lofenac |           | -Rank |        |       |
|             |        |         | 800 mg    | P     |        |       |
|             | 400 mg | 75 mg   | TID       | V     |        |       |
|             | BID    | BID     |           | alues |        |       |
|             |        |         |           | for   |        |       |
|             |        |         |           | Cele  |        |       |
|             |        |         |           | coxib |        |       |
|             |        |         |           |       |        |       |
|             |        |         |           | vs.   |        |       |
|             |        |         |           |       |        |       |
|             |        |         |           | Diclo |        |       |
|             |        |         |           | fenac |        |       |
|             |        |         |           | Ibup  |        |       |
|             |        |         |           | rofen |        |       |
|             |        |         |           | Both  |        |       |
+-------------+--------+---------+-----------+-------+--------+-------+
| ## A        |        |         |           |       |        |       |
| ll Patients |        |         |           |       |        |       |
+-------------+--------+---------+-----------+-------+--------+-------+
|             | n =    | n =     | n = 1985  |       |        |       |
|             | 3987   | 1996    |           |       |        |       |
+-------------+--------+---------+-----------+-------+--------+-------+
| No. of      | 11     | 9       | 11        |       |        |       |
| CSUGIEs     |        |         |           |       |        |       |
|             | 2      | 0       | 2         |       |        |       |
| Uncensored  |        |         |           |       |        |       |
|             | 13     | 9       | 13        |       |        |       |
| Censored^2^ |        |         |           |       |        |       |
|             |        |         |           |       |        |       |
| Total       |        |         |           |       |        |       |
+-------------+--------+---------+-----------+-------+--------+-------+
| Week 26     | 0.28%  | 0.45%   | 0.55%     | **0.  | **0    | **0.  |
| crude       |        |         |           | 264** | .073** | 092** |
| rate^3^     |        |         |           |       |        |       |
+-------------+--------+---------+-----------+-------+--------+-------+
| No. per 100 | 0.76   | 1.27    | 1.63      |       |        |       |
| pt-yrs      |        |         |           |       |        |       |
+-------------+--------+---------+-----------+-------+--------+-------+
| ## Patie    |        |         |           |       |        |       |
| nts not Tak |        |         |           |       |        |       |
| ing Aspirin |        |         |           |       |        |       |
+-------------+--------+---------+-----------+-------+--------+-------+
|             | n =    | n =     | n = 1602  |       |        |       |
|             | 3154   | 1567    |           |       |        |       |
+-------------+--------+---------+-----------+-------+--------+-------+
| No. of      | 5      | 4       | 10        |       |        |       |
| CSUGIEs     |        |         |           |       |        |       |
|             | 1      | 0       | 1         |       |        |       |
| Uncensored  |        |         |           |       |        |       |
|             | 6      | 4       | 11        |       |        |       |
| Censored    |        |         |           |       |        |       |
|             |        |         |           |       |        |       |
| Total       |        |         |           |       |        |       |
+-------------+--------+---------+-----------+-------+--------+-------+
| Week 26     | 0.16%  | 0.26%   | 0.62%     | **0.  | **0    | **0.  |
| crude       |        |         |           | 476** | .005** | 037** |
| rate^3^     |        |         |           |       |        |       |
+-------------+--------+---------+-----------+-------+--------+-------+
| No. per 100 | 0.44   | 0.72    | 1.85      |       |        |       |
| pt-yrs      |        |         |           |       |        |       |
+-------------+--------+---------+-----------+-------+--------+-------+

1.  From T11.1 & T12.1, N49-00-06-035-102, p. 262 and 266/24295.

2.  Occurred before 48 hours after midnight of the first dose day or
    more than 48 hours after midnight of the last dose day (unless
    occurred within two weeks after last dose and was determined by GEC
    to be treatment-related).

3.  Rates and p-values based upon uncensored events.

**Table 14** summarizes the incidence of CSUGIEs and the results during
the entire study in the ITT population. The p-value comparisons are for
uncensored events.

^Table\ 14:\ Summary\ of\ CSUGIE\ Incidence\ (Traditional\ definition)\ -\ Entire\ Study\ Period\ (ITT)2^

+-------------+--------+---------+-----------+-------+-------+-------+
|             | Cel    | Dic     | Ibuprofen | Log   |       |       |
|             | ecoxib | lofenac |           | -Rank |       |       |
|             |        |         | 800 mg    | P     |       |       |
|             | 400 mg | 75 mg   | TID       | V     |       |       |
|             | BID    | BID     |           | alues |       |       |
|             |        |         |           | for   |       |       |
|             |        |         |           | Cele  |       |       |
|             |        |         |           | coxib |       |       |
|             |        |         |           |       |       |       |
|             |        |         |           | vs.   |       |       |
|             |        |         |           |       |       |       |
|             |        |         |           | Diclo |       |       |
|             |        |         |           | fenac |       |       |
|             |        |         |           | Ibup  |       |       |
|             |        |         |           | rofen |       |       |
|             |        |         |           | Both  |       |       |
+-------------+--------+---------+-----------+-------+-------+-------+
| ## A        |        |         |           |       |       |       |
| ll Patients |        |         |           |       |       |       |
+-------------+--------+---------+-----------+-------+-------+-------+
|             | n =    | n =     | n = 1985  |       |       |       |
|             | 3987   | 1996    |           |       |       |       |
+-------------+--------+---------+-----------+-------+-------+-------+
| No. of      | 17     | 10      | 11        |       |       |       |
| CSUGIEs     |        |         |           |       |       |       |
|             | 3      | 1       | 2         |       |       |       |
| Uncensored  |        |         |           |       |       |       |
|             | 20     | 11      | 13        |       |       |       |
| Censored^1^ |        |         |           |       |       |       |
|             |        |         |           |       |       |       |
| Total       |        |         |           |       |       |       |
+-------------+--------+---------+-----------+-------+-------+-------+
| Week 52     | 0.43%  | 0.50%   | 0.55%     | **0.  | **0.  | **0.  |
| crude       |        |         |           | 640** | 414** | 450** |
| rate^3^     |        |         |           |       |       |       |
+-------------+--------+---------+-----------+-------+-------+-------+
| No. per 100 | 0.73   | 0.93    | 0.98      |       |       |       |
| pt-yrs      |        |         |           |       |       |       |
+-------------+--------+---------+-----------+-------+-------+-------+
| ## Patie    |        |         |           |       |       |       |
| nts not Tak |        |         |           |       |       |       |
| ing Aspirin |        |         |           |       |       |       |
+-------------+--------+---------+-----------+-------+-------+-------+
|             | n =    | n =     | n = 1602  |       |       |       |
|             | 3105   | 1551    |           |       |       |       |
+-------------+--------+---------+-----------+-------+-------+-------+
| No. of      | 8      | 4       | 10        |       |       |       |
| CSUGIEs     |        |         |           |       |       |       |
|             | 1      | 0       | 1         |       |       |       |
| Uncensored  |        |         |           |       |       |       |
|             | 9      | 4       | 11        |       |       |       |
| Censored    |        |         |           |       |       |       |
|             |        |         |           |       |       |       |
| Total       |        |         |           |       |       |       |
+-------------+--------+---------+-----------+-------+-------+-------+
| Week 52     | 0.26%  | 0.26%   | 0.62%     | **0.  | **0.  | **0.  |
| crude rate  |        |         |           | 972** | 037** | 185** |
+-------------+--------+---------+-----------+-------+-------+-------+
| No. per 100 | 0.44   | 0.48    | 1.14      |       |       |       |
| pt-yrs      |        |         |           |       |       |       |
+-------------+--------+---------+-----------+-------+-------+-------+

1.  Occurred before 48 hours after midnight of the first dose day or
    more than 48 hours after midnight of the last dose day (unless
    occurred within two weeks after last dose and was determined by GEC
    to be treatment-related).

```{=html}
<!-- -->
```
2.  From Table T14.1 & T15.1, N49-00-06-035-102, p. 271 & 275/24295.

3.  Rates and p-values based upon uncensored events.

**[Censored events and informative censoring:]{.underline}**

# Censored events {#censored-events .unnumbered}

As noted in Table 15, six of the events were censored from the primary
analysis for the entire study period; therefore this also includes the
four censored events described for the first 6 months (Table 13).
**Uncensored events** were defined as those meeting either of the
following two conditions (i.e. events were censored if they failed to
meet either of these two conditions:

1.  Occurred after 48 hours past midnight of the first dosing day and
    before 48 hours following midnight of the last dosing day.

2.  Occurred after 48 hours past midnight of the last dosing day and
    before 2 weeks following midnight of the last dosing day and were
    determined to be causally related to study drug by the GI events
    committee.

In these analyses, **onset of** **a CSUGIE was defined as the day on
which signs or symptoms first occurred that were suggestive of a
potential CSUGIE**; onset of an ulcer was defined as the day of the
endoscopy that disclosed the ulcer. When these censored cases were
included in the analysis along with the uncensored cases, the trends and
comparisons shown in the Tables above were repeated; this includes the
statistically significant difference between celecoxib and ibuprofen
event rates in the non-aspirin-taking cohort.

**Table 15** shows the reasons for censoring of CSUGIEs during the
study. **Case 1029** started therapy (ibuprofen) on 12/4/98, noted GI
symptoms on the second day (12/5,98) and discontinued ibuprofen the
following day (12/6/98). On study day five (12/9/98), the patient was
noted with a heme positive stool (12/9/98) and had endoscopy (12/11/98).
**Case 1056** started therapy (celecoxib) on 12/11/98 (which may have
been her last day of naproxen sodium), developed a rash on study day 9
(12/19/98) or 11 (12/21/98) when therapy was stopped; the patient also
had complaints of abdominal pain at that time. By patient request,
endoscopy was not done until 1/29/99. As typed summary in the CRF for
case 1029 states "it is believed patient began having black stools on
12/12/98".

**Table 15: Reasons for Censoring of CSUGIEs - Entire Study Period**

+-----------------------------------------------------------------------+
| ###                                                                   |
| ###### Case No. Patient No. Treatment Event Type Reason for Censoring |
+-----------------------------------------------------------------------+
| 1029 US0417-035-20397 Ibuprofen 1C Event onset on day 2               |
+-----------------------------------------------------------------------+
| 1056 US0114-035-11573 Celecoxib 1C Event onset on day 2               |
+-----------------------------------------------------------------------+
| 1201 US0039-035-21235 Celecoxib 1D1 Onset 19 days after D/C           |
+-----------------------------------------------------------------------+
| 1245 US0328-102-11895 Celecoxib 1C Onset 8 days after D/C;            |
|                                                                       |
| use of ketorolac                                                      |
+-----------------------------------------------------------------------+
| 1297 US0591-102-10168 Diclofenac 2 Onset 35 days after D/C            |
+-----------------------------------------------------------------------+
| 1383 CA0484-035-12170 Ibuprofen 1C Onset 18 days after D/C            |
+-----------------------------------------------------------------------+

Reviewer's comment: One could argue that case 1056 does not fulfill the
spirit of the censoring rules.

**Homogeneity between the two protocols** was addressed by comparing the
counts and rates of CSUGIEs for celecoxib separately. There were 8 (2
censored) events in protocol 035 and 12 events (1 censored) in protocol
102. By log rank testing with censoring applied to the traditional
endpoint definition, there was no statistically significant difference
(p =0.237; page 2052, N49-00-06-035-102,) noted between these protocols
which suggests these trials were homogeneous with respect to assessment
of this endpoint.

**[Informative censoring]{.underline}**

Univariate analyses of potential risk factors for both end points of
primary interest (CSUGIEs and CSUGIEs/GDUs) showing a statistically
significant factor effect within either the celecoxib or pooled NSAID
group are summarized in **Table 16**.

The common risk factor for both end points (CSUGIEs and CSUGIEs/GDUs) in
both the celecoxib and NSAID treatment groups was advanced age ≥75
years). Additional risk factors specific to NSAIDs for both end points
were a history of UGI bleeding and a history of gastroduodenal ulcer.
For celecoxib, the common risk factors for both end points were a
history of cardiovascular disease and aspirin use. The risk factor
common to celecoxib and NSAIDs for CSUGIEs/GDUs alone was a history of
NSAID intolerance.

**^[Table\ 16:\ Univariate\ Analysis\ of\ Risk\ Factors\ for\ CSUGIEs\ and\ CSUGIEs/GDUs1]{.underline}^**

+---------------------+-----------+------------+---------+-----------+
| **Factor**          | *         |            |         |           |
|                     | *Relative |            |         |           |
|                     | Risk**    |            |         |           |
+---------------------+-----------+------------+---------+-----------+
|                     | **        |            | **      |           |
|                     | CSUGIEs** |            | CSUGIEs |           |
|                     |           |            | /GDUs** |           |
+---------------------+-----------+------------+---------+-----------+
|                     | **Ce      | **NSAIDs** | **Cele  | *         |
|                     | lecoxib** |            | coxib** | *NSAIDs** |
|                     |           |            |         |           |
|                     | **400 mg  |            | **400   |           |
|                     | BID**     |            | mg      |           |
|                     |           |            | BID**   |           |
+---------------------+-----------+------------+---------+-----------+
| Age ≥75 years       | 5.0       | 5.8        | 3.5     | 3.7       |
|                     | (         | (p\<0.001) | (p\     | (         |
| Patient's Global    | p\<0.001) |            | <0.001) | p\<0.001) |
| (baseline)          |           | 2.4        |         |           |
|                     | 2.5       | (p=0.045)  | 1.4     | 1.4       |
| History of UGI      | (p=0.037) |            | (p      | (p=0.144) |
| bleeding            |           | 7.1        | =0.202) |           |
|                     | 3.6       | (p=0.006)  |         | 3.4       |
| History of GD ulcer | (p=0.144) |            | 4.3     | (p=0.019) |
|                     |           | 3.6        | (p      |           |
| History of NSAID    | 1.5       | (p=0.009)  | =0.006) | 2.7       |
| intolerance History | (p=0.509) |            |         | (         |
| of CV disease       |           | 2.3        | 2.9     | p\<0.001) |
| positive H. pylori  | 2.2       | (p=0.105)  | (p      |           |
| serology            | (p=0.183) |            | =0.002) | 1.9       |
|                     |           | 1.6        |         | (p=0.037) |
| Aspirin use         | 6.9       | (p=0.240)  | 3.2     |           |
|                     | (p=0.002) |            | (p      | 1.6       |
|                     |           | 2.2        | =0.001) | (p=0.048) |
|                     | 0.7       | (p=0.072)  |         |           |
|                     | (p=0.460) |            | 2.5     | 2.0       |
|                     |           | 1.8        | (p      | (p=0.005) |
|                     | 4.0       | (p=0.211)  | =0.002) |           |
|                     | (p=0.005) |            |         | 2.3       |
|                     |           |            | 1.1     | (p=0.002) |
|                     |           |            | (p      |           |
|                     |           |            | =0.423) |           |
|                     |           |            |         |           |
|                     |           |            | 3.7     |           |
|                     |           |            | (p\     |           |
|                     |           |            | <0.001) |           |
+---------------------+-----------+------------+---------+-----------+

1.  From Table 8.1 (p. 147), Table T23.1 (p. 303), Table T23.3 (p. 305),
    Table T24.1 (p. 307), Table T24.3 (p. 309), Table T25.1 (p. 311) and
    Table T 25.3 (p. 313); N49-00-06-035-102.

Multivariate regression for the risk factors for CSUGIEs/GDUs common to
celecoxib and NSAIDs are shown in **Table 17**. Risk factors for
CSUGIEs/GDUs were similar between celecoxib and NSAIDs, although their
relative contribution differed between the two groups. For celecoxib,
aspirin use appeared as the most important risk factor, and age the
least important. For NSAIDs, the order was reversed, with age the most
important risk factor and aspirin use the least important.

**^Table\ 17:\ Multivariate\ Analysis\ of\ Risk\ Factors\ for\ CSUGIEs/GDUs1^**

+-----------------------+-----------------------+-----------------------+
| **Treatment Group**   | **Factor**            | **Odds Ratio (p       |
|                       |                       | Value)**              |
+-----------------------+-----------------------+-----------------------+
| Celecoxib             | Aspirin use           | 2.9 (p\<0.001)        |
|                       |                       |                       |
|                       | History of GD ulcer   | 2.5 (p=0.018)         |
|                       |                       |                       |
|                       | Age ≥75 years         | 2.4 (p=0.012)         |
+-----------------------+-----------------------+-----------------------+
| NSAIDs                | Age ≥75 years         | 3.3 (p\<0.001)        |
|                       |                       |                       |
|                       | History of GD ulcer   | 2.6 (p=0.004)         |
|                       |                       |                       |
|                       | Aspirin use           | 2.1 (p=0.006)         |
+-----------------------+-----------------------+-----------------------+

1 From Table 8.m (p. 148); N49-00-06-035-102.

**Withdrawal in Patients with Risk Factors**

The analyses above seem to confirm what is generally accepted that in GI
safety studies in NSAID-treated patients, there are some risk factors
(such as age, history of GI ulcer, GI bleeding, and cardiovascular
disease) that are associated with GI outcomes. **Table 18** addresses,
and seems to confirm, the generally accepted idea that patients falling
into one or more of these categories have a greater chance to develop GI
ulcers or complications than patients without such risk factors when
treated with NSAIDs. It should be noted that this table contains all ITT
patients in all treatment groups.

#### Table 18: Number of CSUGIEs or CSUGIE/GDU by Number of Risk Factors^1^ 

+-------------+-------------+-------------+-------------+-------------+
| **Number of | **Number of | **CSUGIE**  | **C         | **W         |
| Risk        | Patients**  |             | SUGIE/GDU** | ithdrawal** |
| Factors**   |             | **N (%)**   |             |             |
|             |             |             | **N (%)**   | **N (%)**   |
+-------------+-------------+-------------+-------------+-------------+
| 0           | 4073        | 6 (0.1)     | 25 (0.6)    | 2184 (54)   |
|             |             |             |             |             |
| 1           | 2993        | 14 (0.5)    | 43 (1.4)    | 1760 (59)   |
|             |             |             |             |             |
| ≥2          | 902         | 18 (2.0)    | 37 (4.1)    | 615 (68)    |
+-------------+-------------+-------------+-------------+-------------+

1\. From Table 4 (p. 1985); N49-00-06-035-102.

A more detailed examination of the distribution CSUGIEs ± GDUs by
treatment group is shown in **Table 19.**

**Table 19: Number of CSUGIEs or CSUGIE/GDU** **by Treatment and Risk
Factors**^1^

+-----------+-----------------+-------------+-----------+-------------+
| **Number  | **Number of     | **CSUGIE**  | **CSU     | **W         |
| of Risk   | Patients (%)**  |             | GIE/GDU** | ithdrawal** |
| Factors** |                 | **N (%)**   |           |             |
|           |                 |             | **N (%)** | **N (%)**   |
+-----------+-----------------+-------------+-----------+-------------+
| Celecoxib | 2029 (51)       | 6 (\<0.1)   | 7 (0.3)   | 1045 (52)   |
|           |                 |             |           |             |
| 0         | 1497 (38)       | 8 (0.5)     | 20 (1.3)  | 856 (57)    |
|           |                 |             |           |             |
| 1         | 461 (12)        | 8 (1.7)     | 16 (3.5)  | 307 (67)    |
|           |                 |             |           |             |
| ≥2        |                 |             |           |             |
+-----------+-----------------+-------------+-----------+-------------+
| D         | 1019 (51)       | 0 (0.0)     | 2 (0.2)   | 485 (48)    |
| iclofenac |                 |             |           |             |
|           | 738 (37)        | 4 (0.5)     | 13 (1.8)  | 416 (56)    |
| 0         |                 |             |           |             |
|           | 239 (12)        | 6 (2.5)     | 11 (4.6)  | 156 (65)    |
| 1         |                 |             |           |             |
|           |                 |             |           |             |
| ≥2        |                 |             |           |             |
+-----------+-----------------+-------------+-----------+-------------+
| Ibuprofen | 1025 (52)       | 5 (0.5)     | 16 (1.6)  | 654 (64)    |
|           |                 |             |           |             |
| 0         | 758 (38)        | 2 (0.3)     | 10 (1.3)  | 488 (64)    |
|           |                 |             |           |             |
| 1         | 202 (10)        | 4 (2.0)     | 10 (5.0)  | 152 (75)    |
|           |                 |             |           |             |
| ≥2        |                 |             |           |             |
+-----------+-----------------+-------------+-----------+-------------+

1.  From Table 5 (p. 1986); N49-00-06-035-102.

Reviewer's comment: In general, the endpoints of CSUGIE ±GDU and
withdrawals increase with the number of risk factors in all treatment
groups. However, when considering risk factors, there does not appear to
be a consistent pattern of withdrawal (i.e. resulting in less patients
at risk) when comparing celecoxib against ibuprofen and diclofenac.
Patients receiving celecoxib appear more likely to withdraw at any given
risk category than that of diclofenac but not ibuprofen. An association
of endpoints with withdrawal does not seem evident when comparing across
treatments.

**Withdrawal in Patients with Symptoms**

Since many patients showed the occurrence of GI symptoms (specifically,
the development of abdominal pain, diarrhea, dyspepsia, nausea, or
vomiting) as part of the evolution of the case, the question arose as to
whether these GI symptoms represented an additional risk factor for a
CSUGIE or CSUGIE/GDU. Results of this analysis by the Sponsor are
summarized in Table 20. The results indicate that patients with these GI
symptoms have an increased risk of a CSUGIE ± GDU.

**^[Table\ 20:\ Risk\ for\ CSUGIEs\ and\ CSUGIEs/GDUs\ in\ Patients\ With/Without\ GI\ Symptoms1]{.underline}^**

+--------------------------+-------------+-------------+--------------+
|                          | **No.       | **          | **Relative   |
|                          | with**      | Incidence** | Risk**       |
|                          |             |             |              |
|                          | **Ev        |             |              |
|                          | ent/Total** |             |              |
+--------------------------+-------------+-------------+--------------+
| **CSUGIEs**              |             |             |              |
+--------------------------+-------------+-------------+--------------+
| With GI symptoms^2^      | 18/1483     | 1.21%       | 3.9          |
|                          |             |             |              |
| Without GI symptoms      | 20/6485     | 0.31%       |              |
+--------------------------+-------------+-------------+--------------+
| **CSUGIEs/GDUs**         |             |             |              |
+--------------------------+-------------+-------------+--------------+
| With GI symptoms^2^      | 62/1483     | 4.2%        | 6.3          |
|                          |             |             |              |
| Without GI symptoms      | 43/6485     | 0.7%        |              |
+--------------------------+-------------+-------------+--------------+

1.  From Table 8.n (p. 149) and appendix 2.4.17.4 (p. 2085);
    N49-00-06-035-102.

2.  Symptoms are moderate or severe abdominal pain, dyspepsia, nausea,
    diarrhea or vomiting. Total events for celecoxib = 699 (17.5%),
    diclofenac = 448 (22.4%) and ibuprofen = 336 (16.9%). Events are
    non-censored.

If symptomatic GI adverse events represent risk factors for clinically
important events, withdrawals due to these GI symptoms could represent
the loss of patients at risk. This depletion of susceptible individuals,
or "**informative censoring**" as argued by the Sponsor, could result in
misleading analyses, particularly if withdrawal due to GI adverse events
were not similar among the treatment groups. As noted in **Table 21**, a
higher proportion of patients receiving diclofenac withdrew as a result
of some GI adverse events which represented the most common GI adverse
events: abdominal pain, dyspepsia, nausea, diarrhea, and flatulence
during the entire study. The overall incidence of withdrawal due to an
adverse event was statistically significantly lower for celecoxib than
for diclofenac as were several individual events. For example, the
differences between celecoxib and diclofenac for three of the GI events
(abdominal pain, nausea, and diarrhea) and the three hepatic events
(elevations of liver enzyme levels) were statistically significant in
favor of celecoxib. Between celecoxib and ibuprofen, the only
statistically significant differences were in diarrhea, gastric ulcer,
and rash; the incidence of rash with celecoxib was also significantly
different than that seen with diclofenac.

**Table 21: Adverse Events Causing Withdrawal with Incidence 1%: Entire
Study Period**

+-----------------------+--------------+---------------+--------------+
| **Adverse Event (%)** | *            | *             | *            |
|                       | *Celecoxib** | *Diclofenac** | *Ibuprofen** |
|                       |              |               |              |
|                       | **(n=3987)** | **(n=1996)**  | **(n=1985)** |
+-----------------------+--------------+---------------+--------------+
| Any event             | 22.4         | 26.5^2^       | 23.0         |
+-----------------------+--------------+---------------+--------------+
| Abdominal pain        | 4.3          | 6.5^2^        | 4.9          |
|                       |              |               |              |
| Dyspepsia             | 3.8          | 4.4           | 3.9          |
|                       |              |               |              |
| Rash                  | 2.1          | 0.7^2^        | 1.3^2^       |
|                       |              |               |              |
| Nausea                | 1.7          | 2.8^2^        | 1.8          |
|                       |              |               |              |
| Diarrhea              | 1.4          | 2.7^2^        | 0.8^2^       |
|                       |              |               |              |
| Flatulence            | 1.2          | 1.8           | 1.4          |
|                       |              |               |              |
| Gastric ulcer         | 0.3          | 0.7           | 1.0^2^       |
|                       |              |               |              |
| SGOT increased        | 0.1          | 2.1^2^        | 0.1          |
|                       |              |               |              |
| SGPT increased        | 0.1          | 2.3^2^        | 0.1          |
|                       |              |               |              |
| Hepatic function      | \<0.1        | 1.1^2^        | \<0.1        |
| abnormal              |              |               |              |
+-----------------------+--------------+---------------+--------------+

1.  From Table 10d (p. 180) and Table T 42.1 (p. 469);
    N49-00-06-035-102.

2.  P\<0.05 vs. celecoxib.

As noted (Table T42.4, p. 498, N49-00-06-035-102), the incidences of
adverse events leading to withdrawal in the first six months of the
study were in most cases identical to, or slightly below, those in the
entire study period. This indicates that **almost all patients
withdrawing due to adverse events did so within six months of beginning
the study.**

To address whether informative censoring with respect to CSUGIEs ± GDUs
was observed in patients who dropped out due to GI-related adverse
events (i.e. dyspepsia, abdominal pain, nausea, diarrhea, and vomiting),
the rates of these events were compared (**Table 22**). There are no
statistically significant differences between ibuprofen and celecoxib
with regards to overall withdrawal and withdrawal due to any particular
GI adverse event. However, there does appear to be a difference between
celecoxib and diclofenac in the overall withdrawal rate and those
associated with (moderate to severe) diarrhea, abdominal pain and
nausea.

**Table 22: Incidence of Withdrawal for Moderate to Severe GI adverse
events^1^**

+-----------------+-----------------+-----------------+-----------------+
|                 | **Celecoxib**   | **Diclofenac**  | **Ibuprofen**   |
|                 |                 |                 |                 |
|                 | **N=3987**      | **N=1996**      | **N=1985**      |
+-----------------+-----------------+-----------------+-----------------+
| ######### Any G | 699             | 448             | 336             |
| I adverse event |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| **Withdrawal**  | 298 (7.5%)      | 191 (9.6%)^2^   | 149 (7.5%)      |
|                 |                 |                 |                 |
| **Diarrhea**    | 35 (0.9%)       | 40 (2.0%)^2^    | 13 (0.7%)       |
|                 |                 |                 |                 |
| **Vomiting**    | 19 (0.5%)       | 7 (0.4%)        | 5 (0.3%)        |
|                 |                 |                 |                 |
| **Abdominal     | 140 (3.5%)      | 101 (5.1%)^2^   | 80 (4.0%)       |
| pain**          |                 |                 |                 |
|                 | 122 (3.1%)      | 60 (3.0%)       | 58 (2.9%)       |
| **Dyspepsia**   |                 |                 |                 |
|                 | 49 (1.2%)       | 35 (1.8%)^2^    | 25 (1.3%)       |
| **Nausea**      |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

1.  From Table 1 (p. 1980) and Appendix 2.4.17.5 (p. 2086);
    N49-00-06-035-102.

2.  P values from Fischer's exact test. For celecoxib vs. diclofenac
    withdrawal p=0.006; diarrhea p\<0.001; abdominal pain p=0.005;
    nausea p=0.129. All other p-values \>0.20 or could not be
    calculated.

To address whether patients who experienced GI adverse events had a
higher incidence of CSUGIEs ± GDUs than patients who did not report GI
adverse events, the rates of events were compared (Table 23).

**^Table\ 23:\ CSUGIE\ \ GDU\ rates\ and\ relative\ risks\ with/without\ 5\ GI\ symptoms^**1

+-----------------+--------+--------+--------+--------+--------+--------+
|                 | *      |        | **     |        | *      |        |
|                 | *Celec |        | Diclof |        | *Ibupr |        |
|                 | oxib** |        | enac** |        | ofen** |        |
|                 |        |        |        |        |        |        |
|                 | **N=   |        | **N=   |        | **N=   |        |
|                 | 3987** |        | 1996** |        | 1985** |        |
+-----------------+--------+--------+--------+--------+--------+--------+
| #########       | S      | MO^2^  | S      | MO     | S      | MO     |
|                 | ponsor |        | ponsor |        | ponsor |        |
+-----------------+--------+--------+--------+--------+--------+--------+
| #               | 5/699  | 12/699 | 8/448  | 7/448  | 5/336  | 6/336  |
| ######## CSUGIE |        |        |        |        |        |        |
|                 | 1      | 5/3288 | 2/1548 | 3/1548 | 6/1649 | 5/1649 |
| **With AE**     | 2/3288 |        |        |        |        |        |
|                 |        | 11.5   | 13.82  | 8.2    | 4.09   | 5.9    |
| **Without AE**  | 1.96   |        |        |        |        |        |
|                 |        |        |        |        |        |        |
| **Relative      |        |        |        |        |        |        |
| Risk**          |        |        |        |        |        |        |
+-----------------+--------+--------+--------+--------+--------+--------+
| #####           | 22/699 |        | 20/448 |        | 20/336 |        |
| #### CSUGIE/GDU |        |        |        |        |        |        |
|                 | 2      |        | 6/1548 |        | 1      |        |
| **With AE**     | 1/3288 |        |        |        | 6/1649 |        |
|                 |        |        | 11.52  |        |        |        |
| **Without AE**  | 4.93   |        |        |        | 6.13   |        |
|                 |        |        |        |        |        |        |
| **Relative      |        |        |        |        |        |        |
| Risk**          |        |        |        |        |        |        |
+-----------------+--------+--------+--------+--------+--------+--------+

1.  From Table 2 (p. 1981) ; N49-00-06-035-102. Symptoms included
    dyspepsia, abdominal pain, nausea, diarrhea, and vomiting (moderate
    to severe). CSUGIEs or CSUGIE/GDU are those uncensored during the
    entire study.

2.  Per medical officer review of case summaries of CSUGIEs. All
    patients were withdrawn from the trial. All patients had the GI
    symptoms noted in the summaries without regard to rating of severity
    (i.e. mild, moderate, severe). The CSUGIE/GDU cases for celecoxib
    were also reviewed; a relative risk of 12.83 (vs. 4.93) was
    obtained.

Reviewer's comment: There is a difference in adjudication of CSUGIEs
between the sponsor and the medical officer; these differences can
change the inferences that can be drawn from these data. The relative
risk of a CSUGIE ± GDU in patients with an AE appears greater with
celecoxib than with ibuprofen or diclofenac. This observation would tend
not to support the importance of informative censoring in the outcomes.
It does appear that, in all treatment arms, CSUGIEs tend to be found
more commonly in patients with the five GI symptoms listed above than
without these AEs.

The Sponsor argued that withdrawals of susceptible individuals (i.e.
"informative censoring") due to GI adverse events represent the loss of
patients at risk. This loss suggests that standard analyses of risk may
be misleading, particularly because incidences of withdrawal due to GI
adverse events were not similar among the treatment groups. A higher
proportion of patients receiving diclofenac withdrew as a result of GI
signs or symptoms as discussed above.

To address this issue, incidences of events that could not occur because
of withdrawals for GI adverse events were imputed based on risk
calculations with a time-adjusted method (Appendix 1.9,
N49-00-06-035-102). In brief, incidences were calculated for patients
who experienced GI symptoms but continued in the study. The incidences
were then applied to patients who discontinued due to GI symptoms. **As
shown in Table 24, the adjusted rates suggested there would be
differences between treatment groups for both end points within the
first six months and for the entire study period had informative
censoring been an important issue in influencing outcomes.**

**^Table\ 24:\ Crude\ Incidence\ Rates\ and\ Comparisons\ for\ CSUGIEs\ \ GDUs\ Adjusted\ for\ Withdrawals\ for\ GI\ Adverse\ Events^**1

+------------------+--------+---------+---------+----------+---------+
|                  | *      | **Diclo | **Ibup  | ###      | **Cele  |
|                  | *Celec | fenac** | rofen** | ###### C | coxib** |
|                  | oxib** |         |         | elecoxib |         |
|                  |        | **(n=   | **(n=   |          | **vs.** |
|                  | **(n=3 | 1996)** | 1985)** | **vs.**  |         |
|                  | 987)** |         |         |          | **Ibup  |
|                  |        |         |         | **Dicl   | rofen** |
|                  |        |         |         | ofenac** |         |
+------------------+--------+---------+---------+----------+---------+
| **First six      |        |         |         |          |         |
| months**         |        |         |         |          |         |
+------------------+--------+---------+---------+----------+---------+
| CSUGIE           | 15     | 16      | 16      | P=0.036  | P=0.035 |
|                  | (0.4%) | (0.8%)  | (0.8%)  |          |         |
| ####             |        |         |         | P=0.069  | P=0.001 |
| ##### CSUGIE/GDU | 44     | 34      | 44      |          |         |
|                  | (1.1%) | (1.7%)  | (2.2%)  |          |         |
+------------------+--------+---------+---------+----------+---------+
| **Entire Study** |        |         |         |          |         |
+------------------+--------+---------+---------+----------+---------+
| CSUGIE           | 25     | 23      | 21      | P=0.044  | P=0.084 |
|                  | (0.6%) | (1.2%)  | (1.1%)  |          |         |
| ####             |        |         |         | P=0.016  | P       |
| ##### CSUGIE/GDU | 76     | 58      | 73      |          | \<0.001 |
|                  | (1.9%) | (2.9%)  | (3.7%)  |          |         |
+------------------+--------+---------+---------+----------+---------+

1\. From Table 8o (p. 150); N49-00-06-035-102

**[Endpoint of CSUGIE/GDU for first 6 months:]{.underline}**

As discussed earlier (section 8.1.1.3.2), symptomatic ulcer cases were
those cases in which criteria for a CSUGIE were not met but in which a
gastroduodenal ulcer was found by either endoscopy or upper
gastrointestinal series, performed as a result of symptoms or signs. The
combined category of these ulcers with the CSUGIEs was referred to as
"**CSUGIEs/GDUs."** Of note, any patient with either a gastric or
duodenal ulcer, or both, is counted as having a gastroduodenal ulcer.

As noted above, a total of 1214 potential CSUGIEs occurred within the
first six months of these studies. After GEC review, 225 of the 260
potential CSUGIEs were found to be non-CSUGIEs, and 954 were found to be
negative events. Of these 225 non-CSUGIEs, 48 were cases of symptomatic
gastroduodenal ulcers (from figure 8c p. 100, N49-00-06-035-102).

**Table 25** shows that within the first six months of study, a total of
83 CSUGIEs/GDUs were found: 32 occurred on celecoxib treatment, 20 on
diclofenac, and 31 on ibuprofen. Included in this total are all
CSUGIEs/GDUs regardless of censoring. None of the symptomatic ulcer
cases within the first six months was censored; thus all ulcers are
included in the CSUGIE/GDU analyses.

**^Table\ 25:\ Distribution\ of\ CSUGIEs/GDU:\ Traditional\ Definitions\ --First\ Six\ Months1^**

+-------------------------------------------+--------+--------+-------+
| # Event                                   | *      | **     | **I   |
|  Category {#event-category-2 .unnumbered} | *Celec | Diclof | bupro |
|                                           | oxib** | enac** | fen** |
|                                           |        |        |       |
|                                           | **(n=3 | **(n=1 | **    |
|                                           | 987)** | 996)** | (n=19 |
|                                           |        |        | 85)** |
+-------------------------------------------+--------+--------+-------+
| **UGI Bleeding (Category 1)**             | **-**  | **-**  | **-** |
|                                           |        |        |       |
| 1A: Hematemesis with ulcer/large erosion  | **7**  | **4**  | **7** |
|                                           |        |        |       |
| 1B: Ulcer/large erosion with evidence of  | **     | **4**  | **3   |
| bleeding                                  | 3^2^** |        | ^3^** |
|                                           |        | **1**  |       |
| 1C: Melena with ulcer/large erosion       | **     |        | **3** |
|                                           | 2^2^** | **-**  |       |
| [Hemoccult (+) stool with ulcer/large     |        |        | **-** |
| erosion and:]{.underline}                 | **-**  | **-**  |       |
|                                           |        |        | **-** |
| 1D-1: Hematocrit/Hemoglobin drop          | **-**  | **-**  |       |
|                                           |        |        | **-** |
| 1D-2: orthostasis                         | **-**  |        |       |
|                                           |        |        |       |
| 1D-3: transfusion                         |        |        |       |
|                                           |        |        |       |
| 1D-4: blood in stomach                    |        |        |       |
+-------------------------------------------+--------+--------+-------+
| **UGI Perforation (Category 2)**          | **-**  | **-**  | **-** |
+-------------------------------------------+--------+--------+-------+
| **Gastric Outlet Obstruction (Category    | **1**  | **-**  | **-** |
| 3)**                                      |        |        |       |
+-------------------------------------------+--------+--------+-------+
| ######### Symptomatic Ulcers              | **19** | **11** | *     |
|                                           |        |        | *18** |
| Gastroduodenal                            | **13** | **8**  |       |
|                                           |        |        | *     |
| Gastric                                   | **7**  | **5**  | *17** |
|                                           |        |        |       |
| Duodenal                                  |        |        | **1** |
+-------------------------------------------+--------+--------+-------+
| ######### Total                           | **32** | **20** | *     |
|                                           |        |        | *31** |
+-------------------------------------------+--------+--------+-------+
| **Total Uncensored**                      | **30** | **20** | *     |
|                                           |        |        | *29** |
+-------------------------------------------+--------+--------+-------+

1.  From Table 8h (p.101), Table T17.1 (p. 281), appendix 2.6.1 (p.
    2123); N49-00-06-035-102. Any patient with both gastric and duodenal
    ulcers is counted once in the "Gastroduodenal" row.

2.  One of these events censored from primary analysis.

3.  Two of these events censored from primary analysis

**Table 26** summarizes the results for the incidences and comparisons
of CSUGIE/GDU during the first 6 months of the study for the ITT
population. The differences in times to event over the first 26 weeks
achieved statistical significance between celecoxib and NSAIDs pooled,
as well as between celecoxib and ibuprofen. When only the patients not
taking aspirin were included in the analysis, the event rate for
celecoxib over the first 26 weeks was again statistically significantly
lower than the rate for NSAIDs combined (p=0.017) as well as that for
ibuprofen (p\<0.001).

Table 26: Summary of CSGUIE/GDU Incidence -- First Six Months

+---------------+--------+---------+---------+-------+--------+------+
|               | Cel    | Dic     | Ib      | Log   |        |      |
|               | ecoxib | lofenac | uprofen | -Rank |        |      |
|               |        |         |         | P     |        |      |
|               | 400 mg | 75 mg   | 800 mg  | V     |        |      |
|               | BID    | BID     | TID     | alues |        |      |
|               |        |         |         | for   |        |      |
|               |        |         |         | Cele  |        |      |
|               |        |         |         | coxib |        |      |
|               |        |         |         |       |        |      |
|               |        |         |         | vs.   |        |      |
|               |        |         |         |       |        |      |
|               |        |         |         | Diclo |        |      |
|               |        |         |         | fenac |        |      |
|               |        |         |         | Ibup  |        |      |
|               |        |         |         | rofen |        |      |
|               |        |         |         | Both  |        |      |
+---------------+--------+---------+---------+-------+--------+------+
| ##            |        |         |         |       |        |      |
|  All Patients |        |         |         |       |        |      |
+---------------+--------+---------+---------+-------+--------+------+
|               | n =    | n =     | n =     |       |        |      |
|               | 3987   | 1996    | 1985    |       |        |      |
+---------------+--------+---------+---------+-------+--------+------+
| No. of        | 30     | 20      | 29      |       |        |      |
| CSUGIE/GDUs   |        |         |         |       |        |      |
|               | 2      | 0       | 2       |       |        |      |
| Uncensored    |        |         |         |       |        |      |
|               | 32     | 20      | 31      |       |        |      |
| Censored^1^   |        |         |         |       |        |      |
|               |        |         |         |       |        |      |
| Total         |        |         |         |       |        |      |
+---------------+--------+---------+---------+-------+--------+------+
| Week 26 crude | 0.75%  | 1.00%   | 1.46%   | **0.  | **0    | *    |
| rate^3^       |        |         |         | 308** | .005** | *0.0 |
|               |        |         |         |       |        | 23** |
+---------------+--------+---------+---------+-------+--------+------+
| No. per 100   | 2.08   | 2.82    | 4.31    |       |        |      |
| pt-yrs        |        |         |         |       |        |      |
+---------------+--------+---------+---------+-------+--------+------+
| ## P          |        |         |         |       |        |      |
| atients not T |        |         |         |       |        |      |
| aking Aspirin |        |         |         |       |        |      |
+---------------+--------+---------+---------+-------+--------+------+
|               | n =    | n =     | n =     |       |        |      |
|               | 3154   | 1567    | 1602    |       |        |      |
+---------------+--------+---------+---------+-------+--------+------+
| No. of        | 16     | 9       | 23      |       |        |      |
| CSUGIE/GDUs   |        |         |         |       |        |      |
|               | 1      | 0       | 1       |       |        |      |
| Uncensored    |        |         |         |       |        |      |
|               | 17     | 9       | 24      |       |        |      |
| Censored      |        |         |         |       |        |      |
|               |        |         |         |       |        |      |
| Total         |        |         |         |       |        |      |
+---------------+--------+---------+---------+-------+--------+------+
| Week 26 crude | 0.51%  | 0.57%   | 1.44%   | **0.  | **\<0  | *    |
| rate          |        |         |         | 760** | .001** | *0.0 |
|               |        |         |         |       |        | 17** |
+---------------+--------+---------+---------+-------+--------+------+
| No. per 100   | 1.40   | 1.61    | 4.25    |       |        |      |
| pt-yrs        |        |         |         |       |        |      |
+---------------+--------+---------+---------+-------+--------+------+

1.  Occurred before 48 hours after midnight of the first dose day or
    more than 48 hours after midnight of the last dose day (unless
    occurred within two weeks after last dose and was determined by GEC
    to be treatment-related).

2.  From Table T17.1 & T18.1, N49-00-06-035-102, p. 281 & 285/24295.

3.  Rates and p-values based on uncensored data.

**Table 27** shows the rates (both crude and Kaplan-Meier) by time
interval of all CSUGIEs/GDU during the first six months of the study.
These rates are in the entire ITT cohort. The p-values comparisons, as
noted in the footnote of the table suggest statistically significantly
different between celecoxib and the pooled NSAID results, or when
compared against ibuprofen (p=0.005 and 0.004 with censored and
uncensored cases, respectively) but not against diclofenac.

**^Table\ 27:\ CSUGIEs/GDU-First\ 6\ months\ (Crude\ &\ Kaplan-Meier\ rates)^**1,2

+-------------+--------+--------+---------+---------+--------+-------+
|             | *      |        | **Diclo |         | *      |       |
|             | *Celec |        | fenac** |         | *Ibupr |       |
|             | oxib** |        |         |         | ofen** |       |
|             |        |        | **(n=   |         |        |       |
|             | **(n=3 |        | 1996)** |         | **(n=1 |       |
|             | 987)** |        |         |         | 985)** |       |
+-------------+--------+--------+---------+---------+--------+-------+
| Rates       | \+     | \-     | \+      | \-      | \+     | \-    |
|             | cen    | cen    | ce      | ce      | cen    | cens  |
|             | soring | soring | nsoring | nsoring | soring | oring |
+-------------+--------+--------+---------+---------+--------+-------+
| Crude       | 0.03%  | 0.05%  | 0.10%   | 0.10%   | 0.10%  | 0.15% |
|             |        |        |         |         |        |       |
| Week 1      | 0.18%  | 0.20%  | 0.25%   | 0.25%   | 0.30%  | 0.35% |
| (1-7)       |        |        |         |         |        |       |
|             | 0.53%  | 0.58%  | 0.65%   | 0.65%   | 0.91%  | 1.01% |
| Week 4      |        |        |         |         |        |       |
| (8-28)      | 0.75%  | 0.80%  | 1.00%   | 1.00%   | 1.46%  | 1.56% |
|             |        |        |         |         |        |       |
| Week 13     |        |        |         |         |        |       |
| (29-91)     |        |        |         |         |        |       |
|             |        |        |         |         |        |       |
| Week 26     |        |        |         |         |        |       |
| (92-182)    |        |        |         |         |        |       |
+-------------+--------+--------+---------+---------+--------+-------+
| K           | 0.04%  | 0.06%  | 0.10%   | 0.10%   | 0.12%  | 0.17% |
| aplan-Meier |        |        |         |         |        |       |
|             | 0.20%  | 0.23%  | 0.31%   | 0.31%   | 0.32%  | 0.37% |
| Week 1      |        |        |         |         |        |       |
| (1-7)       | 0.65%  | 0.70%  | 0.82%   | 0.82%   | 1.24%  | 1.35% |
|             |        |        |         |         |        |       |
| Week 4      | 0.97%  | 1.02%  | 1.30%   | 1.30%   | 2.05%  | 2.16% |
| (8-28)      |        |        |         |         |        |       |
|             |        |        |         |         |        |       |
| Week 13     |        |        |         |         |        |       |
| (29-91)     |        |        |         |         |        |       |
|             |        |        |         |         |        |       |
| Week 26     |        |        |         |         |        |       |
| (92-182)    |        |        |         |         |        |       |
+-------------+--------+--------+---------+---------+--------+-------+

1.From Table T17.2 (p. 282); N49-00-06-035-102. Kaplan-Meier rates are
based on the highest Kaplan-Meier estimates within that time interval.
Uncensored and censored events were previously defined (Table 7 above).

2\. For **censored events, log Rank P-values** (Table T17.3, p. 283) of
celecoxib vs. NSAIDs = 0.023, celecoxib vs. diclofenac = 0.308,
celecoxib vs. ibuprofen = 0.005. **For uncensored events, log Rank
P-values** (Table T17.4, p. 284) of celecoxib vs. NSAIDs = 0.026,
celecoxib vs. diclofenac = 0.421, celecoxib vs. ibuprofen = 0.004.

**Table 28** shows the rates (both crude and Kaplan-Meier) by time
interval of all CSUGIEs/GDU during the first six months of the study in
patients not taking ASA. These rates are in the entire ITT cohort. The
p-values comparisons, as noted in the footnote of the table, suggest (as
noted earlier with the CSUGIE results) statistically significantly
differences between celecoxib and the pooled NSAID results, or when
compared against ibuprofen (p\<0.001 and 0.001 with censored and
uncensored cases, respectively) but not against diclofenac.

**^Table\ 28:\ CSUGIEs/GDU-First\ 6\ months\ without\ ASA\ (Crude\ &\ Kaplan-Meier\ rates-ITT)^**1,2

+-------------+--------+--------+---------+---------+--------+-------+
|             | Cel    |        | Dic     |         | Ibu    |       |
|             | ecoxib |        | lofenac |         | profen |       |
|             |        |        |         |         |        |       |
|             | (n     |        | (       |         | (n     |       |
|             | =3154) |        | n=1567) |         | =1602) |       |
+-------------+--------+--------+---------+---------+--------+-------+
| Rates       | \+     | \-     | \+      | \-      | \+     | \-    |
|             | cen    | cen    | ce      | ce      | cen    | cens  |
|             | soring | soring | nsoring | nsoring | soring | oring |
+-------------+--------+--------+---------+---------+--------+-------+
| Crude       | 0.03%  | 0.06%  | 0.06%   | 0.06%   | 0.12%  | 0.12% |
|             |        |        |         |         |        |       |
| Week 1      | 0.13%  | 0.16%  | 0.19%   | 0.19%   | 0.37%  | 0.37% |
| (1-7)       |        |        |         |         |        |       |
|             | 0.35%  | 0.38%  | 0.45%   | 0.45%   | 0.87%  | 0.94% |
| Week 4      |        |        |         |         |        |       |
| (8-28)      | 0.51%  | 0.54%  | 0.57%   | 0.57%   | 1.44%  | 1.50% |
|             |        |        |         |         |        |       |
| Week 13     |        |        |         |         |        |       |
| (29-91)     |        |        |         |         |        |       |
|             |        |        |         |         |        |       |
| Week 26     |        |        |         |         |        |       |
| (92-182)    |        |        |         |         |        |       |
+-------------+--------+--------+---------+---------+--------+-------+
| K           | 0.04%  | 0.07%  | 0.10%   | 0.10%   | 0.14%  | 0.14% |
| aplan-Meier |        |        |         |         |        |       |
|             | 0.14%  | 0.17%  | 0.26%   | 0.26%   | 0.39%  | 0.39% |
| Week 1      |        |        |         |         |        |       |
| (1-7)       | 0.44%  | 0.48%  | 0.54%   | 0.54%   | 1.21%  | 1.28% |
|             |        |        |         |         |        |       |
| Week 4      | 0.65%  | 0.68%  | 0.74%   | 0.74%   | 2.00%  | 2.08% |
| (8-28)      |        |        |         |         |        |       |
|             |        |        |         |         |        |       |
| Week 13     |        |        |         |         |        |       |
| (29-91)     |        |        |         |         |        |       |
|             |        |        |         |         |        |       |
| Week 26     |        |        |         |         |        |       |
| (92-182)    |        |        |         |         |        |       |
+-------------+--------+--------+---------+---------+--------+-------+

1\. From Table T18.2 (p. 286); N49-00-06-035-102. Kaplan-Meier rates are
based on the highest Kaplan-Meier estimates within that time interval.
Uncensored and censored events were previously defined (Table 7 above).

2.For **censored events, log rank P-values** (Table T18.3, p. 287) of
celecoxib vs. NSAIDs = 0.017, celecoxib vs. diclofenac = 0.760,
celecoxib vs. ibuprofen \< 0.001. **For uncensored events, log rank
P-values** (Table T18.4, p. 288) of celecoxib vs. NSAIDs = 0.019,
celecoxib vs. diclofenac = 0.872, celecoxib vs. ibuprofen \< 0.001.

**[Endpoint of CSUGIE/GDU for entire study:]{.underline}**

As noted earlier, throughout the full length of the study, a total of
1670 potential CSUGIEs were worked up with 384 reviewed by all members
of the GEC. Of these, 44 were found to be CSUGIEs, 340 were found to be
non-CSUGIEs, and 1286 were found to be negative events. Of the 340
non-CSUGIEs, 67 represented symptomatic gastroduodenal ulcers, for a
total of 111 CSUGIEs/GDUs (i.e. 44 plus 67) occurring throughout the
entire study period.

**Table 29** shows all CSUGIEs/GDUs by treatment group and category.
Forty-six CSUGIEs/GDUs occurred on celecoxib treatment, 27 on
diclofenac, and 38 on ibuprofen. Included in these totals are all
CSUGIEs and symptomatic ulcers regardless of censoring. Three CSUGIEs in
the celecoxib group, one CSUGIE in the diclofenac group, and two CSUGIEs
in the ibuprofen group were censored. None of the ulcer cases was
censored; therefore, all of the ulcers are included in the CSUGIE/GDU
analysis.

**^Table\ 29:\ Distribution\ of\ CSUGIEs/GDU:\ Traditional\ Definitions\ --Entire\ Study1^**

+-------------------------------------------+--------+--------+-------+
| # Event                                   | *      | **     | **I   |
|  Category {#event-category-3 .unnumbered} | *Celec | Diclof | bupro |
|                                           | oxib** | enac** | fen** |
|                                           |        |        |       |
|                                           | **(n=3 | **(n=1 | **    |
|                                           | 987)** | 996)** | (n=19 |
|                                           |        |        | 85)** |
+-------------------------------------------+--------+--------+-------+
| **UGI Bleeding (Category 1)**             | **1**  | **-**  | **-** |
|                                           |        |        |       |
| 1A: Hematemesis with ulcer/large erosion  | **7**  | **4**  | **7** |
|                                           |        |        |       |
| 1B: Ulcer/large erosion with evidence of  | **     | **4**  | **3   |
| bleeding                                  | 5^2^** |        | ^3^** |
|                                           |        | **2**  |       |
| 1C: Melena with ulcer/large erosion       | **     |        | **3** |
|                                           | 3^2^** | **-**  |       |
| [Hemoccult (+) stool with ulcer/large     |        |        | **-** |
| erosion and:]{.underline}                 | **-**  | **-**  |       |
|                                           |        |        | **-** |
| 1D-1: Hematocrit/Hemoglobin drop          | **-**  | **-**  |       |
|                                           |        |        | **-** |
| 1D-2: orthostasis                         | **-**  |        |       |
|                                           |        |        |       |
| 1D-3: transfusion                         |        |        |       |
|                                           |        |        |       |
| 1D-4: blood in stomach                    |        |        |       |
+-------------------------------------------+--------+--------+-------+
| **UGI Perforation (Category 2)**          | **1**  | **1**  | **-** |
+-------------------------------------------+--------+--------+-------+
| **Gastric Outlet Obstruction (Category    | **2**  | **-**  | **-** |
| 3)**                                      |        |        |       |
+-------------------------------------------+--------+--------+-------+
| ##                                        | **26** | **16** | *     |
| ####### Symptomatic Ulcers (all patients) |        |        | *25** |
|                                           | **18** | **13** |       |
| Gastroduodenal                            |        |        | *     |
|                                           | **10** | **5**  | *22** |
| Gastric                                   |        |        |       |
|                                           |        |        | **3** |
| Duodenal                                  |        |        |       |
+-------------------------------------------+--------+--------+-------+
| ########                                  | **(n=3 | **(n=1 | **    |
| # Symptomatic Ulcers (not taking aspirin) | 105)** | 561)** | (n=15 |
|                                           |        |        | 73)** |
| Gastroduodenal                            | **13** | **6**  |       |
|                                           |        |        | *     |
| Gastric                                   | **8**  | **5**  | *18** |
|                                           |        |        |       |
| #########  Duodenal                       | **6**  | **2**  | *     |
|                                           |        |        | *16** |
|                                           |        |        |       |
|                                           |        |        | **2** |
+-------------------------------------------+--------+--------+-------+
| ######### Total                           | **46** | **27** | *     |
|                                           |        |        | *38** |
+-------------------------------------------+--------+--------+-------+
| **Total Uncensored**                      | **43** | **26** | *     |
|                                           |        |        | *36** |
+-------------------------------------------+--------+--------+-------+

1.  From Table 8j (p.105), Table 8r (p. 154) and appendix 2.6.1 (p.
    2123); N49-00-06-035-102. Any patient with both gastric and duodenal
    ulcers is counted once in the "Gastroduodenal" row.

2.  One of these events censored from primary analysis.

3.  Two of these events censored from primary analysis

**Table 30** summarizes the results for the incidences and comparisons
of CSUGIE/GDU during the entire study for the ITT population. The
cumulative times to event were significantly lower through the entire
study period for celecoxib than for the NSAID comparators pooled
(p=0.040) and ibuprofen individually (p=0.017). When only patients not
taking aspirin were included in the analysis, the celecoxib event rate
over 52 weeks was statistically significantly lower than the rate for
the NSAIDs pooled (p=0.020) and the rate for ibuprofen individually
(p\<0.001). When both censored and uncensored cases were included in the
analysis, the trends and comparisons shown above were repeated (Table
20.4, p. 295; and Table 21.4, p. 299 of N49-00-06-035-102), including
the statistically significant difference between celecoxib and ibuprofen
event rates in the patients not taking aspirin. Celecoxib was not
statistically significantly different from diclofenac for any
comparison.

Table 30: Summary of CSGUIE/GDU Incidence (Traditional Definitions) --
Entire Study Period

+---------------+--------+---------+---------+-------+--------+------+
|               | Cel    | Dic     | Ib      | Log   |        |      |
|               | ecoxib | lofenac | uprofen | -Rank |        |      |
|               |        |         |         | P     |        |      |
|               | 400 mg | 75 mg   | 800 mg  | V     |        |      |
|               | BID    | BID     | TID     | alues |        |      |
|               |        |         |         | for   |        |      |
|               |        |         |         | Cele  |        |      |
|               |        |         |         | coxib |        |      |
|               |        |         |         |       |        |      |
|               |        |         |         | vs.   |        |      |
|               |        |         |         |       |        |      |
|               |        |         |         | Diclo |        |      |
|               |        |         |         | fenac |        |      |
|               |        |         |         | Ibup  |        |      |
|               |        |         |         | rofen |        |      |
|               |        |         |         | Both  |        |      |
+---------------+--------+---------+---------+-------+--------+------+
| ##            |        |         |         |       |        |      |
|  All Patients |        |         |         |       |        |      |
+---------------+--------+---------+---------+-------+--------+------+
|               | n =    | n =     | n =     |       |        |      |
|               | 3987   | 1996    | 1985    |       |        |      |
+---------------+--------+---------+---------+-------+--------+------+
| No. of        | 43     | 26      | 36      |       |        |      |
| CSUGIE/GDUs   |        |         |         |       |        |      |
|               | 3      | 1       | 2       |       |        |      |
| Uncensored    |        |         |         |       |        |      |
|               | 46     | 27      | 38      |       |        |      |
| Censored^1^   |        |         |         |       |        |      |
|               |        |         |         |       |        |      |
| Total         |        |         |         |       |        |      |
+---------------+--------+---------+---------+-------+--------+------+
| Week 52 crude | 1.05%  | 1.30%   | 1.76%   | **0.  | **0    | *    |
| rate^3^       |        |         |         | 296** | .017** | *0.0 |
|               |        |         |         |       |        | 40** |
+---------------+--------+---------+---------+-------+--------+------+
| No. per 100   | 1.85   | 2.41    | 3.21    |       |        |      |
| pt-yrs        |        |         |         |       |        |      |
+---------------+--------+---------+---------+-------+--------+------+
| ## P          |        |         |         |       |        |      |
| atients not T |        |         |         |       |        |      |
| aking Aspirin |        |         |         |       |        |      |
+---------------+--------+---------+---------+-------+--------+------+
|               | n =    | n =     | n =     |       |        |      |
|               | 3105   | 1551    | 1573    |       |        |      |
+---------------+--------+---------+---------+-------+--------+------+
| No. of        | 21     | 10      | 28      |       |        |      |
| CSUGIE/GDUs   |        |         |         |       |        |      |
|               | 1      | 0       | 1       |       |        |      |
| Uncensored    |        |         |         |       |        |      |
|               | 22     | 10      | 29      |       |        |      |
| Censored      |        |         |         |       |        |      |
|               |        |         |         |       |        |      |
| Total         |        |         |         |       |        |      |
+---------------+--------+---------+---------+-------+--------+------+
| Week 52 crude | 0.68%  | 0.64%   | 1.72%   | **0.  | **\<0  | *    |
| rate          |        |         |         | 992** | .001** | *0.0 |
|               |        |         |         |       |        | 20** |
+---------------+--------+---------+---------+-------+--------+------+
| No. per 100   | 1.16   | 1.19    | 3.20    |       |        |      |
| pt-yrs        |        |         |         |       |        |      |
+---------------+--------+---------+---------+-------+--------+------+

1.  Occurred before 48 hours after midnight of the first dose day or
    more than 48 hours after midnight of the last dose day (unless
    occurred within two weeks after last dose and was determined by GEC
    to be treatment-related).

2.  From Table T20.1 & T21.1, N49-00-06-035-102, p. 292 & 296/24295.

3.  Rates and p-values from uncensored data.

**Table 31** shows the rates (both crude and Kaplan-Meier) by time
interval of all CSUGIEs/GDU during the entire study. These rates are in
the entire ITT cohort. The p-values comparisons, as noted in the
footnote of the table, suggest again statistically significantly
differences between celecoxib and the pooled NSAID results, or when
compared against ibuprofen (p=0.017 and 0.016 with censored and
uncensored cases, respectively) but not against diclofenac.

**^Table\ 31:\ CSUGIEs/GDU-Entire\ Study-ITT\ (Crude\ &\ Kaplan-Meier\ rates)^**1,2

+---------------+--------+-------+---------+-------+--------+-------+
|               | Cel    |       | Dic     |       | Ibu    |       |
|               | ecoxib |       | lofenac |       | profen |       |
|               |        |       |         |       |        |       |
|               | (n     |       | (       |       | (n     |       |
|               | =3987) |       | n=1996) |       | =1985) |       |
+---------------+--------+-------+---------+-------+--------+-------+
| Rates         | \+     | \-    | \+      | \-    | \+     | \-    |
|               | cen    | cens  | ce      | cens  | cen    | cens  |
|               | soring | oring | nsoring | oring | soring | oring |
+---------------+--------+-------+---------+-------+--------+-------+
| Crude         | 0.03%  | 0.05% | 0.10%   | 0.10% | 0.10%  | 0.15% |
|               |        |       |         |       |        |       |
| Week 1 (1-7)  | 0.18%  | 0.20% | 0.25%   | 0.25% | 0.30%  | 0.35% |
|               |        |       |         |       |        |       |
| Week 4 (8-28) | 0.53%  | 0.58% | 0.65%   | 0.65% | 0.91%  | 1.01% |
|               |        |       |         |       |        |       |
| Week 13       | 0.75%  | 0.80% | 1.00%   | 1.00% | 1.46%  | 1.56% |
| (29-91)       |        |       |         |       |        |       |
|               | 0.83%  | 0.90% | 1.25%   | 1.25% | 1.61%  | 1.71% |
| Week 26       |        |       |         |       |        |       |
| (92-182)      | 1.05%  | 1.13% | 1.30%   | 1.35% | 1.76%  | 1.86% |
|               |        |       |         |       |        |       |
| Week 39       |        |       |         |       |        |       |
| (183-273)     |        |       |         |       |        |       |
|               |        |       |         |       |        |       |
| Week 52       |        |       |         |       |        |       |
| (274-364)     |        |       |         |       |        |       |
+---------------+--------+-------+---------+-------+--------+-------+
| Kaplan-Meier  | 0.04%  | 0.06% | 0.10%   | 0.10% | 0.12%  | 0.17% |
|               |        |       |         |       |        |       |
| Week 1 (1-7)  | 0.20%  | 0.23% | 0.31%   | 0.31% | 0.32%  | 0.37% |
|               |        |       |         |       |        |       |
| Week 4 (8-28) | 0.65%  | 0.70% | 0.82%   | 0.82% | 1.24%  | 1.35% |
|               |        |       |         |       |        |       |
| Week 13       | 1.00%  | 1.05% | 1.31%   | 1.31% | 2.06%  | 2.17% |
| (29-91)       |        |       |         |       |        |       |
|               | 1.14%  | 1.24% | 1.83%   | 1.86% | 2.43%  | 2.54% |
| Week 26       |        |       |         |       |        |       |
| (92-182)      | 1.95%  | 2.05% | 1.91%   | 2.02% | 2.84%  | 2.94% |
|               |        |       |         |       |        |       |
| Week 39       |        |       |         |       |        |       |
| (183-273)     |        |       |         |       |        |       |
|               |        |       |         |       |        |       |
| Week 52       |        |       |         |       |        |       |
| (274-364)     |        |       |         |       |        |       |
+---------------+--------+-------+---------+-------+--------+-------+

1\. From Table T20.2 (p. 293); N49-00-06-035-102. Kaplan-Meier rates are
based on the highest Kaplan-Meier estimates within that

time interval. Uncensored and censored events were previously defined
(Table 7 above).

2\. For **censored events, log rank P-values** (Table T20.3, p. 294) of
celecoxib vs. NSAIDs = 0.040, celecoxib vs. diclofenac = 0.296

celecoxib vs. ibuprofen = 0.017. **For uncensored events, log rank
P-values** (Table T20.4, p. 295) of celecoxib vs. NSAIDs = 0.045,
celecoxib vs. diclofenac = 0.349, celecoxib vs. ibuprofen = 0.016.

**Table 32** shows the rates (both crude and Kaplan-Meier) by time
interval of all CSUGIEs/GDU during the entire study in patients not
taking ASA. These rates are in the entire ITT cohort. The p-values
comparisons, as noted in the footnote of the table, suggest again (as
noted earlier with the CSUGIE results) statistically significantly
differences between celecoxib and the pooled NSAID results, or when
compared against ibuprofen (p\<0.001 and 0.001 with censored and
uncensored cases, respectively) but not against diclofenac.

**^Table\ 32:\ CSUGIEs/GDU-Entire\ Study\ without\ ASA-ITT\ (Crude\ &\ Kaplan-Meier\ rates)^**1,2

+---------------+--------+-------+---------+-------+--------+-------+
|               | Cel    |       | Dic     |       | Ibu    |       |
|               | ecoxib |       | lofenac |       | profen |       |
|               |        |       |         |       |        |       |
|               | (n     |       | (       |       | (n     |       |
|               | =3105) |       | n=1551) |       | =1573) |       |
+---------------+--------+-------+---------+-------+--------+-------+
| Rates         | \+     | \-    | \+      | \-    | \+     | \-    |
|               | cen    | cens  | ce      | cens  | cen    | cens  |
|               | soring | oring | nsoring | oring | soring | oring |
+---------------+--------+-------+---------+-------+--------+-------+
| Crude         | 0.03%  | 0.06% | 0.06%   | 0.06% | 0.13%  | 0.13% |
|               |        |       |         |       |        |       |
| Week 1 (1-7)  | 0.13%  | 0.16% | 0.19%   | 0.19% | 0.38%  | 0.38% |
|               |        |       |         |       |        |       |
| Week 4 (8-28) | 0.35%  | 0.39% | 0.45%   | 0.45% | 0.89%  | 0.95% |
|               |        |       |         |       |        |       |
| Week 13       | 0.52%  | 0.55% | 0.58%   | 0.58% | 1.46%  | 1.53% |
| (29-91)       |        |       |         |       |        |       |
|               | 0.58%  | 0.61% | 0.58%   | 0.58% | 1.65%  | 1.72% |
| Week 26       |        |       |         |       |        |       |
| (92-182)      | 0.68%  | 0.71% | 0.64%   | 0.64% | 1.72%  | 1.78% |
|               |        |       |         |       |        |       |
| Week 39       |        |       |         |       |        |       |
| (183-273)     |        |       |         |       |        |       |
|               |        |       |         |       |        |       |
| Week 52       |        |       |         |       |        |       |
| (274-364)     |        |       |         |       |        |       |
+---------------+--------+-------+---------+-------+--------+-------+
| Kaplan-Meier  | 0.04%  | 0.07% | 0.10%   | 0.10% | 0.15%  | 0.15% |
|               |        |       |         |       |        |       |
| Week 1 (1-7)  | 0.14%  | 0.18% | 0.26%   | 0.26% | 0.40%  | 0.40% |
|               |        |       |         |       |        |       |
| Week 4 (8-28) | 0.45%  | 0.48% | 0.54%   | 0.54% | 1.24%  | 1.31% |
|               |        |       |         |       |        |       |
| Week 13       | 0.71%  | 0.74% | 0.75%   | 0.75% | 2.07%  | 2.14% |
| (29-91)       |        |       |         |       |        |       |
|               | 0.80%  | 0.84% | 0.89%   | 0.89% | 2.55%  | 2.63% |
| Week 26       |        |       |         |       |        |       |
| (92-182)      | 1.13%  | 1.16% | 0.92%   | 0.92% | 3.00%  | 3.07% |
|               |        |       |         |       |        |       |
| Week 39       |        |       |         |       |        |       |
| (183-273)     |        |       |         |       |        |       |
|               |        |       |         |       |        |       |
| Week 52       |        |       |         |       |        |       |
| (274-364)     |        |       |         |       |        |       |
+---------------+--------+-------+---------+-------+--------+-------+

1\. From Table T21.2 (p. 297); N49-00-06-035-102. Kaplan-Meier rates are
based on the highest Kaplan-Meier estimates within that time interval.
Uncensored and censored events were previously defined (Table 7 above).

2\. For **censored events, log rank P-values** (Table T21.3, p. 298) of
celecoxib vs. NSAIDs = 0.020, celecoxib vs. diclofenac = 0.992,
celecoxib vs. ibuprofen \< 0.001. **For uncensored events, log rank
P-values** (Table T21.4, p. 295) of celecoxib vs. NSAIDs = 0.022,
celecoxib vs. diclofenac = 0.907, celecoxib vs. ibuprofen \< 0.001.

**[Summary of GI endpoint results:]{.underline}**

**Table 33** summarizes the log-rank p-values for the endpoints of
CSUGIEs and CSUGIEs/GDU for both the first six months and for the entire
study in the ITT population both with and without the use of ASA.

**During the first 6 months**, analysis of the CSUGIE data in the entire
cohort showed a numerical trend toward a decrease in the incidence with
celecoxib compared to NSAIDs combined; these trends were not
statistically significant. When the observed rates were analyzed in the
subgroup of patients not taking aspirin, there was a statistically
significant decrease in the incidence of CSUGIEs observed with celecoxib
relative to pooled NSAIDs (Table 13). Although the reduction in CSUGIEs
was not statistically significant in the entire study population at 6
months, the reduction in symptomatic ulcers combined with CSUGIEs
(CSUGIEs/GDUs) was significant (Table 26). This analysis also showed a
significant difference in patients not receiving aspirin for celecoxib
and NSAIDs.

In terms of individual comparisons with ibuprofen and diclofenac, all
comparisons significant for celecoxib vs. NSAIDs combined were
significant for celecoxib vs. ibuprofen. In contrast to the results for
ibuprofen, no differences were seen between celecoxib and diclofenac for
any of the end points.

**Analysis of the entire study period** showed that the difference
between celecoxib and pooled NSAIDs for CSUGIEs in the entire study
population was not statistically significant. Statistical significance
was also not achieved when patients not taking aspirin were analyzed
specifically (Table 14). This absence of statistical significance
appeared to reflect a decline in the NSAID event rate between six months
and the end of the study; this decline was argued to be attributable to
the phenomenon of depletion of susceptible patients. When the combined
end point of CSUGIEs/GDUs was analyzed, the difference between celecoxib
and pooled NSAIDs became statistically significant. A statistically
significant difference between celecoxib and the pooled NSAIDs was also
noted when the confounding effects of low-dose aspirin use were removed
from the analysis (Table 30).

With respect to specific comparisons, all differences that were
statistically significant between celecoxib and the pooled NSAIDs were
also significant for celecoxib versus ibuprofen. Consistent with the
six-month analysis, the differences between celecoxib and diclofenac
were not statistically significant for any of the endpoints. Again, it
was argued that the absence of statistical significance may be a
function of the larger proportion of patients withdrawing from the
diclofenac group because of GI adverse events.

**Table 33: Overall summary of log-rank p-values (CSUGIEs and
CSUGIES/GDU-ITT)^1^**

+----------------------------------+-----------+-----------+---------+
| **Endpoint (Traditional          | **        |           |         |
| Definition)**                    | Celecoxib |           |         |
|                                  | vs.**     |           |         |
+----------------------------------+-----------+-----------+---------+
|                                  | *         | **Dic     | **Ibup  |
|                                  | *NSAIDs** | lofenac** | rofen** |
+----------------------------------+-----------+-----------+---------+
| CSUGIE-First 6 months            | 0.092     | 0.264     | 0.073   |
|                                  |           |           |         |
| Censored                         | 0.112     | 0.445     | 0.053   |
|                                  |           |           |         |
| Uncensored                       |           |           |         |
+----------------------------------+-----------+-----------+---------+
| CSUGIE-First 6 months without    | 0.037     | 0.476     | 0.005   |
| ASA                              |           |           |         |
|                                  | 0.047     | 0.651     | 0.005   |
| Censored                         |           |           |         |
|                                  |           |           |         |
| Uncensored                       |           |           |         |
+----------------------------------+-----------+-----------+---------+
| CSUGIE-Entire study              | 0.450     | 0.640     | 0.414   |
|                                  |           |           |         |
| Censored                         | 0.474     | 0.752     | 0.372   |
|                                  |           |           |         |
| Uncensored                       |           |           |         |
+----------------------------------+-----------+-----------+---------+
| CSUGIE-Entire Study without ASA  | 0.185     | 0.972     | 0.037   |
|                                  |           |           |         |
| Censored                         | 0.204     | 0.870     | 0.033   |
|                                  |           |           |         |
| Uncensored                       |           |           |         |
+----------------------------------+-----------+-----------+---------+
| CSUGIE/GDU-First 6 months        | 0.023     | 0.308     | 0.005   |
|                                  |           |           |         |
| Censored                         | 0.026     | 0.421     | 0.004   |
|                                  |           |           |         |
| Uncensored                       |           |           |         |
+----------------------------------+-----------+-----------+---------+
| CSUGIE/GDU-First 6 months        | 0.017     | 0.760     | \<0.001 |
| without ASA                      |           |           |         |
|                                  | 0.019     | 0.872     | \<0.001 |
| Censored                         |           |           |         |
|                                  |           |           |         |
| Uncensored                       |           |           |         |
+----------------------------------+-----------+-----------+---------+
| CSUGIE/GDU-Entire Study          | 0.040     | 0.296     | 0.017   |
|                                  |           |           |         |
| Censored                         | 0.045     | 0.349     | 0.016   |
|                                  |           |           |         |
| Uncensored                       |           |           |         |
+----------------------------------+-----------+-----------+---------+
| CSUGIE/GDU-Entire Study without  | 0.020     | 0.992     | \<0.001 |
| ASA                              |           |           |         |
|                                  | 0.022     | 0.907     | \<0.001 |
| Censored                         |           |           |         |
|                                  |           |           |         |
| Uncensored                       |           |           |         |
+----------------------------------+-----------+-----------+---------+

1\. From sNDA 20-998 (S-009) review tables 7, 8, 10, 11, 13, 14, 26, 27,
28, 30, 31 & 32.

> ***Reviewer's comment: These results tend to emphasize that celecoxib
> was not able to demonstrate it was statistically superior to
> diclofenac in terms of the clinically important UGI endpoints and
> conditions as defined in this study. The same is not true when
> comparisons are made to ibuprofen.***

**[Arthritis Efficacy and QOL:]{.underline}**

# Patient global {#patient-global .unnumbered}

The patient's global assessment of arthritis was based on a scale of 1
(very good) to 5 (very poor) and was assessed at baseline, weeks 4,13,
26, 39, and 52, and the final visit. The observed mean scores (not
shown, Table T31.1, p. 329, N49-00-06-035-102) were nearly identical for
the celecoxib, diclofenac, and ibuprofen treatment groups at baseline
(ranging from 2.9 to 3.0). Maximal efficacy was evident at the first
post-baseline assessment for all treatment groups, with mean scores
decreasing to 2.6 or 2.7. The degree of arthritis efficacy was identical
at week 26 and the final visit within all treatment groups. At these
time points, the mean score for celecoxib fell from 3.0 to 2.7.
Similarly, the mean score for diclofenac decreased from 3.0 to 2.6,
while the mean score for ibuprofen fell from 2.9 to 2.8. As seen in
**Table 34**, based on analysis of least square means, there were
generally no differences among the three treatment groups with respect
to changes from baseline. Although not compared statistically, least
square mean analysis also indicated no differences among post-baseline
scores within any of the three treatment groups, suggesting that the
maximal efficacy achieved was maintained through the end of the study.

Also noted in Table 34, the percentages of patients who reported an
improvement, worsening, or no change were similar between the celecoxib
and diclofenac treatment groups at week 26 and the final visit. However,
comparison of confidence intervals indicated differences between the
celecoxib and ibuprofen treatment groups. At week 26, the percentage of
celecoxib patients who reported an improvement in arthritis status was
higher than that for ibuprofen patients. In addition, the percentage of
celecoxib patients who reported a worsening in arthritis status was
lower than for ibuprofen patients. At the final visit, the percentage of
patients who reported an improvement in arthritis status was higher for
the celecoxib group than for the ibuprofen group. These results suggest
that celecoxib was comparable to diclofenac and ibuprofen (at the doses
studied in these trials) in treating the signs and symptoms of OA and
RA, as measured by the patient's global assessment of arthritis; no
inferences regarding superiority or equivalence can be drawn.

^Table\ 34:\ Summary\ of\ Patient's\ Global\ Assessment\ Results2^

+----------------------+---------------+---------------+--------------+
|                      | **Celecoxib** | *             | *            |
|                      |               | *Diclofenac** | *Ibuprofen** |
|                      | **(n=3987)**  |               |              |
|                      |               | **(n=1996)**  | **(n=1985)** |
+----------------------+---------------+---------------+--------------+
| Mean (95% CI)^1^     | 2.96          | 2.95          | 2.96         |
|                      | (2.93-2.98)   | (2.91-2.99)   | (2.92-3.00)  |
| Baseline             |               |               |              |
|                      | 2.68          | 2.71          | 2.73         |
| Week 26              | (2.65-2.71)   | (2.67-2.76)   | (2.68-2.78)  |
|                      |               |               |              |
| Final                | 2.71          | 2.72          | 2.76         |
|                      | (2.68-2.74)   | (2.67-2.77)   | (2.71-2.81)  |
+----------------------+---------------+---------------+--------------+
| Categorical          | 38 (37-40)    | 40 (38-42)    | 32 (30-34)   |
| analysis, % (95% CI) |               |               |              |
|                      | 46 (45-48)    | 43 (41-45)    | 48 (46-50)   |
| Week 26              |               |               |              |
|                      | 16 (15-17)    | 17 (15-18)    | 20 (18-21)   |
| Improved^3^          |               |               |              |
|                      | 37 (35-38)    | 40 (38-43)    | 31 (29-33)   |
| No Change            |               |               |              |
|                      | 46 (44-47)    | 42 (40-44)    | 48 (46-50)   |
| Worsened             |               |               |              |
|                      | 18 (16-19)    | 18 (16-19)    | 21 (19-23)   |
| Final                |               |               |              |
|                      |               |               |              |
| Improved             |               |               |              |
|                      |               |               |              |
| No Change            |               |               |              |
|                      |               |               |              |
| Worsened             |               |               |              |
+----------------------+---------------+---------------+--------------+

1.  Means are least square means. Decreases represent improvements.
    Global scale ranged from 1 (very good) to 5 (very poor).

2.  From Table 9a (p. 169); T31.2 (p 330); T31.3 (p. 331),
    N49-00-06-035-102. All results based on LOCF approach.

3.  Improved or worsened is defined as a reduction or increase,
    respectively, of at least one grade from baseline.

##### Patient's Assessment of Arthritis Pain-VAS:

The patient's assessment of arthritis pain was assessed on a visual
analog scale from 0 mm (no pain) to 100 mm (most severe pain) and was
evaluated at baseline, weeks 4, 13, 26, 39, and 52, and the final visit.
Although not shown (Table T32.1, p. 332, N49-00-06-035-102) observed
mean scores showed improvements in arthritis pain relative to baseline
at all post-baseline time points in each treatment group. Decreases in
pain scores ranged from 6.5 to 12.9 mm. Comparable improvements in
arthritis status were observed between the celecoxib and diclofenac
groups at week 26 (decreases of 8.3 mm and 10.1 mm, respectively) and
the final visit (decreases of 7.2 mm and 9.5 mm, respectively). Compared
with ibuprofen, celecoxib appeared to provide pain relief at both week
26 (decrease of 8.3 mm-celecoxib versus 3.9 mm-ibuprofen) and the final
visit (decrease of 7.2 mm -celecoxib versus 3.1 mm-ibuprofen).

Although not compared statistically, least square mean analysis
indicated similar changes from baseline among the three treatment
groups, based on comparison of confidence intervals. Results at week 26
and the final visit are shown in **Table 35.** While post-baseline least
square mean values for each treatment group increased over the course of
the study, overlapping of confidence intervals within groups suggested
that the efficacy of each treatment was constant during the study. These
results suggest that celecoxib was comparable to diclofenac and
ibuprofen (at the doses studied in these trials) in treating the signs
and symptoms of OA and RA, as measured by the patient's assessment of
arthritis pain; no inferences regarding superiority or equivalence can
be drawn.

Table 35: Patient's Assessment of Arthritis Pain - VAS

+-----------------+-----------------+-----------------+-----------------+
|                 | Celecoxib       | Diclofenac      | Ibuprofen       |
|                 |                 |                 |                 |
|                 | (n=3987)        | (n=1996)        | (n=1985)        |
+-----------------+-----------------+-----------------+-----------------+
| Mean (95% CI)   | 50.7            | 50.8            | 50.6            |
|                 | (49.9-51.6)     | (49.6-52.1)     | (49.3-51.9)     |
| Baseline        |                 |                 |                 |
|                 | 42.9            | 43.4            | 45.0            |
| Week 26         | (42.0-43.7)     | (42.0-44.8)     | (43.6-46.4)     |
|                 |                 |                 |                 |
| Final           | 44.0            | 44.2            | 45.9            |
|                 | (43.1-44.9)     | (42.7-45.6)     | (44.5-47.4)     |
+-----------------+-----------------+-----------------+-----------------+

1\. Means are least square means. Decreases represent improvements.

2\. From Table 9b (p. 170), N49-00-06-035-102.

Reviewer's comment: While these protocols were not primarily intended to
address effectiveness, it is disappointing that celecoxib at four times
and twice the upper recommended dose for OA and RA, respectively,
appeared to offer no substantial therapeutic gains.

**[QOL Results:]{.underline}**

Quality of Life measures were performed in protocol N49-98-02-035 only,
and consisted

of the Health Assessment Questionnaire (HAQ) and the SF-36 Health
Survey. Both the HAQ and the SF-36 Health Survey were conducted at
Baseline, Week 26, and the Final Visit.

As summarized in **Table 36**, observed mean HAQ scores were identical
for patients in the celecoxib and ibuprofen treatment groups at Baseline
(0.9 on the scale of 0 to 3). Celecoxib-treated patients reported
slightly less disability at Week 26 (0.8 versus 0.9 for ibuprofen) and
the same degree of disability at the Final Visit (0.9 in both groups).
Although statistical comparisons were not done, least square mean
analysis indicated that the treatments were similar and were maintained
through the final visit.

**^Table\ 36:\ HAQ-Observed\ Means,\ Least\ Square\ Means\ and\ 95%\ Confidence\ Intervals^**1

+-----------------------+-----------------------+-----------------------+
|                       | **Celecoxib**         | **Ibuprofen**         |
|                       |                       |                       |
|                       | **(N= 1990)**         | **(N= 1985)**         |
+-----------------------+-----------------------+-----------------------+
| Baseline              | 1986                  | 1981                  |
|                       |                       |                       |
| N                     | 0.9 (0.62)            | 0.9 (0.6              |
|                       |                       |                       |
| Mean (SD)             | 0.93 (0.90-0.96)      | 0.92 (0.89-0.95)      |
|                       |                       |                       |
| LS Mean and 95% CI    |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Week 26               | 1990                  | 1985                  |
|                       |                       |                       |
| N                     | 0.8 (0.65)            | 0.9 (0.65)            |
|                       |                       |                       |
| Mean (SD)             | 0.85 (0.83-0.87)      | 0.88 (0.86-0.90)      |
|                       |                       |                       |
| LS Mean and 95% CI    |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Final                 | 1990                  | 1985                  |
|                       |                       |                       |
| N                     | 0.9 (0.66)            | 0.9 (0.66)            |
|                       |                       |                       |
| Mean (SD)             | 0.86 (0.84-0.88)      | 0.89 (0.87-0.91)      |
|                       |                       |                       |
| LS Mean and 95% CI    |                       |                       |
+-----------------------+-----------------------+-----------------------+

1.  Based on LOCF data. HAQ scores range from 0-3 with lower scores
    indicating less disability. From Table T33 (p. 334),
    N49-00-06-035-102.

2.  From analysis of covariance with treatment and center as factors and
    baseline (for visit other than baseline) value as covariate.

Results of selected SF-36 Health Survey at baseline, week 26, and the
final visit are summarized in **Table 37**. In the celecoxib group,
improvements relative to baseline were observed at week 26 and the final
visit in three SF-36 domains: bodily pain, physical function, and
role-physical. In the vitality domain, celecoxib also produced an
improvement compared to baseline at week 26 only. In the ibuprofen
group, improvements relative to baseline at week 26 and the final visit
were observed in only one domain, bodily pain. Although statistical
comparisons were not done between celecoxib than ibuprofen, the
confidence intervals suggested that the treatments were similar in the
effect of treatment.

**^Table\ 37:\ Summary\ of\ Results\ in\ Selected\ SF-36\ Health\ Survey\ Domains^**1

+---------------------------------------+---------------+--------------+
| **SF-36 Health Survey Domain**        | **Celecoxib** | *            |
|                                       |               | *Ibuprofen** |
|                                       | **(n=1990)**  |              |
|                                       |               | **(n=1985)** |
+---------------------------------------+---------------+--------------+
| Bodily Pain                           | 39.5          | 39.9         |
|                                       | (38.6-40.4)   | (39.0-40.8)  |
| Baseline                              |               |              |
|                                       | 46.0          | 44.8         |
| Week 26                               | (45.1-46.9)   | (43.9-45.8)  |
|                                       |               |              |
| Final                                 | 45.9          | 44.7         |
|                                       | (45.0-46.9)   | (43.8-45.7)  |
+---------------------------------------+---------------+--------------+
| Physical Function                     | 48.3          | 48.6         |
|                                       | (47.1-49.5)   | (47.4-49.9)  |
| Baseline                              |               |              |
|                                       | 51.4          | 50.4         |
| Week 26                               | (50.5-52.3)   | (49.4-51.3)  |
|                                       |               |              |
| Final                                 | 50.8          | 50.1         |
|                                       | (49.9-51.7)   | (49.2-51.0)  |
+---------------------------------------+---------------+--------------+
| Vitality                              | 45.4          | 46.1         |
|                                       | (44.3-46.4)   | (45.0-47.1)  |
| Baseline                              |               |              |
|                                       | 47.6          | 46.9         |
| Week 26                               | (46.7-48.4)   | (46.0-47.7)  |
|                                       |               |              |
| Final                                 | 47.0          | 46.3         |
|                                       | (46.1-47.8)   | (45.5-47.1)  |
+---------------------------------------+---------------+--------------+
| Role-Physical                         | 37.9          | 38.4         |
|                                       | (35.9-39.8)   | (36.4-40.3)  |
| Baseline                              |               |              |
|                                       | 42.6          | 41.0         |
| Week 26                               | (40.8-44.4)   | (39.2-42.8)  |
|                                       |               |              |
| Final                                 | 42.1          | 41.0         |
|                                       | (40.4-43.9)   | (39.2-42.8)  |
+---------------------------------------+---------------+--------------+

1.  From Table 9c (p. 171), N49-00-06-035-102. All values are least
    square means (95% confidence intervals). Scales range from 0-100
    with lower scores as worse.

[Patient Satisfaction Questionnaire:]{.underline}

The patient satisfaction questionnaire (administered at the final visit)
evaluated patient satisfaction in the following four domains:
satisfaction with pain relief, improvement with walking and bending,
stomach discomfort or problems, and overall performance of study
medication. Observed mean scores (data not shown, Table T35, p. 343,
N49-00-06-035_102) were generally similar among the three treatment
groups. For the three measures in which higher scores indicated greater
satisfaction, the scores for ibuprofen were lower than for celecoxib and
diclofenac; however, comparison of confidence intervals did not suggest
a difference. For stomach discomfort or problems, celecoxib and
ibuprofen were similar, while diclofenac patients indicated more
dissatisfaction. Again, the confidence intervals did not confirm the
difference.

**[SODA Results:]{.underline}**

The Severity of Dyspepsia Assessment (SODA) was administered only in
protocol N49-98-02-102 and consisted of three domains (Pain Intensity,
Non-Pain Symptoms, and Satisfaction). The SODA was administered at
baseline, weeks 4, 13, 26, and 52 or the final visit. At baseline (Table
9d, p.172, N49-00-06-035_102), there were no statistically significant
differences in observed mean scores between the celecoxib and diclofenac
treatment groups in any of the three SODA domains (p≥0.204). With
respect to pain intensity and satisfaction, all observed mean changes
from baseline associated with diclofenac were statistically
significantly higher (i.e., worse) than those associated with celecoxib
(p\<0.001). With respect to non-pain symptoms, diclofenac produced a
statistically significantly higher mean change relative to baseline than
celecoxib only at week 4 (p=0.005).

**[Withdrawal Due to Lack of Arthritis Efficacy:]{.underline}**

Times to and incidences of withdrawal due to lack of arthritis efficacy
(Table T37.1-.2, p.350-1, N49-00-06-035_102) revealed a total of 1456
patients withdrew due to treatment failure (number of patients, ITT):

-   Celecoxib (n=3987) - 691 (17%)

-   Diclofenac (n=1996)- 309 (15%)

-   Ibuprofen (n=1985) - 456 (23%)

Based on this comparison, the withdrawal incidences of the celecoxib and
diclofenac treatment groups were similar. However, ibuprofen was
associated with a higher incidence of withdrawal than either celecoxib
or diclofenac. The percentages of celecoxib and diclofenac patients who
withdrew from the study due to lack of arthritis efficacy were generally
similar over time: the ibuprofen group had a slightly higher withdrawal
than that for either the celecoxib or diclofenac group. When withdrawals
due to lack of arthritis efficacy or adverse events (see Table 40) were
combined, a total of 3362 patients withdrew for one of these two reasons
as follows:

-   1596 (40%) in the celecoxib group

-   849 (43%) in the diclofenac group

-   917 (46%) in the ibuprofen group

As before, celecoxib and diclofenac were similar, but the incidence was
higher for ibuprofen than for celecoxib.

**[Overview of Safety (Section 10):]{.underline}**

**Deaths (Section 10.1.1):**

A total of 36 deaths (Appendix 2.9.1, p. 3918; N49-00-06-035-102)
occurred during the study or during post-study follow-up: 19 in the
celecoxib group, 9 in the diclofenac group, and 8 in the ibuprofen
group. Not expectedly in the population studied, the majority of deaths
(25 of 36, 69%) occurred in elderly patients (65 years old or older).
**Most deaths were cardiovascular** in nature. Of note, **none of the
deaths resulted from a GI or liver-related cause.**

In all cases except one, the principle investigator and the sponsor's
safety monitor believed that the death had no relationship to study
medication. The exception was a case in which the cause of death was
cardiopulmonary arrest/hypertension, and the investigator attributed the
relationship to study medication as uncertain (patient US0383-102-12691;
DER no. 990629-CL696). In this case, the date of the patient's last dose
could not be determined, but the death was believed to have occurred
more than 28 days after the patient discontinued taking study
medication.

Noted below (**Table 38**) is a summary of the 16 deaths that occurred
either during or within 28 days of participation in the entire study.

**^Table\ 38:\ Summary\ of\ Deaths-Entire\ Study\ or\ within\ 28\ days\ of\ Treatment^**1

+----------------------------------+----------+-----------+-----------+
| **Adverse Event^2^**             | **C      | **D       | **Ib      |
|                                  | elecoxib | iclofenac | uprofen** |
|                                  | (n       | (         |           |
|                                  | =3987)** | n=1996)** | **(       |
|                                  |          |           | n=1985)** |
+----------------------------------+----------+-----------+-----------+
| Patient-years of Exposure^3^     | 2320     | 1080      | 1122      |
+----------------------------------+----------+-----------+-----------+
| Myocardial infarction (MI)       | 3        | \-        | 1         |
|                                  |          |           |           |
| Cardiac arrest                   | 1        | 4         | 1         |
|                                  |          |           |           |
| Accidental injury                | 1        | \-        | \-        |
|                                  |          |           |           |
| Circulatory failure/MI           | \-       | \-        | 1         |
|                                  |          |           |           |
| Sepsis                           | 1        | \-        | \-        |
|                                  |          |           |           |
| Carcinoma                        | 1        | \-        | \-        |
|                                  |          |           |           |
| Coronary artery disorder         | \-       | 1         | \-        |
|                                  |          |           |           |
| Arrhythmia/MI                    | 1        | \-        | \-        |
+----------------------------------+----------+-----------+-----------+
| Total (No. per 100 pt-yr)        | 8 (0.34) | 5 (0.46)  | 3 (0.27)  |
+----------------------------------+----------+-----------+-----------+

1.  From Table 10.e (p 182); N49-00-06-035-102.

2.  For cases in with no adverse event term , the event was classified
    by the cause of death listed in the end-of-study CRF.

3.  Rounded estimates of pt.-yr exposures (p. 174, N49-00-06-035-102).

> ***Reviewer's comment: Of the deaths noted above, there were 5 (0.22),
> 4 (0.46) and 3 (0.27) deaths that appear to be attributable to
> cardiovascular causes for celecoxib, diclofenac and ibuprofen,
> respectively. Numbers in () are calculations based on the rounded
> estimates of patient exposure as noted in the table above.***

Noted below (**Table 39**) is a summary of the 20 deaths that occurred
28 days or more after participation in the study.

**^Table\ 39:\ Summary\ of\ Deaths\ Occurring\ more\ than\ 28\ days\ after\ Treatment^**1

+----------------------------------+----------+-----------+-----------+
| **Adverse Event^2^**             | **C      | **D       | **Ib      |
|                                  | elecoxib | iclofenac | uprofen** |
|                                  | (n       | (         |           |
|                                  | =3987)** | n=1996)** | **(       |
|                                  |          |           | n=1985)** |
+----------------------------------+----------+-----------+-----------+
| Myocardial infarction (MI)       | 2        | \-        | 1         |
|                                  |          |           |           |
| Cardiac arrest                   | 1        | 1         | \-        |
|                                  |          |           |           |
| Cardiac arrest/tamponade         | 1        | \-        | \-        |
|                                  |          |           |           |
| Pulmonary                        | 2        | 2         | 1         |
| fibrosis/pneumonia/carcinoma     |          |           |           |
|                                  | \-       | \-        | 1         |
| Accidental injury                |          |           |           |
|                                  | 1        | \-        | \-        |
| Sepsis                           |          |           |           |
|                                  | 1        | \-        | \-        |
| Carcinoma                        |          |           |           |
|                                  | 1        | \-        | 1         |
| Coronary artery disorder         |          |           |           |
|                                  | \-       | 1         | \-        |
| Aneurysm/subarachnoid hemorrhage |          |           |           |
|                                  | 1        | \-        | \-        |
| Cerebrovascular disorder         |          |           |           |
|                                  | \-       | \-        | 1         |
| Cardiac failure                  |          |           |           |
|                                  | 1        | \-        | \-        |
| Cardiopulmonary                  |          |           |           |
| arrest/hypertension              |          |           |           |
+----------------------------------+----------+-----------+-----------+
| Total (No. per 100 pt-yr)^1^     | 11       | 4 (0.37)  | 5 (0.45)  |
|                                  | (0.47)   |           |           |
+----------------------------------+----------+-----------+-----------+

1.  From Table 10.f (p 183); N49-00-06-035-102. Pt-years as noted in
    Table 38.

2.  For cases in with no adverse event term , the event was classified
    by the cause of death listed in the end-of-study CRF.

> ***Reviewer's comment: The table below summarizes results after review
> of the deaths noted above. Overall, most of the deaths were
> cardiovascular in origin, with the exclusion of 2 cases of CHF. Where
> it was unclear in the CRF when study drug was stopped, these cases
> have been included as occurring \< 28 days after trial; hence the
> difference with the Sponsor. It is unclear whether any of these
> cardiovascular deaths are directly related to the treatment. Given the
> relatively few deaths, no large excess mortality (total or cardiac,
> with or without ASA) is consistently evident for celecoxib as compared
> to controls.***

+-----------------+-----------------+-----------------+---------------+
|                 | **Celecoxib**   | **Diclofenac**  | **Ibuprofen** |
|                 |                 |                 |               |
|                 | **(n=3987       | **(n=1          | **(n=198      |
|                 | /882/3105)^1^** | 996/445/1551)** | 5/412/1573)** |
|                 |                 |                 |               |
|                 | **(pt-yrs:      | **(pt-yrs:      | **(pt-yrs:    |
|                 | 2               | 1081/239/841)** | 11            |
|                 | 320/517/1803)** |                 | 22/249/874)** |
+-----------------+-----------------+-----------------+---------------+
| Deaths-all      | 19 (.82)        | 9 (.83)         | 8 (.71)       |
| causes          |                 |                 |               |
|                 | 6 (1.2)         | 1 (.4)          | 4 (1.6)       |
| ASA users       |                 |                 |               |
|                 | 13 (0.7)        | 8 (1.0)         | 4 (0.5)       |
| Non-ASA users   |                 |                 |               |
+-----------------+-----------------+-----------------+---------------+
| Deaths-cardiac  | 11 (0.5)        | 5 (.46)         | 5 (0.4)       |
|                 |                 |                 |               |
| (entire study)  | 5 (1.0)         | 0               | 3 (1.2)       |
|                 |                 |                 |               |
| ASA users       | 6 (0.3)         | 5 (.63)         | 2 (0.2)       |
|                 |                 |                 |               |
| Non-ASA users   |                 |                 |               |
+-----------------+-----------------+-----------------+---------------+
| Deaths-cardiac  | **10 (.43): [5  | **5 (.46): [4   | 3 (.27)       |
|                 | (0.2)^2^        | (0.4)           |               |
| (during or \<28 | ]{.underline}** | ]{.underline}** | 2 (.8)        |
| day after       |                 |                 |               |
| trial)          | **5 (1.0): [2   | 0               | 1 (.11)       |
|                 | (0.4)           |                 |               |
| ASA users       | ]{.underline}** | **5 (.63): [4   |               |
|                 |                 | (0.5)           |               |
| Non-ASA users   | **5 (.27): [3   | ]{.underline}** |               |
|                 | (0.2)           |                 |               |
|                 | ]{.underline}** |                 |               |
+-----------------+-----------------+-----------------+---------------+

1.  n = number of patients in entire group/ASA users/ASA non-users,
    respectively. Pt-yrs (estimates) are in same order.

2.  Numbers in () are rate/100 patient years. Numbers following : and
    underlined are per Sponsor.

**[Adverse Events Causing Withdrawal:]{.underline}**

The most common adverse events causing withdrawal \>1% in any treatment
group) are shown in **Table 40**. The overall incidence of withdrawal
(also see Table 3) due to an adverse event was statistically
significantly lower for celecoxib than for diclofenac. Six of the 10
most common events were related to the GI system, five of which
represented the most common GI adverse events described above:
**abdominal pain, dyspepsia, nausea, diarrhea, and flatulence**. Three
of the events (SGOT/SGPT increased, and hepatic function abnormal) were
related to elevations in liver function test results; these events led
to noteworthy incidences of withdrawals in the diclofenac group. The
differences between celecoxib and diclofenac for three of the GI events
(abdominal pain, nausea, and diarrhea) and the three hepatic events were
statistically significant in favor of celecoxib. Rash led to withdrawal
in more than 1% of patients in the celecoxib and ibuprofen groups with
statistically significant differences between celecoxib and both
ibuprofen and diclofenac.

Table 40: Adverse Events Causing Withdrawal (Incidence \>1%) in Any
Treatment Group-Entire Study

+-----------------+-----------------+-----------------+-----------------+
| Adverse Event   | Celecoxib 400   | Diclofenac 75   | Ibuprofen 800   |
|                 | mg BID          | mg BID          | mg TID          |
|                 |                 |                 |                 |
|                 | (n=3987)        | (n=1996)        | (n=1985)        |
+-----------------+-----------------+-----------------+-----------------+
| Any event (% of | 22.4            | **26.5**\*      | 23.0            |
| patients)       |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Abdominal Pain  | 4.3             | **6.5**\*       | 4.9             |
|                 |                 |                 |                 |
| Dyspepsia       | 3.8             | **4.4**         | 3.9             |
|                 |                 |                 |                 |
| Rash            | **2.1**         | 0.7\*           | 1.3\*           |
|                 |                 |                 |                 |
| Nausea          | 1.7             | **2.8**\*       | 1.8             |
|                 |                 |                 |                 |
| Diarrhea        | 1.4             | **2.7**\*       | 0.8\*           |
|                 |                 |                 |                 |
| Flatulence      | 1.2             | **1.8**         | 1.4             |
|                 |                 |                 |                 |
| Gastric ulcer   | 0.3             | 0.7             | **1.0**\*       |
|                 |                 |                 |                 |
| SGOT increased  | 0.1             | **2.1**\*       | 0.1             |
|                 |                 |                 |                 |
| SGPT increased  | 0.1             | **2.3**\*       | 0.1             |
|                 |                 |                 |                 |
| Hepatic         | \<0.1           | **1.1**\*       | \<0.1           |
| function        |                 |                 |                 |
| abnormal        |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

\* p\<0.05 vs. celecoxib. From Table 10d (p. 180), N49-00-06-035-102.

As noted in Table T42.4 (p. 498, N49-00-06-035-102, data not shown), the
incidences of adverse events leading to withdrawal in the first six
months of the study were in most cases identical to, or slightly below,
those in the entire study period. This suggests that **almost all
patients withdrawing due to adverse events did so within six months of
beginning the study**.

**[Other Serious Adverse Events:]{.underline}**

A total of 500 patients experienced **serious adverse events (SAE)**
during or 28 days after study participation:

-   270 patients in the celecoxib group

-   111 patients in the diclofenac group

-   119 patients in the ibuprofen group

The most common SAEs are summarized in **Table 41**. As can be seen, the
difference between any two treatment groups was no more than 0.6 per 100
patient-years. The highest rate seen for

any serious adverse event was 0.8 per 100 patient-years, seen in at
least one treatment group for myocardial infarction, coronary artery
disorder, accidental fracture, cardiac failure, and back pain. Although
the results are similar to those shown for general adverse events, the
patterns suggested by the general adverse events were not replicated
exactly in the serious adverse events. This difference in pattern may
reflect the fact that there were smaller numbers of serious events than
general adverse events.

**^Table\ 41:\ Summary\ of\ Serious\ Adverse\ Events-Entire\ Study\ Period1^**

+----------------------+-----------------+-------------+--------------+
| **Adverse Event**    | **Celecoxib**   | **D         | *            |
|                      |                 | iclofenac** | *Ibuprofen** |
|                      | **(n=3987)**    |             |              |
|                      |                 | *           | **(n=1985)** |
|                      | **2320.4        | *(n=1996)** |              |
|                      | pt-yrs**        |             | **1122.5     |
|                      |                 | **1080.5    | pt-yrs**     |
|                      |                 | pt-yrs**    |              |
+----------------------+-----------------+-------------+--------------+
| Any serious event    | 270 (11.6)      | 111 (10.3)  | 119 (10.6)   |
+----------------------+-----------------+-------------+--------------+
| Abdominal pain       | 6 (0.3)         | 6 (0.6)     | 2 (0.2)      |
|                      |                 |             |              |
| Accidental fracture  | 10 (0.4)        | 4 (0.4)     | 9 (0.8)      |
|                      |                 |             |              |
| Accidental injury    | 3 (0.1)         | 4 (0.4)     | 7 (0.6)      |
|                      |                 |             |              |
| Angina pectoris      | 4 (0.2)         | 5 (0.5)     | 6 (0.5)      |
|                      |                 |             |              |
| Atrial fibrillation  | 9 (0.4)         | 2 (0.2)     | 3 (0.3)      |
|                      |                 |             |              |
| Back pain            | 15 (0.6)        | 3 (0.3)     | 9 (0.8)      |
|                      |                 |             |              |
| Cardiac failure      | 9 (0.4)         | 2 (0.2)     | 9 (0.8)      |
|                      |                 |             |              |
| Cellulitis           | 8 (0.3)         | 1 (\<0.1)   | 1 (\<0.1)    |
|                      |                 |             |              |
| Cerebrovascular      | 4 (0.2)         | 6 (0.6)     | 6 (0.5)      |
| disorder             |                 |             |              |
|                      | 11 (0.5)        | 5 (0.5)     | 7 (0.6)      |
| Chest pain           |                 |             |              |
|                      | 19 (0.8)        | 5 (0.5)     | 5 (0.4)      |
| Coronary artery      |                 |             |              |
| disorder             | 7 (0.3)         | 5 (0.5)     | 1 (\<0.1)    |
|                      |                 |             |              |
| Deep                 | 7 (0.3)         | 2 (0.2)     | 1 (\<0.1)    |
| thrombophlebitis     |                 |             |              |
|                      | 19 (0.8)        | 4 (0.4)     | 9 (0.8)      |
| GI hemorrhage        |                 |             |              |
|                      | 14 (0.6)        | 5 (0.5)     | 5 (0.4)      |
| Myocardial           |                 |             |              |
| infarction           | 5 (0.2)         | 4 (0.4)     | 3 (0.3)      |
|                      |                 |             |              |
| Pneumonia            | 8 (0.3)         | 4 (0.4)     | 0            |
|                      |                 |             |              |
| Syncope              |                 |             |              |
|                      |                 |             |              |
| Unstable angina      |                 |             |              |
+----------------------+-----------------+-------------+--------------+

1.  From Table 10.g (p 184); N49-00-06-035-102. Owing primarily to the
    unequal randomization, results are displayed as normalized for
    length of exposure, rather than crude incidence rates. Table
    includes any event experienced by a total of at least 10 patients
    across the three treatment groups.

> *Reviewer's comment: Generally, these normalized incidences do not
> seem to suggest any important differences or obvious trends of
> specific target organ or organ-system involvement by any treatment
> group.*

[Other safety findings ( Section 10.2):]{.underline}

**ADR incidence (Section 10.2.1):**

A total of 6493 patients reported at least one adverse event during
study participation:

-   3260 (81.8%) in the celecoxib group

-   1654 (82.9%) in the diclofenac group

-   1579 (79.5%) in the ibuprofen group**.**

The most common adverse events occurring in any treatment group are
shown in **Table 42**. The majority of the common adverse events were
gastrointestinal or upper respiratory in nature. The **most common event
in any treatment group was dyspepsia, followed by upper respiratory
tract infection, headache, and abdominal pain.** Of the GI adverse
events shown in Table 42 (dyspepsia, abdominal pain, diarrhea, nausea,
flatulence, vomiting, constipation), all but one event (vomiting) were
statistically significant in favor of celecoxib vs. diclofenac. Adverse
events relating to liver function tests (SGOT or SGPT increases) were
also statistically significantly lower for celecoxib than for diclofenac

Other comparisons of note, peripheral edema, hypertension, and anemia
were statistically significantly less common for celecoxib than for
ibuprofen whereas the incidence of rash was statistically significantly
higher for celecoxib than for either diclofenac or ibuprofen.

The incidences of the most common respiratory adverse events were
similar among the three treatment groups. Symptoms suggest typical
seasonal allergies and minor upper respiratory infections. The incidence
of bronchitis was significantly higher for ibuprofen.

Table 42: Adverse Events with Incidence 3%- Entire Study Period

+-----------------+-----------------+-----------------+-----------------+
| Adverse Event   | Celecoxib 400   | Diclofenac 75   | Ibuprofen 800   |
|                 | mg BID          | mg BID          | mg TID          |
|                 |                 |                 |                 |
|                 | (n=3987)        | (n=1996)        | (n=1985)        |
+-----------------+-----------------+-----------------+-----------------+
| Any event (% of | 81.8            | 82.9            | **79.5\***      |
| patients)       |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Dyspepsia       | 16.5            | **19.5\***      | 16.5            |
|                 |                 |                 |                 |
| URTI            | 15.4            | 14.7            | 15.8            |
|                 |                 |                 |                 |
| Headache        | 13.9            | **16.6\***      | 13.0            |
|                 |                 |                 |                 |
| Abdominal Pain  | 11.7            | **18.5\***      | 11.3            |
|                 |                 |                 |                 |
| Diarrhea        | 10.9            | **15.0\***      | **7.5\***       |
|                 |                 |                 |                 |
| Sinusitis       | 8.8             | 8.6             | 9.5             |
|                 |                 |                 |                 |
| Nausea          | 8.2             | **12.1\***      | 9.0             |
|                 |                 |                 |                 |
| Flatulence      | 7.3             | **11.4\***      | 7.2             |
|                 |                 |                 |                 |
| Rash            | 6.2             | **2.8\***       | **3.8\***       |
|                 |                 |                 |                 |
| Influenza-like  | 5.4             | 5.6             | 6.1             |
| symptoms        |                 |                 |                 |
|                 | 5.3             | 5.0             | 5.5             |
| Injury          |                 |                 |                 |
| accidental      | 4.4             | 5.3             | **8.7\***       |
|                 |                 |                 |                 |
| Anemia          | 4.4             | 3.5             | 4.6             |
|                 |                 |                 |                 |
| Coughing        | 4.3             | 3.9             | 3.7             |
|                 |                 |                 |                 |
| Rhinitis        | 4.0             | 4.1             | **5.1\***       |
|                 |                 |                 |                 |
| Bronchitis      | 3.7             | 3.3             | 4.0             |
|                 |                 |                 |                 |
| Back pain       | 3.7             | 3.5             | **5.2\***       |
|                 |                 |                 |                 |
| Edema           | 3.6             | 3.7             | 3.2             |
| peripheral      |                 |                 |                 |
|                 | 3.5             | 3.4             | 4.2             |
| Insomnia        |                 |                 |                 |
|                 | 2.9             | **4.3\***       | **4.4\***       |
| Dizziness       |                 |                 |                 |
|                 | 2.9             | **2.7**         | 3.5             |
| Tooth disorder  |                 |                 |                 |
|                 | 2.8             | **1.8\***       | 3.0             |
| Pharyngitis     |                 |                 |                 |
|                 | 2.6             | 3.5             | 2.7             |
| Urinary tract   |                 |                 |                 |
| infection       | 2.0             | 2.0             | **3.1\***       |
|                 |                 |                 |                 |
| Vomiting        | 2.2             | **6.8\***       | **6.5\***       |
|                 |                 |                 |                 |
| Hypertension    | 1.0             | **5.1\***       | 1.2             |
|                 |                 |                 |                 |
| Constipation    | 0.9             | **4.3\***       | 1.0             |
|                 |                 |                 |                 |
| SGPT increased  |                 |                 |                 |
|                 |                 |                 |                 |
| SGOT increased  |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

\* p\<0.05 vs. celecoxib. From Table 10.b (p 177) and Table T41.1 (p.
357), N49-00-06-035-102.

**The majority of adverse events occurred during the first six months**
(182 days) of treatment (Table T41.4, p. 415; N49-00-06-035-102). In
fact (Appendix 2.8.4, p. 3832; N49-00-06-035-102), the large majority of
events occurred within the first 90 days. During the first 6 months,
events were reported for 3023 (75.8%) patients in the celecoxib group,
1564 (78.3%) in the diclofenac group, and 1488 (75.0%) in the ibuprofen
group. Although the incidences of almost all events were slightly lower
during the first six months than during the entire study period, the
differences among the treatment groups were similar in magnitude to
those in Table 42, particularly with respect to the GI system. The
statistical comparisons were similarly maintained, despite the lower
numbers of events. All of the statistically significant differences
shown in Table 42 were also statistically significant within the first
six months, with two exceptions (tooth disorder between celecoxib and
ibuprofen, and urinary tract infection between celecoxib and
diclofenac). Conversely, certain differences that were not shown to be
statistically significant in Table 42 were significant at six months.
The incidence of anemia between celecoxib and diclofenac (2.0% vs. 3.2%,
respectively; p=0.009) and the incidence of BUN increased between
celecoxib and diclofenac (0.7% vs. 1.6%, respectively; p=0.004) being
examples.

Events that occurred with incidences above 2% in intervals after the
first 90 days are summarized in **Table 43**. As discussed above, these
events generally were similar to those occurring most commonly during
the entire study. The declining incidences of most events over time
could reflect adaptation as well as the withdrawal of susceptible
patients. However, there are exceptions to this trend such as anemia or
upper respiratory infections; the latter may reflect the background
incidence of these common events. Of note, the incidences of events for
diclofenac in the last interval may well be influenced by the fact that
protocol 102 was not extended to 15 months. The 64 patients remaining
after Day 360 were only in the study for a maximum of two additional
weeks; the longest treatment duration in this group was 374 days (Table
T2.4.1, p. 357; N49-00-06-035-102). Therefore, there was a decreased
possibility for adverse events in this period, but when an event did
occur, it caused a high incidence owing to the low sample size.

**^Table\ 43:\ Adverse\ Events\ with\ 2%\ Incidence\ in\ Any\ Interval\ After\ the\ First\ 90\ days^**1

+----------------------+----------+-----------+----------+-----------+
| **Adverse Event**    | **91-180 | **181-270 | *        | **361-450 |
|                      | Days**   | Days**    | *271-360 | Days**    |
|                      |          |           | Days**   |           |
+----------------------+----------+-----------+----------+-----------+
| No. who entered      | 2836     | 2343      | 2028     | 585       |
| interval             |          |           |          |           |
|                      | 1394     | 1127      | 977      | 64        |
| Celecoxib (C) 400 mg |          |           |          |           |
| BID                  | 1297     | 1045      | 894      | 479       |
|                      |          |           |          |           |
| Diclofenac (D) 75 mg |          |           |          |           |
| BID                  |          |           |          |           |
|                      |          |           |          |           |
| Ibuprofen (I) 800 mg |          |           |          |           |
| TID                  |          |           |          |           |
+----------------------+----------+-----------+----------+-----------+
| Dyspepsia            | C D I    | C D I     | C D I    | C D I     |
|                      |          |           |          |           |
| Headache             |          |           |          |           |
|                      |          |           |          |           |
| Upper respiratory.   |          |           |          |           |
| tract infection      |          |           |          |           |
|                      |          |           |          |           |
| ####                 |          |           |          |           |
| ##### Abdominal pain |          |           |          |           |
|                      |          |           |          |           |
| ######### Sinusitis  |          |           |          |           |
|                      |          |           |          |           |
| ######### Diarrhea   |          |           |          |           |
|                      |          |           |          |           |
| ######### Nausea     |          |           |          |           |
|                      |          |           |          |           |
| Flatulence           |          |           |          |           |
|                      |          |           |          |           |
| Anemia               |          |           |          |           |
|                      |          |           |          |           |
| SGOT increased       |          |           |          |           |
|                      |          |           |          |           |
| SGPT increased       |          |           |          |           |
+----------------------+----------+-----------+----------+-----------+
|                      | 3.1 3.4  | 2.6 2.6   | 1.7 1.5  | 0.4 - 0.5 |
|                      | 3.8      | 2.8       | 2.0      |           |
|                      |          |           |          | 0.4 - 0.5 |
|                      | 3.1 3.0  | 2.0 2.1   | 0.9 0.9  |           |
|                      | 2.9      | 2.0       | 0.9      | 3.1 3.8   |
|                      |          |           |          | 2.5       |
|                      | 2.8 3.1  | 2.4 3.7   | 4.2 3.5  |           |
|                      | 4.7      | 2.8       | 3.0      | 1.1 - 0.7 |
|                      |          |           |          |           |
|                      | 2.7 5.2  | 2.2 2.2   | 1.3 1.7  | 0.8 - 2.2 |
|                      | 3.0      | 2.2       | 1.4      |           |
|                      |          |           |          | 1.0 - 0.2 |
|                      | 2.4 1.5  | 1.9 2.8   | 1.4 0.8  |           |
|                      | 2.3      | 1.7       | 2.0      | 0.4 - 0.2 |
|                      |          |           |          |           |
|                      | 2.3 3.7  | 1.5 1.8   | 1.3 1.1  | \- - -    |
|                      | 1.7      | 1.8       | 1.2      |           |
|                      |          |           |          | 2.0 1.7   |
|                      | 1.9 2.9  | 1.6 1.8   | 0.8 0.4  | 2.8       |
|                      | 1.6      | 1.8       | 1.2      |           |
|                      |          |           |          | 0.9 - 0.4 |
|                      | 1.6 2.2  | 0.9 1.8   | 0.6 1.0  |           |
|                      | 1.7      | 0.8       | 0.6      | 0.7 - 0.8 |
|                      |          |           |          |           |
|                      | 1.3 2.3  | 1.4 1.7   | 2.7 2.7  |           |
|                      | 3.4      | 2.2       | 3.5      |           |
|                      |          |           |          |           |
|                      | 0.2 2.1  | 0.4 1.1   | 0.2 1.1  |           |
|                      | 0.2      | 0.3       | 0.7      |           |
|                      |          |           |          |           |
|                      | 0.2 2.1  | 0.3 1.3   | 0.3 1.2  |           |
|                      | 0.3      | 0.3       | 0.8      |           |
+----------------------+----------+-----------+----------+-----------+

1\. From Table 10.c (p 179) and Appendix 2.8.4 (p. 3832),
N49-00-06-035-102.

The majority of events were mild to moderate in severity (Appendix
2.8.1, p. 3627; N49-00-06-035-102). The **overall incidences of severe
adverse events** were similar among the three treatment groups:

-   16.3% for celecoxib

-   18.1% for diclofenac

-   17.6% for ibuprofen.

**[Clinical Laboratory Evaluation (Section 10.2.2):]{.underline}**

**Table 44** summarizes the mean changes from baseline to the final
visit for each standard laboratory test performed during the study.
Although in most cases the change at the final visit does not represent
the greatest change in laboratory values during the study, it includes
the largest numbers of patients. Patients with at least one
post-baseline laboratory result, including patients withdrawn owing to
an abnormal result, are included in the final visit values.

**^Table\ 44:\ Mean\ Changes\ from\ Baseline\ to\ Final\ Visit\ in\ Laboratory\ Values1^**

+----------------------+----------------+-------------+---------------+
| **Laboratory Test**  | **Celecoxib**  | **D         | **Ibuprofen** |
|                      |                | iclofenac** |               |
+----------------------+----------------+-------------+---------------+
| Hemoglobin, g/dL     | -0.06 (0.013)  | -0.26       | -0.37 (0.019) |
|                      |                | (0.020) \*  | \*            |
| Hematocrit           | -0.001         |             |               |
|                      | (0.0004)       | -0.007      | -0.012        |
| Platelet count,      |                | (0.0006) \* | (0.0007) \*   |
| x10^9^/L             | -2.3 (0.70)    |             |               |
|                      |                | 10.0 (1.11) | 7.9 (0.94) \* |
| WBC, x10^9^/L        | -0.09 (0.029)  | \*          |               |
|                      |                |             | 0.01 (0.041)  |
| Total bilirubin,     | 0.0 (0.05)     | 0.06        | \*            |
| µmol/L               |                | (0.038) \*  |               |
|                      | 0.9 (0.23)     |             | -1.0 (0.07)   |
| Alkaline             |                | 0.1 (0.06)  | \*            |
| phosphatase, U/L     | 0.3 (0.12)     |             |               |
|                      |                | 1.6 (0.38)  | -0.5 (0.31)   |
| AST, U/L             | -0.2 (0.18)    | \*          | \*            |
|                      |                |             |               |
| ALT, U/L             | -2.0 (1.17)    | 5.0 (0.57)  | 0.9 (0.16)    |
|                      |                | \*          |               |
| Creatine kinase, U/L | 0.8 (0.22)     |             | 1.3 (0.24)    |
|                      |                | 11.6 (1.10) |               |
| Creatinine, µmol/L   | 0.66 (0.027)   | \*          | -0.1 (1.97)   |
|                      |                |             |               |
| BUN, mmol/L          | -0.1 (0.05)    | 1.3 (2.18)  | 1.5 (0.33)    |
|                      |                |             |               |
| Sodium, mmol/L       | 0.05 (0.007)   | 2.4 (0.33)  | 0.52 (0.039)  |
|                      |                | \*          | \*            |
| Potassium, mmol/L    | 0.7 (0.05)     |             |               |
|                      |                | 0.58        | 0.0 (0.07)    |
| Chloride, mmol/L     | 0.2 (0.04)     | (0.041)     |               |
|                      |                |             | -0.03 (0.010) |
| Bicarbonate, mmol/L  | 0.009 (0.0030) | -0.4 (0.07) | \*            |
|                      |                | \*          |               |
| Inorganic            |                |             | 0.7 (0.07)    |
| phosphorus, mmol/L   |                | 0.03        |               |
|                      |                | (0.010)     | 0.1 (0.06) \* |
|                      |                |             |               |
|                      |                | 0.4 (0.07)  | -0.003        |
|                      |                | \*          | (0.0046)      |
|                      |                |             |               |
|                      |                | 0.3 (0.06)  |               |
|                      |                |             |               |
|                      |                | -0.012      |               |
|                      |                | (0.0042) \* |               |
+----------------------+----------------+-------------+---------------+

1\. From Table 10.h (p 187); N49-00-06-035-102. All numbers are mean
(SE) from baseline. (\*) =p\<0.05 vs. celecoxib.

Reviewer's Comment: Many differences among groups were statistically
significant, owing to the large numbers of patients in each group.
However, it is unclear if these differences were clinically meaningful;
the LFT abnormalities associated with diclofenac may be the remarkable
exception.

For most laboratory tests, incidences of extreme laboratory values
(according to the predefined criteria ) occurred in very few patients at
any time. Those for which at least 20 patients across the three
treatment groups had an extreme value are summarized in **Table 45**.
The percentages of patients with extreme hemoglobin or hematocrit values
were higher in the NSAID groups than for celecoxib. This data appears
consistent with the adverse event (anemia) and mean laboratory data
noted previously. Two of the differences between celecoxib and
diclofenac were statistically significant while the difference in
minimum value between celecoxib and ibuprofen (hemoglobin) approached
but did not achieve statistical significance (p=0.053).

Other differences of note were the incidences of extreme ALT and AST
values. Although only the ALT results are shown in Table 45, differences
in both of these tests (AST data, Table 45.1, p. 541;
N49-00-06-035-102.) were statistically significant between celecoxib and
diclofenac for both the final visit as well as for the maximum value
measured during the study. Analysis of laboratory shift data (Appendix
2.12, p. 4214; N49-00-06-035-102) and scatter-plots (Appendix 2.13, p.
4230; N49-00-06-035-102) for the liver function tests (ALT and AST) also
show that a higher proportion of patients in the diclofenac group
experienced elevations at the final visit.

No difference was seen among the treatment groups in extreme high
bicarbonate values (above 35 mmol/L), with incidences ranging from 0.2
to 0.4 in the three groups. Only one celecoxib patient and two
diclofenac patients experienced extreme low bicarbonate values (below 15
mmol/L) at any time during the study. The only statistically significant
difference in extreme laboratory values not shown in Table 45 was that
between celecoxib and ibuprofen in potassium levels: 0.3% of celecoxib
patients and 0.0% of ibuprofen patients had a maximum value above 6.0
mmol/L (p=0.021). Any trends for other laboratory data suggested in the
means and extremes, and the differences among the groups, were not
sufficiently robust to be detected by visual examination of these shift
tables or the scatter-plots.

**^Table\ 45:\ Analysis\ of\ Extreme\ Laboratory\ Test\ Values:\ Entire\ Study\ Period1^**

+----------------------------+------------+-------------+-------------+
| **Laboratory Test**        | **C        | **D         | **          |
|                            | elecoxib** | iclofenac** | Ibuprofen** |
+----------------------------+------------+-------------+-------------+
| # Low {#low .unnumbered}   |            |             |             |
+----------------------------+------------+-------------+-------------+
| **Hemoglobin^2^**          | 9/3708     | 9/1851      | 7/1805      |
|                            | (0.2)      | (0.5)       | (0.4)       |
| Final visit                |            |             |             |
|                            | 12/3708    | 17/1851     | 13/1805     |
| Minimum value              | (0.3)      | (0.9) \*    | (0.7)       |
+----------------------------+------------+-------------+-------------+
| **Hematocrit^2^**          | 5/3701     | 12/1849     | 6/1802      |
|                            | (0.1)      | (0.6) \*    | (0.3)       |
| Minimum value              |            |             |             |
+----------------------------+------------+-------------+-------------+
| # High {#high .unnumbered} |            |             |             |
+----------------------------+------------+-------------+-------------+
| **ALT (SGPT) (\>200 U/L)** | 2/3692     | 22/1848     | 0/1785 (0)  |
|                            | (\<0.1)    | (1.2) \*    |             |
| Final visit                |            |             | 1/1785      |
|                            | 4/3692     | 29/1848     | (\<0.1)     |
| Maximum value              | (0.1)      | (1.6) \*    |             |
+----------------------------+------------+-------------+-------------+
| **Creatine kinase (\>300   | 67/3667    | 33/1840     | 27/1758     |
| U/L)**                     | (1.8)      | (1.8)       | (1.5)       |
|                            |            |             |             |
| Final visit                | 184/3667   | 83/1840     | 85/1758     |
|                            | (5.0)      | (4.5)       | (4.8)       |
| Maximum value              |            |             |             |
+----------------------------+------------+-------------+-------------+
| **BUN (\>14.3 mmol/L)**    | 17/3692    | 8/1849      | 12/1786     |
|                            | (0.5)      | (0.4)       | (0.7)       |
| Final visit                |            |             |             |
|                            | 31/3692    | 20/1849     | 16/1786     |
| Maximum value              | (0.8)      | (1.1)       | (0.9)       |
+----------------------------+------------+-------------+-------------+
| **Bicarbonate (\>35        | 13/3689    | 7/1844      | 3/1782      |
| mmol/L)**                  | (0.4)      | (0.4)       | (0.2)       |
|                            |            |             |             |
| Maximum value              |            |             |             |
+----------------------------+------------+-------------+-------------+

1.  From Table 10.j (p 189); N49-00-06-035-102. Data are expressed as
    No./total and percentage of patients. Includes all tests for which
    at least 20 patients had an extreme value. (\*) =p\<0.05 vs.
    celecoxib.

2.  Hemoglobin-below 6.0 g/dL or 3.0 g/dL decrease from baseline.
    Hematocrit - below 0.25 or 0.10 decrease from baseline.

**[Contingency table analyses:]{.underline}**

Contingency table analyses of patients whose post-treatment laboratory
results met certain predefined criteria for combinations of values or
changes in values included the following:

-   Decreases in both hemoglobin and hematocrit

-   Increases in both creatinine and BUN

-   Increases in both AST and ALT

-   Increases in both alkaline phosphatase and total bilirubin

-   Increases in both ALT and alkaline phosphatase

-   Increases in both ALT and total bilirubin.

**Table 46** summarizes the results in those patients who experienced an
extreme decrease in either hematocrit or hemoglobin at any time during
the study. The results show that in all analyses, proportions of
diclofenac or ibuprofen patients who had the specified decreases in
hematocrit and/or hemoglobin were two- to three-fold higher than in
patients receiving celecoxib. Here, the addition of aspirin increased
the incidence rate in all treatment groups, but appeared to preserve the
differences among the groups.

**Table 46: Summary of Hemoglobin/Hematocrit Contingency Tables: Entire
Study Period^1^**

+-----------------------------+-----------+-------------+------------+
| **Patients with hemoglobin  | **Ce      | **D         | **I        |
| decrease \>2 g/dL and/or    | lecoxib** | iclofenac** | buprofen** |
| hematocrit decrease ≥0.10** |           |             |            |
+-----------------------------+-----------+-------------+------------+
| All patients                | 87/3701   | 82/1849     | 102/1802   |
|                             | (2.4)^2^  | (4.4)       | (5.7)      |
| Excluding CSUGIEs           |           |             |            |
|                             | 83/3682   | 81/1840     | 95/1792    |
| Excluding CSUGIEs/ulcers    | (2.3)^2^  | (4.4)       | (5.3)      |
|                             |           |             |            |
| Excluding all adjudicated   | 82/3659   | 78/1824     | 93/1768    |
| potential CSUGIEs           | (2.2)     | (4.3)       | (5.3)      |
|                             |           |             |            |
| Excluding all reported      | 73/3545   | 68/1753     | 81/1693    |
| potential CSUGIEs           | (2.1)     | (3.9)       | (4.8)      |
|                             |           |             |            |
|                             | 41/3068   | 41/1490     | 42/1364    |
|                             | (1.3)     | (2.8)       | (3.1)      |
+-----------------------------+-----------+-------------+------------+
| OA patients                 | 63/2675   | 48/1340     | 74/1299    |
|                             | (2.4)^2^  | (3.6)       | (5.7)      |
| RA patients                 |           |             |            |
|                             | 24/1026   | 34/509      | 28/503     |
|                             | (2.3)^2^  | (6.7)       | (5.6)      |
+-----------------------------+-----------+-------------+------------+
| Patients not taking aspirin | 53/2864   | 53/1428     | 73/1414    |
|                             | (1.9)^2^  | (3.7)       | (5.2)      |
| Patients taking aspirin     |           |             |            |
|                             | 34/837    | 29/421      | 29/388     |
|                             | (4.1)^2^  | (6.9)       | (7.5)      |
+-----------------------------+-----------+-------------+------------+

1.  From Table 10.l (p 192); N49-00-06-035-102. Data are expressed as
    No./ total and percentage of patients.

2.  p≤0.05 versus both other treatments by Fischer's Exact Test. Figures
    10a-c, p 203-4; N49-00-06-035-102).

**Table 47** summarizes the results of the hepatobiliary and renal
laboratory contingency analyses. As with the hematocrit and hemoglobin
analyses above, this table includes all patients who experienced either
extreme laboratory value at any point during the study. The results are
consistent with those reported above in adverse events and extreme
laboratory values. Elevations in renal function tests were somewhat more
frequent in the diclofenac group than in the celecoxib or ibuprofen
group, and elevation in liver function tests were strikingly more
frequent for diclofenac.

**^Table\ 47:\ Summary\ of\ Hepatobiliary\ and\ Renal\ Contingency\ Tables:\ Entire\ Study1^**

+--------------------------------+-----------+-----------+-----------+
|                                | **Ce      | **Dic     | **Ib      |
|                                | lecoxib** | lofenac** | uprofen** |
+--------------------------------+-----------+-----------+-----------+
| Creatinine ≥159 µmol/L and/or  | 47/3702   | 39/1852   | 26/1807   |
|                                | (1.3)^2^  | (2.1)     | (1.4)     |
| BUN ≥14.3 mmol/L               |           |           |           |
|                                | 14/3702   | 68/1851   | 13/1806   |
| AST and/or ALT ≥3xULN          | (0.4)     | (3.7)     | (0.7)     |
|                                |           |           |           |
| Alkaline phosphatase ≥3xULN    | 4/3696    | 3/1851    | 0/1800    |
|                                | (0.1)     | (0.2)     | (0.0)     |
| and/or bilirubin ≥1.8xULN      |           |           |           |
|                                | 13/3696   | 62/1851   | 11/1800   |
| ALT and/or alkaline            | (0.4)     | (3.3)     | (0.6)     |
| Phosphatase ≥3xULN             |           |           |           |
|                                | 15/3701   | 63/1851   | 11/1806   |
| ALT ≥3xULN and/or bilirubin ≥  | (0.4)     | (3.4)     | (0.6)     |
| 1.8xULN                        |           |           |           |
+--------------------------------+-----------+-----------+-----------+

1.  From Table 10.m (p 193); N49-00-06-035-102. Data are expressed as
    No./ total and percentage of patients.

2.  p≤0.05 versus diclofenac by Fischer's Exact Test. Figure 10.d, p.
    202: ); N49-00-06-035-102.

Vital Signs and Physical Examination Results:

Group mean changes from baseline in blood pressure, pulse, and weight
disclosed no

obvious treatment effects, patterns or differences of clinical relevance
among the groups. The only statistically significant difference was the
change from baseline in weight in the subgroup of male patients with
baseline weight above 90 kg: weight in the celecoxib group increased by
0.53 kg, while that for diclofenac decreased by 1.11 kg (p\<0.001). The
clinical significance of this finding is unknown.

**[Special studies-review of systems (Section 10.2.3):]{.underline}**

# Gastrointestinal Effects {#gastrointestinal-effects .unnumbered}

The GI tolerability profiles of the three treatment groups in the study
are summarized for these events by time interval (Table 48) or aspirin
status (Table 49).

**Table 48** demonstrates that the results at six months were quite
similar to those for the entire study period. For the common GI adverse
events, six-month incidences were all within 2% of the overall
incidences; this was also true for withdrawals due to GI adverse events.
In these GI adverse event measures, celecoxib appeared to be better
tolerated than diclofenac and was generally similar to ibuprofen in
tolerability. Most of these common GI adverse events were statistically
significantly more frequent for diclofenac than for celecoxib.
Statistically significant differences were seen between celecoxib and
ibuprofen in only two types of events, one in favor of celecoxib
(constipation) and one in favor of ibuprofen (diarrhea).

**^Table\ 48:\ Summary\ of\ GI\ Adverse\ Events\ by\ Time\ Interval1^**

+------------------------------+------------+------------+------------+
| # Adverse Event              | *          | **         | **I        |
| {#adverse-event .unnumbered} | *Celecoxib | Diclofenac | buprofen** |
|                              | (n=3987)** | (n=1996)** |            |
|                              |            |            | **         |
|                              |            |            | (n=1985)** |
+------------------------------+------------+------------+------------+
| **Entire Treatment Period**  |            |            |            |
+------------------------------+------------+------------+------------+
| **Any GI event**             | **45.6**   | **55.0     | **46.2**   |
|                              |            | \***       |            |
+------------------------------+------------+------------+------------+
| Dyspepsia                    | 16.5       | 19.5 \*    | 16.5       |
|                              |            |            |            |
| Abdominal pain               | 11.7       | 18.5 \*    | 11.3       |
|                              |            |            |            |
| Diarrhea                     | 10.9       | 15.0 \*    | 7.5 \*     |
|                              |            |            |            |
| Nausea                       | 8.2        | 12.1 \*    | 9.0        |
|                              |            |            |            |
| Flatulence                   | 7.3        | 11.4 \*    | 7.2        |
|                              |            |            |            |
| Tooth disorder               | 2.9        | 4.3 \*     | 4.4 \*     |
|                              |            |            |            |
| Vomiting                     | 2.6        | 3.5        | 2.7        |
|                              |            |            |            |
| Constipation                 | 2.2        | 6.8 \*     | 6.5 \*     |
+------------------------------+------------+------------+------------+
| **Any GI event causing       | **12.2**   | **16.6     | **13.4**   |
| withdrawal**                 |            | \***       |            |
+------------------------------+------------+------------+------------+
| # First Six Months {#f       |            |            |            |
| irst-six-months .unnumbered} |            |            |            |
+------------------------------+------------+------------+------------+
| **Any GI event**             | **40.3**   | **49.9     | **40.5**   |
|                              |            | \***       |            |
+------------------------------+------------+------------+------------+
| Dyspepsia                    | 14.4       | 17.7 \*    | 14.4       |
|                              |            |            |            |
| Abdominal pain               | 9.7        | 16.7 \*    | 9.5        |
|                              |            |            |            |
| Diarrhea                     | 9.4        | 13.6 \*    | 6.0 \*     |
|                              |            |            |            |
| Nausea                       | 6.9        | 11.0 \*    | 7.6        |
|                              |            |            |            |
| Flatulence                   | 6.6        | 10.1 \*    | 6.5        |
|                              |            |            |            |
| Tooth disorder               | 2.4        | 3.6 \*     | 3.2        |
|                              |            |            |            |
| Vomiting                     | 2.1        | 3.1\*      | 2.3        |
|                              |            |            |            |
| Constipation                 | 1.7        | 5.9 \*     | 5.9 \*     |
+------------------------------+------------+------------+------------+
| **Any GI event causing       | **10.8**   | **15.5     | **12.0**   |
| withdrawal**                 |            | \***       |            |
+------------------------------+------------+------------+------------+

1\. From Table 10.n (p 196); N49-00-06-035-102. All numbers are
percentages of patients. Includes any GI adverse event with incidence
\>3% in any treatment group. (\*) =p\<0.05 vs. celecoxib.

The incidence (data not shown) of diverticular disease (diverticulitis
and diverticulosis) was lower for celecoxib than for ibuprofen. For
these two events combined, the difference between the groups was 0.4% vs
1.0%. The difference was statistically significant for diverticulosis
(0.2% vs. 0.6%; p=0.028).

The incidence of GI adverse events in patients not taking aspirin were
similar to those in the overall population, though generally reduced by
approximately 1% across treatment groups (**Table 49**). For the most
part, the statistical relationships described above were maintained.
Some variations (i.e. incidence of dyspepsia), however, could be seen in
the analysis of patients taking aspirin. Several of the statistically
significant differences between celecoxib and diclofenac did not retain
significance in this analysis, most notably in overall incidence of a GI
adverse event: 54.0% vs 59.1% (p=0.079). **In general, the use of
aspirin appears to have increased incidences of GI adverse events across
groups, and attenuated some of the differences between the treatment
groups.**

As noted in Tables 48 and 49, there appears to be a difference in
withdrawal rates from the treatment groups as a result of GI signs or
symptoms. **Whether during the first six months or the entire study
period, or whether patients were taking aspirin or not, significantly
more patients withdrew from the diclofenac group than from the celecoxib
group owing to GI adverse events.** The issue of differential dropouts
for GI symptoms has been discussed under "Informative Censoring" above.
Withdrawal due to a GI adverse event over the entire study period was
16.6% for diclofenac and 12.2% for celecoxib (p\<0.001), and almost all
of these withdrawals took place in the first six months. For ibuprofen,
GI withdrawals were numerically more frequent than for celecoxib, but
the differences were not statistically significant.

Kaplan-Meier plots of cases (data not shown, Tables T55.1 through T55.4,
p. 564-7; N49-00-06-035_102) of time to moderate/severe abdominal pain,
dyspepsia, or nausea revealed that diclofenac was distinguished from
celecoxib (for abdominal pain, nausea or all three) early during the
study; this trend was maintained through the end of the study. In these
three analyses, the differences between celecoxib and diclofenac were
statistically significant (p≤0.013). However, no difference was found
between celecoxib and diclofenac with regards to dyspepsia alone.

**^Table\ 49:\ Summary\ of\ GI\ Adverse\ Events\ by\ Aspirin\ Use-Entire\ Study1^**

+------------------------------+------------+------------+------------+
| # Adverse Event {#           | *          | **         | **I        |
| adverse-event-1 .unnumbered} | *Celecoxib | Diclofenac | buprofen** |
|                              | (n=3987)** | (n=1996)** |            |
|                              |            |            | **         |
|                              |            |            | (n=1985)** |
+------------------------------+------------+------------+------------+
| **Patients not Taking        |            |            |            |
| Aspirin**                    |            |            |            |
+------------------------------+------------+------------+------------+
| No. of patients              | 3105       | 1551       | 1573       |
+------------------------------+------------+------------+------------+
| **Any GI event**             | **43.3**   | **53.8     | **44.5**   |
|                              |            | \***       |            |
+------------------------------+------------+------------+------------+
| Dyspepsia                    | 15.6       | 19.5 \*    | 15.6       |
|                              |            |            |            |
| Abdominal pain               | 10.9       | 17.3 \*    | 10.7       |
|                              |            |            |            |
| Diarrhea                     | 10.5       | 13.9 \*    | 7.2 \*     |
|                              |            |            |            |
| Nausea                       | 8.0        | 11.6 \*    | 8.5        |
|                              |            |            |            |
| Flatulence                   | 7.1        | 10.8 \*    | 7.5        |
|                              |            |            |            |
| Tooth disorder               | 2.3        | 4.1 \*     | 3.9 \*     |
|                              |            |            |            |
| Vomiting                     | 2.4        | 3.4        | 3.0        |
|                              |            |            |            |
| Constipation                 | 1.9        | 6.5 \*     | 5.9 \*     |
+------------------------------+------------+------------+------------+
| **Any GI event causing       | **11.5**   | **15.4     | **13.2**   |
| withdrawal**                 |            | \***       |            |
+------------------------------+------------+------------+------------+
| # Patien                     |            |            |            |
| ts Taking Aspirin {#patients |            |            |            |
| -taking-aspirin .unnumbered} |            |            |            |
+------------------------------+------------+------------+------------+
| No. of patients              | 882        | 445        | 412        |
+------------------------------+------------+------------+------------+
| **Any GI event**             | **54.0**   | **59.1**   | **52.7**   |
+------------------------------+------------+------------+------------+
| Dyspepsia                    | 19.7       | 19.8       | 19.9       |
|                              |            |            |            |
| Abdominal pain               | 14.5       | 22.7 \*    | 13.6       |
|                              |            |            |            |
| Diarrhea                     | 12.1       | 18.6 \*    | 8.3 \*     |
|                              |            |            |            |
| Nausea                       | 9.0        | 13.9 \*    | 10.7       |
|                              |            |            |            |
| Flatulence                   | 7.9        | 13.5 \*    | 6.1        |
|                              |            |            |            |
| Tooth disorder               | 5.0        | 4.7        | 6.1        |
|                              |            |            |            |
| Vomiting                     | 3.1        | 3.8        | 1.5        |
|                              |            |            |            |
| Constipation                 | 3.3        | 7.9 \*     | 9.0 \*     |
|                              |            |            |            |
| Gastroenteritis              | 2.8        | 3.1        | 1.7        |
|                              |            |            |            |
| Gastroesophageal reflux      | 3.5        | 2.2        | 2.2        |
|                              |            |            |            |
| Hemoccult positivity         | 2.7        | 3.1        | 3.9        |
+------------------------------+------------+------------+------------+
| **Any GI event causing       | **14.9**   | **20.7     | **14.1**   |
| withdrawal**                 |            | \***       |            |
+------------------------------+------------+------------+------------+

1\. From Table 10.o (p 197); N49-00-06-035-102. All numbers are
percentages of patients. Includes any GI adverse event with incidence
≥3% in any treatment group. (\*) =p\<0.05 vs. celecoxib.

# Renal Effects {#renal-effects .unnumbered}

Table 50 shows the incidences of selected renal adverse events occurring
throughout the entire study period. In general, the incidences were low
in all treatment groups, not suggesting any pronounced renal effects of
any of these treatments. However, patients receiving ibuprofen
experienced more edema and hypertension than celecoxib or diclofenac
patients; these differences were statistically significant. Adverse
events relating to increases in renal function laboratory values (BUN
increased and NPN increased) were more frequent for diclofenac than for
celecoxib. The differences were statistically significant when examined
in the six-month analysis, but not over the entire treatment period.

**^Table\ 50:\ Selected\ Adverse\ Events\ Relating\ to\ Renal\ Function:\ Entire\ Study\ Period1^**

+--------------------------------+-----------+-----------+------------+
| **Adverse Event**              | **        | **D       | **I        |
|                                | Celecoxib | iclofenac | buprofen** |
|                                | (         | (         |            |
|                                | n=3987)** | n=1996)** | **         |
|                                |           |           | (n=1985)** |
+--------------------------------+-----------+-----------+------------+
| Hypertension                   | 2.0       | 2.0       | 3.1 \*     |
|                                |           |           |            |
| Hypertension aggravated        | 0.8       | 0.6       | 1.2        |
|                                |           |           |            |
| Edema generalized              | 0.5       | 0.6       | 1.0 \*     |
|                                |           |           |            |
| Edema peripheral               | 3.7       | 3.5       | 5.2 \*     |
|                                |           |           |            |
| Cardiac failure                | 0.3       | 0.2       | 0.5        |
|                                |           |           |            |
| BUN increased                  | 1.1       | 1.7       | 0.9        |
|                                |           |           |            |
| NPN increased                  | 1.3       | 1.9       | 1.2        |
|                                |           |           |            |
| Renal failure acute            | 0.0       | \<0.1     | 0.0        |
|                                |           |           |            |
| Renal function abnormal        | \<0.1     | \<0.1     | 0.1        |
+--------------------------------+-----------+-----------+------------+

1\. From Table 10.q (p 201); N49-00-06-035-102. All numbers are
percentages of patients. (\*) =p\<0.05 vs. celecoxib.

Reviewer's comment: For a more detailed analysis of the cardiovascular
and renal effects of celecoxib and the comparator groups in this trial,
the reader is referred to the review by Douglas Throckmorton, M.D.

**Table 51** shows group mean changes and extreme changes in BUN and
creatinine. Although the meaning is unclear, the results suggest an
effect of diclofenac on mean creatinine values, and of celecoxib on BUN
as compared to ibuprofen. Few patients experienced an extreme BUN value;
the incidence appeared higher for ibuprofen than for the other two
groups, but the difference was not statistically significant. When the
extreme creatinine threshold of 265 µmol/L was used, only one patient in
the entire study period experienced an extreme value. However, as noted
above for the renal contingency tables, when the lower threshold of 159
µmol/L for creatinine with or without BUN changes was utilized, percent
increases of 1.3 for celecoxib, 2.1 for diclofenac, and 1.4 for
ibuprofen were noted. The difference between celecoxib and diclofenac
was statistically significant.

Not shown in Table 51 was that between celecoxib and ibuprofen in
elevated potassium levels: 0.3% of celecoxib patients and 0.0% of
ibuprofen patients had a maximum potassium value above 6.0 mmol/L
(p=0.021; Table 45.1,p. 535). Five of these 11 cases of extreme
potassium levels in celecoxib patients were isolated increases that were
bracketed by values within the normal range, and may be artifactual
(i.e., due to hemolysis). One additional case was an isolated value
drawn four days after discontinuation of study medication and is of
uncertain clinical significance.

**^Table\ 51:\ Mean\ Changes\ from\ Baseline\ to\ Final\ Visit/Extreme\ Values\ in\ Specific\ Renal\ Laboratory\ Values1^**

+-------------------------------+-------------+------------+-----------+
| **Laboratory Test**           | **          | **Di       | **Ib      |
|                               | Celecoxib** | clofenac** | uprofen** |
+-------------------------------+-------------+------------+-----------+
| **Group Mean Changes from     |             |            |           |
| Baseline (Mean \[SE\])**      |             |            |           |
+-------------------------------+-------------+------------+-----------+
| BUN, mmol/L                   | 0.66        | 0.58       | 0.52      |
|                               | (0.027)     | (0.041)    | (         |
| Creatinine, µmol/L            |             |            | 0.039)^1^ |
|                               | 0.8 (0.22)  | 2.4        |           |
|                               |             | (0.33)^1^  | 1.5       |
|                               |             |            | (0.33)    |
+-------------------------------+-------------+------------+-----------+
| **Incidence of Extreme Values |             |            |           |
| (No./total \[%\])**           |             |            |           |
+-------------------------------+-------------+------------+-----------+
| BUN (\>14.3 mmol/L)           | 17/3692     | 8/1849     | 12/1786   |
|                               | (0.5)       | (0.4)      | (0.7)     |
| Final visit                   |             |            |           |
|                               | 31/3692     | 20/1849    | 16/1786   |
| Maximum value                 | (0.8)       | (1.1)      | (0.9)     |
+-------------------------------+-------------+------------+-----------+
| Creatinine (\>265.2 µmol/L)   | 0/3692      | 0/1850     | 0/1786    |
|                               | (0.0)       | (0.0)      | (0.0)     |
| Final visit                   |             |            |           |
|                               | 1/3692      | 0/1850     | 0/1786    |
| Maximum value                 | (\<0.1)     | (0.0)      | (0.0)     |
+-------------------------------+-------------+------------+-----------+

1\. From Table 10.r (p 202); N49-00-06-035-102. p\<0.05 vs. celecoxib.

# Vascular (Cardiac and Noncardiac) Effects {#vascular-cardiac-and-noncardiac-effects .unnumbered}

The incidences of cardiac and noncardiac vascular adverse events
throughout the entire study period are shown in Table 52. The table
shows that vascular events were rare in all treatment groups, and
incidences were similar between celecoxib and the two NSAIDs. The only
statistically significant difference in incidences was for
cerebrovascular disorder between celecoxib (0.2%) and ibuprofen (0.5%).

**^[Table\ 52:\ Incidences\ of\ Selected\ Cardiac/Noncardiac\ Vascular\ Adverse\ Events:\ Entire\ Study\ Period1]{.underline}^**

+--------------------------+---------------+-------------+-----------+
| **Adverse Event**        | **Celecoxib** | *           | **Ib      |
|                          |               | *Diclofenac | uprofen** |
|                          | **(n=3987)**  | (n=1996)**  |           |
|                          |               |             | **(       |
|                          |               |             | n=1985)** |
+--------------------------+---------------+-------------+-----------+
| Angina pectoris          | 0.6           | 0.5         | 0.6       |
|                          |               |             |           |
| Arteriosclerosis         | \<0.1         | 0.0         | \<0.1     |
|                          |               |             |           |
| Atherosclerosis          | \<0.1         | \<0.1       | 0.1       |
|                          |               |             |           |
| Carotid bruit            | \<0.1         | 0.1         | \<0.1     |
|                          |               |             |           |
| Carotid stenosis         | \<0.1         | 0.0         | 0.0       |
|                          |               |             |           |
| Cerebrovascular disorder | 0.2           | 0.5         | 0.5^1^    |
|                          |               |             |           |
| Coronary artery disorder | 0.6           | 0.4         | 0.3       |
|                          |               |             |           |
| Embolism                 | \<0.1         | 0.0         | 0.0       |
|                          |               |             |           |
| Embolism pulmonary       | 0.1           | \<0.1       | 0.1       |
|                          |               |             |           |
| Myocardial infarction    | 0.5           | 0.3         | 0.5       |
|                          |               |             |           |
| Myocardial ischemia      | \<0.1         | 0.1         | 0.0       |
|                          |               |             |           |
| Peripheral gangrene      | \<0.1         | 0.0         | 0.0       |
|                          |               |             |           |
| Peripheral ischemia      | 0.1           | 0.0         | 0.1       |
|                          |               |             |           |
| Peripheral vascular      | \<0.1         | 0.0         | \<0.1     |
| disease                  |               |             |           |
|                          | \<0.1         | 0.0         | \<0.1     |
| Phlebitis                |               |             |           |
|                          | \<0.1         | 0.0         | \<0.1     |
| Thrombophlebitis         |               |             |           |
|                          | \<0.1         | 0.0         | \<0.1     |
| Thrombophlebitis arm     |               |             |           |
|                          | 0.3           | 0.3         | \<0.1     |
| Thrombophlebitis deep    |               |             |           |
|                          | 0.0           | \<0.1       | \<0.1     |
| Thrombophlebitis leg     |               |             |           |
|                          | \<0.1         | \<0.1       | 0.0       |
| Thrombophlebitis leg     |               |             |           |
| deep                     | \<0.1         | \<0.1       | 0.0       |
|                          |               |             |           |
| Thrombophlebitis leg     | 0.3           | 0.2         | 0.1       |
| superficial              |               |             |           |
|                          |               |             |           |
| Unstable angina          |               |             |           |
+--------------------------+---------------+-------------+-----------+

1\. From Table 10.s (p 204); N49-00-06-035-102. Numbers are percentages.
p\<0.05 vs. celecoxib.

***Reviewer's comment: There does not appear to be any clinically or
statistically significant trend with celecoxib to suggest additional
cardiovascular risks over the comparator drugs.***

Incidences of the same group of adverse events are shown and
statistically analyzed by aspirin status in **Table 53**. Patients in
the two NSAID groups were pooled for this analysis. As might be
expected, incidences of the cardiovascular-related events were higher in
the patients taking aspirin, since these patients were more likely to
have a significant cardiovascular medical history than the overall study
population. The absence of statistical significance for any of the
events suggest that the differences between celecoxib and NSAID were not
markedly altered by the use of aspirin.

**^[Table\ 53:\ Incidences\ of\ Selected\ Cardiac/Noncardiac\ Vascular\ Adverse\ Events\ with/without\ Aspirin\ Use:\ Entire\ Study1]{.underline}^**

+-----------------------+--------+--------+-----+-------+-------+---+
|                       | **With |        |     | **Wi  |       |   |
|                       | Asp    |        |     | thout |       |   |
|                       | irin** |        |     | Aspi  |       |   |
|                       |        |        |     | rin** |       |   |
+-----------------------+--------+--------+-----+-------+-------+---+
|                       | *      | **NS   | **  | **C   | **NSA | * |
|                       | *Celec | AIDs** | RD\ | eleco | IDs** | * |
|                       | oxib** |        | *** | xib** |       | R |
|                       |        | **(n=  |     |       | **    | D |
|                       | **(n=  | 857)** |     | **    | (n=31 | \ |
|                       | 882)** |        |     | (n=31 | 24)** | * |
|                       |        |        |     | 05)** |       | * |
|                       |        |        |     |       |       | * |
+-----------------------+--------+--------+-----+-------+-------+---+
| ######### Any         | 6.1    | 5.7    | 0.4 | 1.5   | 1.2   | 0 |
| thromboembolic event  |        |        |     |       |       | . |
|                       |        |        |     |       |       | 3 |
+-----------------------+--------+--------+-----+-------+-------+---+
| Angina pectoris       | 1.5    | 1.6    | -   | 0.3   | 0.3   | 0 |
|                       |        |        | 0.2 |       |       | . |
| Arteriosclerosis      | 0.2    | 0.1    |     | 0.0   | 0.0   | 0 |
|                       |        |        | \-  |       |       |   |
| Atherosclerosis       | 0.1    | 0.2    |     | \<0.1 | \<0.1 | \ |
|                       |        |        | -   |       |       | - |
| Carotid bruit         | 0.0    | 0.1    | 0.1 | \<0.1 | \<0.1 |   |
|                       |        |        |     |       |       | 0 |
| Carotid stenosis      | 0.1    | 0.0    | -   | 0.0   | 0.0   | . |
|                       |        |        | 0.1 |       |       | 0 |
| Cerebrovascular       | 0.6    | 1.2    |     | \<0.1 | 0.3   |   |
| disorder              |        |        | \-  |       |       | 0 |
|                       | 1.7    | 0.9    |     | 0.3   | 0.2   | . |
| Coronary artery       |        |        | -   |       |       | 0 |
| disorder              | 0.0    | 0.0    | 0.6 | \<0.1 | 0.0   |   |
|                       |        |        |     |       |       | \ |
| Embolism              | 0.1    | 0.0    | 0.8 | \<0.1 | \<0.1 | - |
|                       |        |        |     |       |       |   |
| Embolism pulmonary    | 1.5    | 1.2    | \-  | 0.2   | 0.1   | - |
|                       |        |        |     |       |       | 0 |
| Myocardial infarction | 0.1    | 0.2    | 0.1 | \<0.1 | 0.0   | . |
|                       |        |        |     |       |       | 2 |
| Myocardial ischemia   | 0.0    | 0.0    | 0.3 | \<0.1 | 0.0   |   |
|                       |        |        |     |       |       | 0 |
| Peripheral gangrene   | 0.3    | 0.1    | -   | \<0.1 | \<0.1 | . |
|                       |        |        | 0.1 |       |       | 2 |
| Peripheral ischemia   | 0.1    | 0.0    |     | \<0.1 | \<0.1 |   |
|                       |        |        | \-  |       |       | \ |
| Peripheral vascular   | 0.0    | 0.0    |     | \<0.1 | \<0.1 | - |
| disease               |        |        | 0.2 |       |       |   |
|                       | 0.0    | 0.0    |     | \<0.1 | \<0.1 | 0 |
| Phlebitis             |        |        | 0.1 |       |       | . |
|                       | 0.0    | 0.0    |     | \<0.1 | \<0.1 | 0 |
| Thrombophlebitis      |        |        | \-  |       |       |   |
|                       | 0.3    | 0.4    |     | 0.3   | \<0.1 | 0 |
| Thrombophlebitis arm  |        |        | \-  |       |       | . |
|                       | 0.0    | 0.0    |     | 0.0   | \<0.1 | 1 |
| Thrombophlebitis deep |        |        | \-  |       |       |   |
|                       | 0.0    | 0.0    |     | \<0.1 | \<0.1 | 0 |
| Thrombophlebitis leg  |        |        | 0.0 |       |       | . |
|                       | 0.0    | 0.1    |     | \<0.1 | 0.0   | 0 |
| Thrombophlebitis leg  |        |        | \-  |       |       |   |
| deep                  | 0.9    | 0.6    |     | \<0.1 | \<0.1 | \ |
|                       |        |        | \-  |       |       | - |
| Thrombophlebitis leg  |        |        |     |       |       |   |
| superficial           |        |        | -   |       |       | 0 |
|                       |        |        | 0.1 |       |       | . |
| Unstable angina       |        |        |     |       |       | 0 |
|                       |        |        | 0.3 |       |       |   |
|                       |        |        |     |       |       | 0 |
|                       |        |        |     |       |       | . |
|                       |        |        |     |       |       | 0 |
|                       |        |        |     |       |       |   |
|                       |        |        |     |       |       | \ |
|                       |        |        |     |       |       | - |
|                       |        |        |     |       |       |   |
|                       |        |        |     |       |       | \ |
|                       |        |        |     |       |       | - |
|                       |        |        |     |       |       |   |
|                       |        |        |     |       |       | \ |
|                       |        |        |     |       |       | - |
|                       |        |        |     |       |       |   |
|                       |        |        |     |       |       | 0 |
|                       |        |        |     |       |       | . |
|                       |        |        |     |       |       | 2 |
|                       |        |        |     |       |       |   |
|                       |        |        |     |       |       | \ |
|                       |        |        |     |       |       | - |
|                       |        |        |     |       |       |   |
|                       |        |        |     |       |       | \ |
|                       |        |        |     |       |       | - |
|                       |        |        |     |       |       |   |
|                       |        |        |     |       |       | 0 |
|                       |        |        |     |       |       | . |
|                       |        |        |     |       |       | 0 |
|                       |        |        |     |       |       |   |
|                       |        |        |     |       |       | 0 |
|                       |        |        |     |       |       | . |
|                       |        |        |     |       |       | 0 |
+-----------------------+--------+--------+-----+-------+-------+---+

1\. From Table 10.t (p 205); N49-00-06-035-102. Numbers are percentages.
RD indicates risk reduction. None of the differences were statistically
significant at p\<0.05.

**Table 54** (from Cardiorenal review, Doug Throckmorton, M.D.) shows
selected cardiac adverse events reported during the trial according to
aspirin use. For anginal disorders (especially the combined disorders),
there seems to be a trend toward more events in those patients receiving
celecoxib, regardless of aspirin use. However, for edema, there appears
to be a trend toward more events in those patients receiving ibuprofen.

**Table 54: Selected Cardiac Adverse Events Reported During CLASS
According to ASA Use^a^**.

+-----------------------------------------+---------+--------+---------+
| **Adverse Event**                       | **Cele  | **     | **Ibup  |
|                                         | coxib** | Diclof | rofen** |
|                                         |         | enac** |         |
|                                         | **400   |        | **800   |
|                                         | mg      | **75   | mg      |
|                                         | BID**   | mg     | TID**   |
|                                         |         | BID**  |         |
+-----------------------------------------+---------+--------+---------+
| **[ASA-Users]{.underline}**             | N=882   | N=445  | N=412   |
+-----------------------------------------+---------+--------+---------+
| Edema                                   |         |        |         |
+-----------------------------------------+---------+--------+---------+
| > Edema peripheral                      | 35      | 17     | **23    |
|                                         | (4.0%)  | (3.8%) | (       |
|                                         |         |        | 5.6%)** |
+-----------------------------------------+---------+--------+---------+
| > Edema (pooled reporting)^b^           | 38      | 20     | **28    |
|                                         | (4.3%)  | (4.5%) | (       |
|                                         |         |        | 6.8%)** |
+-----------------------------------------+---------+--------+---------+
| Angina                                  |         |        |         |
+-----------------------------------------+---------+--------+---------+
| > Unstable Angina                       | 8       | 4      | 1       |
|                                         | (0.9%)  | (0.9%) | (0.2%)  |
+-----------------------------------------+---------+--------+---------+
| > Angina Pectoris                       | 13      | 8      | 6       |
|                                         | (1.5%)  | (1.8%) | (1.5%)  |
+-----------------------------------------+---------+--------+---------+
| > Coronary Artery Disorder              | 15      | 3      | 5       |
|                                         | (1.7%)  | (0.7%) | (1.2%)  |
+-----------------------------------------+---------+--------+---------+
| > **Combined Anginal Disorders^c^**     | **36    | **15   | **12    |
|                                         | (       | (3     | (       |
|                                         | 4.1%)** | .4%)** | 2.9%)** |
+-----------------------------------------+---------+--------+---------+
| Myocardial Ischemia                     | 1       | 2      | 0 (0%)  |
|                                         | (0.1%)  | (0.4%) |         |
+-----------------------------------------+---------+--------+---------+
| Myocardial Infarction                   | 13      | 3      | 7       |
|                                         | (1.5%)  | (0.7%) | (1.7%)  |
+-----------------------------------------+---------+--------+---------+
| Hypertension                            | 24      | 14     | 19      |
|                                         | (2.7%)  | (3.1%) | (4.6%)  |
+-----------------------------------------+---------+--------+---------+
| Hypertension Aggravated                 | 12      | 2      | 7       |
|                                         | (1.4%)  | (0.4%) | (1.7%)  |
+-----------------------------------------+---------+--------+---------+
| Thrombophlebitis                        |         |        |         |
+-----------------------------------------+---------+--------+---------+
| > Thrombophlebitis, Deep                | 3       | 2      | 1       |
|                                         | (0.2%)  | (0.4%) | (0.2%)  |
+-----------------------------------------+---------+--------+---------+
| > Thrombophebitis, Combined^d^          | 3       | 3      | 1       |
|                                         | (0.2%)  | (0.4%) | (0.2%)  |
+-----------------------------------------+---------+--------+---------+
| Vasculitis                              | 1       | 0 (0%) | 0 (0%)  |
|                                         | (0.1%)  |        |         |
+-----------------------------------------+---------+--------+---------+
| **[Non-ASA Users]{.underline}**         | N=3105  | N=1551 | N=1573  |
+-----------------------------------------+---------+--------+---------+
| > Edema peripheral                      | 111     | 53     | **81    |
|                                         | (3.6%)  | (3.4%) | (       |
|                                         |         |        | 5.1%)** |
+-----------------------------------------+---------+--------+---------+
| > Edema (pooled reporting)^b^           | 127     | 61     | **96    |
|                                         | (4.1%)  | (3.9%) | (       |
|                                         |         |        | 6.1%)** |
+-----------------------------------------+---------+--------+---------+
| Angina                                  |         |        |         |
+-----------------------------------------+---------+--------+---------+
| > Unstable Angina                       | 2       | 0 (0%) | 1       |
|                                         | (       |        | (       |
|                                         | \<0.1%) |        | \<0.1%) |
+-----------------------------------------+---------+--------+---------+
| > Angina Pectoris                       | 9       | 2      | 6       |
|                                         | (0.3%)  | (0.1%) | (0.4%)  |
+-----------------------------------------+---------+--------+---------+
| > Coronary Artery Disorder              | 10      | 4      | 1       |
|                                         | (0.3%)  | (0.3%) | (       |
|                                         |         |        | \<0.1%) |
+-----------------------------------------+---------+--------+---------+
| > **Combined Anginal Disorders^c^**     | **21    | **6    | **8     |
|                                         | (0      | (0.    | (0      |
|                                         | .67%)** | 38%)** | .51%)** |
+-----------------------------------------+---------+--------+---------+
| Myocardial Ischemia                     | 1       | 0 (0%) | 0 (0%)  |
|                                         | (       |        |         |
|                                         | \<0.1%) |        |         |
+-----------------------------------------+---------+--------+---------+
| Myocardial Infarction                   | 6       | 2      | 2       |
|                                         | (0.2%)  | (0.1%) | (0.1%)  |
+-----------------------------------------+---------+--------+---------+
| Hypertension                            | 54      | 26     | 42      |
|                                         | (1.7%)  | (1.7%) | (2.7%)  |
+-----------------------------------------+---------+--------+---------+
| Hypertension Aggravated                 | 20      | 10     | 17      |
|                                         | (0.6%)  | (0.6%) | (1.1%)  |
+-----------------------------------------+---------+--------+---------+
| Thrombophlebitis                        |         |        |         |
+-----------------------------------------+---------+--------+---------+
| > Thrombophlebitis, Deep                | 9       | 3      | 0 (0%)  |
|                                         | (0.3%)  | (0.2%) |         |
+-----------------------------------------+---------+--------+---------+
| > Thrombophlebitis, Combined^d^         | 14      | 5      | 4       |
|                                         | (0.45%) | (0.3%) | (0.25%) |
+-----------------------------------------+---------+--------+---------+
| Vasculitis                              | 1       | 0 (0%) | 1       |
|                                         | (       |        | (       |
|                                         | \<0.1%) |        | \<0.1%) |
+-----------------------------------------+---------+--------+---------+

a\. Data from electronic submission, NDA 20-998 supplement S-009, Table
T41.1.

b\. Includes edema, edema generalized, and edema peripheral.

c\. Includes unstable angina, angina pectoris and coronary artery
disorder.

d\. Includes AEs reported under the following terms: phlebitis,
thrombophlebitis, thrombophlebitis arm, thrombophlebitis deep,
thrombophlebitis leg, thrombophlebitis leg deep, thrombophlebitis leg
superficial.

**Table 55** (from Cardiorenal review, Doug Throckmorton, M.D.) shows
serious cardiac adverse events reported during the trial according to
aspirin use. In the non-aspirin users, there appears to be a slight
trend toward more events in those patients receiving celecoxib for
combined atrial and anginal disorders; this does not appear to be the
case for aspirin users.

**Table 55: Serious Adverse Events (SAEs) per 100 Pt-Yrs Reported During
CLASS by ASA Use^a^**.

+---------------------------------------+---------+---------+---------+
| **Adverse Event**                     | **Cele  | **Diclo | **Ibup  |
|                                       | coxib** | fenac** | rofen** |
|                                       |         |         |         |
|                                       | **400   | **75 mg | **800   |
|                                       | mg      | BID**   | mg      |
|                                       | BID**   |         | TID**   |
+---------------------------------------+---------+---------+---------+
| ######### ASA Users                   | N=882   | N=445   | N=412   |
|                                       |         |         |         |
|                                       | 517     | N=239   | 249     |
|                                       | Pt-Yrs  | Pt-Yrs  | Pt-Yrs  |
+---------------------------------------+---------+---------+---------+
| Cardiac SAEs                          |         |         |         |
+---------------------------------------+---------+---------+---------+
| > Atrial Arrhythmias                  |         |         |         |
+---------------------------------------+---------+---------+---------+
| > Arrhythmia Atrial                   | 2       | 0 (0%)  | 1       |
|                                       | (0.4%)  |         | (0.4%)  |
+---------------------------------------+---------+---------+---------+
| > Bradycardia                         | 0 (0%)  | 0 (0%)  | 0 (0%)  |
+---------------------------------------+---------+---------+---------+
| > Fibrillation Atrial                 | 4       | 1       | 3       |
|                                       | (0.8%)  | (0.4%)  | (1.2%)  |
+---------------------------------------+---------+---------+---------+
| > Tachycardia Supraventricular        | 1       | 0 (0%)  | 0 (0%)  |
|                                       | (0.2%)  |         |         |
+---------------------------------------+---------+---------+---------+
| > Combined Atrial SAEs^b^             | 7       | 1       | 4       |
|                                       | (1.4%)  | (0.4%)  | (1.6%)  |
+---------------------------------------+---------+---------+---------+
| > Angina                              |         |         |         |
+---------------------------------------+---------+---------+---------+
| > Unstable Angina                     | 6       | 4       | 0 (0%)  |
|                                       | (1.2%)  | (1.7%)  |         |
+---------------------------------------+---------+---------+---------+
| > Angina Pectoris                     | 3       | 5       | 4       |
|                                       | (0.6%)  | (2.1%)  | (1.6%)  |
+---------------------------------------+---------+---------+---------+
| > Coronary Artery Disorder            | 11      | 2       | 5       |
|                                       | (2.1%)  | (0.8%)  | (2.0%)  |
+---------------------------------------+---------+---------+---------+
| > Combined Anginal Disorders^c^       | 20      | 11      | 8       |
|                                       | (3.9%)  | (4.6%)  | (3.2%)  |
+---------------------------------------+---------+---------+---------+
| > Myocardial Infarction               | 13      | 2       | 7       |
|                                       | (2.5%)  | (0.8%)  | (2.8%)  |
+---------------------------------------+---------+---------+---------+
| > Thrombophlebitis Combined^d^        | 0 (0%)  | 2       | 1       |
|                                       |         | (0.8%)  | (0.4%)  |
+---------------------------------------+---------+---------+---------+
| ######### Non-ASA Users               | N=3105  | N=1551  | N=1573  |
|                                       |         |         |         |
|                                       | 1804    | 841     | 874     |
|                                       | Pt-Yrs  | Pt-Yrs  | Pt-Yrs  |
+---------------------------------------+---------+---------+---------+
| Cardiac SAEs                          |         |         |         |
+---------------------------------------+---------+---------+---------+
| > Atrial Arrhythmias                  |         |         |         |
+---------------------------------------+---------+---------+---------+
| > Arrhythmia Atrial                   | 0 (0%)  | 0 (0%)  | 0 (0%)  |
+---------------------------------------+---------+---------+---------+
| > Bradycardia                         | 2       | 0 (0%)  | 0 (0%)  |
|                                       | (0.1%)  |         |         |
+---------------------------------------+---------+---------+---------+
| > Fibrillation Atrial                 | 5       | 1       | 0 (0%)  |
|                                       | (0.3%)  | (0.1%)  |         |
+---------------------------------------+---------+---------+---------+
| > Tachycardia Supraventricular        | 2       | 0 (0%)  | 0 (0%)  |
|                                       | (0.1%)  |         |         |
+---------------------------------------+---------+---------+---------+
| > **Combined Atrial SAEs^b^**         | **6     | **1     | **0     |
|                                       | (       | (       | (0%)**  |
|                                       | 0.3%)** | 0.1%)** |         |
+---------------------------------------+---------+---------+---------+
| > Angina                              |         |         |         |
+---------------------------------------+---------+---------+---------+
| > Unstable Angina                     | 2       | 0 (0%)  | 0 (0%)  |
|                                       | (0.1%)  |         |         |
+---------------------------------------+---------+---------+---------+
| > Angina Pectoris                     | 1       | 2       | 0 (0%)  |
|                                       | (0.1%)  | (0.2%)  |         |
+---------------------------------------+---------+---------+---------+
| > Coronary Artery Disorder            | 8       | 3       | 0 (0%)  |
|                                       | (0.4%)  | (0.4%)  |         |
+---------------------------------------+---------+---------+---------+
| > **Combined Anginal Disorders^c^**   | **10    | **2     | **0     |
|                                       | (       | (       | (0%)**  |
|                                       | 0.6%)** | 0.2%)** |         |
+---------------------------------------+---------+---------+---------+
| > Myocardial Infarction               | 6       | 2       | 2       |
|                                       | (0.3%)  | (0.2%)  | (0.2%)  |
+---------------------------------------+---------+---------+---------+
| > Thrombophlebitis Combined^d^        | 8       | 4       | 0 (0%)  |
|                                       | (0.4%)  | (0.5%)  |         |
+---------------------------------------+---------+---------+---------+

a\. Data from electronic data submission, Appendix 2.9.4 and 2.9.3.

b\. Sum of atrial arrhythmia, atrial fibrillation, bradycardia and
tachycardia.

c\. Includes unstable angina, angina pectoris and coronary artery
disorder.

d\. Includes AEs reported under the following terms: phlebitis,
thrombophlebitis, thrombophlebitis arm, thrombophlebitis deep,
thrombophlebitis leg, thrombophlebitis leg deep, thrombophlebitis leg
superficial.

e\. These SAEs were not reported by investigators.

# Hepatobiliary Effects {#hepatobiliary-effects .unnumbered}

As has been noted previously in this review, the use of diclofenac was
associated with increases in liver function values. These findings are
summarized in **Table 56**. A consistent pattern of enzyme elevation was
seen in diclofenac patients. The clinical significance of these
elevations is indicated by the data on withdrawals: approximately half
of diclofenac patients for whom liver enzyme elevations were reported as
adverse events were withdrawn from the study as a result. Findings of
statistically significant (p\<0.001) increases of SGOT/SGPT for
diclofenac (3.3%/3.9%, respectively) compared to celecoxib (0.5%/0.6%
respectively) and ibuprofen (0.4%/0.5%, respectively) was also obvious
at six months (Table T41.4, p.423). These findings are consistent with
the known hepatotoxic nature of diclofenac. Neither celecoxib nor
ibuprofen had results obviously suggestive of a hepatic effect.

**^[Table\ 56:\ Adverse\ Events\ and\ Laboratory\ Values\ Related\ to\ Hepatic\ Function:\ Entire\ Study1]{.underline}^**

+-------------------------+--------------+--------------+-------------+
| #### Laboratory Test    | *            | **           | **          |
|                         | *Celecoxib** | Diclofenac** | Ibuprofen** |
+-------------------------+--------------+--------------+-------------+
| **Adverse Events (% of  |              |              |             |
| Patients)**             |              |              |             |
+-------------------------+--------------+--------------+-------------+
| SGOT increased          | 0.9          | 4.3^1^       | 1.0         |
|                         |              |              |             |
| SGPT increased          | 1.0          | 5.1^1^       | 1.2         |
|                         |              |              |             |
| Hepatic function        | 0.3          | 1.6^1^       | 0.3         |
| abnormal                |              |              |             |
+-------------------------+--------------+--------------+-------------+
| **Adverse Events        |              |              |             |
| Causing Withdrawal (%   |              |              |             |
| of Patients)**          |              |              |             |
+-------------------------+--------------+--------------+-------------+
| SGOT increased          | 0.1          | 2.1^1^       | 0.1         |
|                         |              |              |             |
| SGPT increased          | 0.1          | 2.3^1^       | 0.1         |
|                         |              |              |             |
| Hepatic function        | \<0.1        | 1.1^1^       | \<0.1       |
| abnormal                |              |              |             |
+-------------------------+--------------+--------------+-------------+
| **Changes from Baseline |              |              |             |
| in Group Mean           |              |              |             |
| Laboratory Values (Mean |              |              |             |
| \[SE\])**               |              |              |             |
+-------------------------+--------------+--------------+-------------+
| AST (SGOT), U/L         | 0.3 (0.12)   | 5.0          | 0.9 (0.16)  |
|                         |              | (0.57)^1^    |             |
| ALT (SGPT), U/L         | -0.2 (0.18)  |              | 1.3 (0.24)  |
|                         |              | 11.6         |             |
|                         |              | (1.1)^1^     |             |
+-------------------------+--------------+--------------+-------------+
| **Incidence of Extreme  |              |              |             |
| Values (No./total       |              |              |             |
| \[%\])**                |              |              |             |
+-------------------------+--------------+--------------+-------------+
| AST (SGOT) (\>200 U/L)  | 0/3692 (0.0) | 7/1848       | 0/1785      |
|                         |              | (0.4)^1^     | (0.0)       |
| Final visit             | 1/3692       |              |             |
|                         | (\<0.1)      | 12/1848      | 1/1785      |
| Maximum value           |              | (0.6)^1^     | (\<0.1)     |
|                         | 2/3692       |              |             |
| ALT (SGPT) (\>200 U/L)  | (\<0.1)      | 22/1848      | 0/1785      |
|                         |              | (1.2)^1^     | (0.0)       |
| Final visit             | 4/3692 (0.1) |              |             |
|                         |              | 29/1848      | 1/1785      |
| Maximum value           |              | (1.6)^1^     | (\<0.1)     |
+-------------------------+--------------+--------------+-------------+

1\. From Table 10.u (p 206); N49-00-06-035-102. Entries are No. (%) of
patients. p\<0.05 versus celecoxib.

***Reviewer's comment: Of note, there were no deaths noted in any
treatment group due to hepatic causes.***

**Dermatologic Effects:**

As noted earlier and seen in **Table 57**, the incidence of rash (either
within the first 28 days or for the entire study period) was
statistically significantly higher for celecoxib than for either
diclofenac or ibuprofen. The incidence of pruritus was also
statistically significantly higher for celecoxib than for ibuprofen, but
not diclofenac. Although not included here (Tables T41.4 and T42.4, p.
429 and 506, respectively) the results shown above were similar when
examined for the first six months; these incidences of rash and pruritus
were only slightly lower than in the entire study period, and the
statistical comparisons were the same. Similarly, **all withdrawals due
to pruritus, and all but five withdrawals due to rash, occurred within
the first six months of treatment.** The percentage of patients
withdrawing for either rash or pruritis was generally higher in the
celecoxib group compared to the other treatments: approximately one half
to one quarter of rash or pruritus events led to withdrawal. Cases of
rash or pruritus in any treatment group tended to be either mild or
moderate in severity versus severe; the proportions for severe rash were
somewhat higher with celecoxib.

To assess the incidence of true drug-related rashes of clinical
significance, those cases that were severe and caused early withdrawal
from the study were examined. Of the 19 severe rashes in the celecoxib
group, 13 led to withdrawal within the first 28 days of treatment. Using
this index, the incidence of clinically significant rash associated with
celecoxib would be estimated at 13 of 3987, or 0.33%. Performing a
similar analysis on cases of pruritus, five events in the celecoxib
group are shown to have been rated as severe and to have led to early
withdrawal. This yields an incidence of 0.13%. Events coded as
erythematous, maculopapular, or psoriaform rash had incidences of 0.4%
or less in any treatment group. None of these values were statistically
significantly different between celecoxib and either of the NSAID
treatment groups.

None of the rashes or any other dermatologic adverse events in the
celecoxib group were serious. Only three serious adverse events relating
to skin occurred: two were skin ulcerations, one each occurring in the
diclofenac and ibuprofen groups, and one skin disorder occurred in the
ibuprofen group.

***Reviewer's comment: There were no cases of Stevens Johnson syndrome,
toxic epidermal necrosis or erythema multiforme noted for any of the
treatment groups.***

**^Table\ 57:\ Characteristics\ of\ Rash\ and\ Pruritus\ Among\ the\ Three\ Treatment\ Groups1^**

+-----------------+-----------------+-----------------+-----------------+
|                 | **Celecoxib**   | **Diclofenac    | **Ibuprofen**   |
|                 |                 | (n=1996)**      |                 |
|                 | **(n=3987)**    |                 | **(n=1985)**    |
+-----------------+-----------------+-----------------+-----------------+
| # First 28      |                 |                 |                 |
|  Days of Treatm |                 |                 |                 |
| ent {#first-28- |                 |                 |                 |
| days-of-treatme |                 |                 |                 |
| nt .unnumbered} |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| # Rash {#ra     |                 |                 |                 |
| sh .unnumbered} |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Overall         | 149 (3.7)       | 24 (1.2)^1^     | 22 (1.1)^1^     |
| incidence       |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Severity        | 69 (1.7)        | 16 (0.8)        | 11 (0.6)        |
|                 |                 |                 |                 |
| Mild            | 64 (1.6)        | 8 (0.4)         | 9 (0.5)         |
|                 |                 |                 |                 |
| Moderate        | 15 (0.4)        | 0 (0.0)         | 2 (0.1)         |
|                 |                 |                 |                 |
| Severe          |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Causing         | 74 (1.9)        | 10 (0.5)^1^     | 9 (0.5)^1^      |
| withdrawal      |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| # Pr            |                 |                 |                 |
| uritus {#prurit |                 |                 |                 |
| us .unnumbered} |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Overall         | 68 (1.7)        | 21 (1.1)        | 15 (0.8) \*     |
| incidence       |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Severity        | 42 (1.1)        | 14 (0.7)        | 7 (0.4)         |
|                 |                 |                 |                 |
| Mild            | 21 (0.5)        | 7 (0.4)         | 7 (0.4)         |
|                 |                 |                 |                 |
| Moderate        | 5 (0.1)         | 0 (0.0)         | 1 (\<0.1)       |
|                 |                 |                 |                 |
| Severe          |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Causing         | 27 (0.7)        | 6 (0.3)         | 4 (0.2)         |
| withdrawal      |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| # Entire St     |                 |                 |                 |
| udy Period {#en |                 |                 |                 |
| tire-study-peri |                 |                 |                 |
| od .unnumbered} |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| # Rash {#rash   |                 |                 |                 |
| -1 .unnumbered} |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Overall         | 247 (6.2)       | 55 (2.8)^1^     | 75 (3.8)^1^     |
| incidence       |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Severity        | 126 (3.2)       | 35 (1.8)        | 42 (2.2)        |
|                 |                 |                 |                 |
| Mild            | 101 (2.5)       | 18 (0.9)        | 29 (1.5)        |
|                 |                 |                 |                 |
| Moderate        | 19 (0.5)        | 2 (0.1)         | 3 (0.2)         |
|                 |                 |                 |                 |
| Severe          |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Causing         | 85 (2.1)        | 13 (0.7)^1^     | 25 (1.3)^1^     |
| withdrawal      |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| # Prur          |                 |                 |                 |
| itus {#pruritus |                 |                 |                 |
| -1 .unnumbered} |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Overall         | 97 (2.4)        | 38 (1.9)        | 28 (1.4)^1^     |
| incidence       |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Severity        | 61 (1.5)        | 23 (1.2)        | 15 (0.8)        |
|                 |                 |                 |                 |
| Mild            | 28 (0.7)        | 14 (0.7)        | 11 (0.6)        |
|                 |                 |                 |                 |
| Moderate        | 7 (0.2)         | 1 (\<0.1)       | 2 (0.1)         |
|                 |                 |                 |                 |
| Severe          |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| Causing         | 29 (0.7)        | 7 (0.4)         | 6 (0.3)^1^      |
| withdrawal      |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

1\. From Table 10.v (p 207); N49-00-06-035-102. Numbers are percentages.
p\<0.05 versus celecoxib.

**[Respiratory, endocrine/metabolic, CNS/PNS, infectious disease
safety:]{.underline}**

Reviewer's comment: Since the original NDA review (including this sNDA
and post-marketing data), there have been no new issues or clinically
important concerns with regards to celecoxib and these general areas of
safety.

[Discussion/Conclusions (Section 12):]{.underline}

# Discussion {#discussion .unnumbered}

The results of this CLASS trial, which represents the combination of two
large safety trials, stands at any important juncture in the evolution
of our understanding of the relative safety and efficacy of drugs that
have been used for their analgesic and anti-inflammatory properties for
more than 100 years. From the "black box" approach of employing extracts
of willow bark, the precursor of acetylsalicylic acid, to "targeted"
therapy of the recently discovered COX-2 enzyme with compounds such as
celecoxib in this sNDA, the safety and efficacy of drugs in this
important therapeutic area has been the topic of what is now an immense
literature. One of the questions posed during the review of the original
NDA was the consequences of "long-term, high-grade" inhibition of COX-2
and what types of compensatory mechanisms may come into play in this
situation. This discussion will attempt to capture some of the "lessons
learned" in this sNDA.

#### Efficacy/Effectiveness

#### The efficacy of celecoxib was not a primary outcome for this sNDA. The original NDA (NDA 20-998, Review July 8, 1998) addressed the issue of efficacy with studies of pain/analgesia and trials in patients with OA and RA. The original approval of Celebrex included indications for OA and RA, but not pain. Since then, the indication for use in familial adenomatous polyposis (FAP) was added. Of note, the recommended dose for FAP is 400 mg BID which was the same dose employed in the CLASS trials. Interestingly, as noted in the open-label studies that followed the original NDA trials, up to 70% of patients (p. 121, NDA review July 8, 1998) increased their dose of celecoxib. This "dose creep" phenomenon for RA patients resulted in doses again similar to those employed in this sNDA. Therefore, are there any lessons learned regarding the efficacy or effectiveness of celecoxib from the CLASS trial?

#### 

Unfortunately, the incomplete assessment of efficacy in the CLASS trial
limits any detailed understanding of the efficacy of celecoxib at 400 mg
BID, noted to be 2-4 times the recommended (i.e. currently labeled) dose
for RA and OA, respectively. However, the patient global (Table 34),
patient assessment of pain (Table 35), HAQ scores (Table 36), SF-36
results (Table 37) and patient disposition (i.e. withdrawals for
treatment failure, Table 3) would seem to allow some general statements
in this area. If one looks at withdrawals from the CLASS trial for
arthritis treatment failure, either during the first 6 months or during
the entire study, there is no clear trend that celecoxib offers any
consistent advantage over the "conventional" doses of NSAIDs,
represented here as diclofenac and ibuprofen. At best, it could be
argued that celecoxib appears comparable to diclofenac and generally
better than ibuprofen in this regard. It is of interest to note that the
withdrawal rates for treatment failure in the CLASS trial were lower
than the 12-week trials in OA or RA in the original NDA. Withdrawals for
treatment failure in the original NDA ranged from 21-35% for the various
doses of celecoxib compared to 18-26% for naproxen in OA (p 176, July 8,
1998); withdrawals ranged from 21-40% for the various doses of celecoxib
compared to 29-30% for naproxen in RA (p.210, July 8, 1998). If one
looks at the combination of treatment failure and noncompliance (as
another estimate of treatment failure), the comments noted above seem to
hold. Comparisons of celecoxib to the NSAIDs regarding the patient
global assessment, assessment of arthritis pain, HAQ and SF-36 scores
suggest that celecoxib was comparable to diclofenac and ibuprofen with
no consistent and clear trends suggesting superiority. Therefore, based
upon these variables as endpoint estimates, it would appear that
celecoxib (even at multiples of doses for labeled indications) does not
offer a consistent advantage over the comparator NSAIDs in terms of
efficacy or effectiveness in OA or RA.

#### 

#### Safety

In contrast to efficacy, the CLASS trial was designed to assess safety
endpoints of celecoxib relative to the NSAIDs, diclofenac and ibuprofen.
In so doing, arguments were made that this trial was also testing the
COX-2 safety hypothesis; this hypothesis being (in general terms) that
if COX-2 is not present in any particular organ or cell, drugs targeting
COX-2 should not be a problem. Safety may be considered more from the
molecular understanding of receptor structure and function, and less so
from the prospective of a xenobiotic with its potentially unknown (and
non-mechanism based) safety hazards.

The central clinical trial feature in CLASS that tested this hypothesis
was the bona fide use of twice to four-fold the highest doses for two
FDA-approved labeled indications, RA and OA respectively. As noted by
the Sponsor, the multiples of dosing employed for celecoxib was to make
comparisons of safety in a "robust" fashion. A safety trial, with
"NSAIDs" at similar multiples of their respective labeled doses for OA
and RA has not yet been conducted despite the long history of usage of
these important and widely used drugs. Unfortunately, the fact that such
multiples of the NSAIDs selected for this trial were not included
ultimately confounds all discussions and/or conclusions of this CLASS
trial.

While some might comment that these multiples were not robust enough
(i.e. should be 10X), it appears clear that the dosing, sample size, and
selection of safety endpoints all contributed to the highly unique and
progressive character of the CLASS trial. Certainly, pushing the
envelope in terms of safety has the potential for improvements in safety
at both the patient and population levels. As noted, one of the unique
aspects of the CLASS trial was the selection of the primary UGI safety
endpoint. The gastrointestinal toxicity of NSAIDs, particularly to the
upper GI tract, has long been felt by many to be one of the most
important iatrogenic adverse events associated with modern drug
therapies.

# Gastrointestinal events {#gastrointestinal-events .unnumbered}

(*More details of GI events are found in the review by Larry Goldkind,
M.D)*

Arguments have been made that the selection of CSUGIEs as a safety
endpoint was attempting to address the endpoints of safety with the same
rigor usually attributed to the assessment of efficacy. **The primary
end point in the GI safety analyses was the development of a CSUGIE**
(i.e., UGI bleeding, perforation, or obstruction with important clinical
manifestations). The primary endpoint was a safety endpoint. The **null
hypothesis** being tested was that there was no difference between the
incidence of **CSUGIEs** associated with celecoxib and that associated
with NSAIDs, pooled and then individually. When the endpoint of CSUGIEs
in all ITT patients during either the first 6 months or the entire study
was analyzed, **celecoxib did not exhibit a statistically significant
difference from the NSAIDs studied in this trial, either singly or
combined.** The CSUGIE event rate for the entire study period (Table
12), as defined by the alternate definition, reinforces the observation
that celecoxib did not show significant differences from either NSAID.
However, the trends (Table 13 and 14) for CSUGIEs in all patients during
either the first 6 months or the entire study period did favor
celecoxib. Of importance though, at no time in the CLASS trial, and
without regard to endpoint or aspirin use, was celecoxib superior to
diclofenac.

The representative NSAIDs for this trial, ibuprofen and diclofenac,
turned out to be useful comparators. Of note, when the confounding
effects of aspirin use were addressed, or the endpoint was expanded to
include gastric or duodenal ulcers (i.e. GDU) that were not felt to be
clinically important enough to be classified as a CSUGIEs, celecoxib did
demonstrate differences from ibuprofen, but not from diclofenac. This
was seen during both the first 6 months (Table 13) and the entire study
period (Table 14) for CSUGIEs/GDUs. Undoubtedly, the comparisons with
ibuprofen accounted for the results of NSAIDs as pooled events; Table 33
may best illustrate these points. In any trial of safety, one could
argue that superiority should always be the goal; the safety of drugs
developed today should (ideally) be better than drugs developed years
ago. Therefore, particularly for making drug class (i.e. COX-2 vs.
NSAIDs) comparisons, it could be argued that beating one NSAID does not
mean you beat them all, but losing to one NSAID (or failing to beat it)
is losing to them all.

Why was celecoxib, as given under these exaggerated dosing multiples,
not able to show statistical superiority to diclofenac? Certainly, there
are a variety of possible explanations. One explanation could be that
the use of the multiples of the "x" dose of celecoxib resulted in more
clinically important UGI adverse events than would have occurred with
the x dose alone. This result, unfortunately, was not testable in this
trial but may well nullify the safety hypothesis of COX-2 had it
occurred.

Among other possibilities for the results with celecoxib versus
diclofenac could be that the event rates for diclofenac where not at
their usual "NSAID" pace. In the CLASS trial, these clinically important
UGI events seemed to occur early for diclofenac with rates seeming to
level off at later time points in the trial while UGI events for
celecoxib continued to occur at a steady rate (see below). Could a
process of "differential adaptation" to the daily biochemical/biological
insult of these drugs have played a role?

To help interpret and understand the comparisons with regards to
diclofenac, one possible explanation that was brought forward by the
Sponsor, and discussed in detail, was the idea of "informative
censoring" as it relates to the GI adverse events. Such censoring, if it
occurred, could influence the clinical outcomes provided these
influences were not balanced in all treatment arms. In particular, the
five adverse event symptoms of dyspepsia, abdominal pain, nausea,
diarrhea and vomiting were cited as important contributors to the
confounding effects of informative censoring with the consequence of
removing at-risk patients from the diclofenac treatment arm. However, it
is unclear that the potential for informative censoring represented a
significant bias in assessment of the outcome of the CSUGIEs as defined
in this trial. For example, if the symptoms as specified by the Sponsor
(i.e. moderate to severe) are considered, it appears that informative
censoring may be an important confounder. However, if the less
restrictive definitions of symptoms (i.e. to include mild) as reasons
for the withdrawal of the susceptible patient are applied, then such
censoring may not have an important role (Table 23).

The timing of UGI events may also hold clues to understanding any role
for informative censoring. For example, both crude and Kaplan-Meier
event rates in the first 6 months (Tables 7) showed that for celecoxib,
seven of the 11 uncensored events occurred in the first three months.
However, in the diclofenac group, all nine events occurred in the first
100 days, with a cluster of five events within the first 15 days and
four more events occurring sporadically through approximately day 85.

One could argue (as noted above) that this pattern might suggest a
"shift to the right" for events associated with the use of celecoxib as
compared to diclofenac. If this shift were real, than any loss of
at-risk patients may influence the celecoxib CSUGIE rate more than that
for diclofenac. Any shifting of events to a later point in time could
also be one reason for the lack of CSUGIEs noted during the entire trial
(Table 10) of NSAIDs as compared to celecoxib whose rates tended to
increase at a generally steady pace with time. Therefore, although it
does seem that more patients dropped out of the diclofenac group due to
GI symptoms, this does not seem to be an adequate explanation for the
observed UGI results between diclofenac and celecoxib.

When comparisons with ibuprofen are made, the importance of any
censoring as an explanation for the results in the diclofenac group as
compared to celecoxib become less evident. For example, in the entire
population studied, only one uncensored event occurred in the diclofenac
group after 182 days and none in the ibuprofen group; yet celecoxib was
able to demonstrate statistical superiority to ibuprofen in certain
settings as noted above. Similarly, when the overall withdrawal pattern
was considered, and not just those due to adverse events, rates are
highest in the ibuprofen group (Table 3) versus diclofenac or celecoxib.
Further, when viewed from the prospective of risk factors (Table 19),
patients receiving celecoxib appear more likely to withdraw at any given
risk category than that of diclofenac, but not ibuprofen. Therefore, a
consistent association of endpoints with patterns of withdrawal does not
seem evident when comparing across treatments.

Was informative censoring an important component in the CLASS trial? One
way to attempt to answer this question is with a clinical trial designed
to do so. The hypothesis-generating conclusion that the confounding
effect of UGI informative censoring is important in the outcomes of
large clinical trials can be tested in prospectively-designed trials for
confirmation and validation.

The absence of GI-related deaths in the CLASS trial is noteworthy. This
might be attributable to the heightened vigilance for GI events
maintained throughout the study since the occurrence of GI signs and
symptoms related to the primary end points of this study. Therefore,
events that if left untreated may have progressed to clinically
significant events were identified early and these patients were treated
and/or discontinued from study medication. On the other hand, it may
suggest that prior estimates of GI-related deaths from NSAIDs have been
over estimates.

During the first six months, all but one of the events (a gastric outlet
obstruction in the celecoxib group) represented bleeding events in which
an ulcer or large erosion which was associated with either visual
evidence of bleeding, melena, or hemoccult-positive stools and a
decrease in hematocrit or hemoglobin. There were no UGI perforations
(Table 6). During the entire trial, all events were classified into the
same categories as those that occurred in the first six months, with
these exceptions: one bleeding event in the celecoxib group represented
category 1A, and two UGI perforations occurred, one in the celecoxib
group and one in the diclofenac group (Table 9).

Not unexpectedly, since this had been seen in the original NDA endoscopy
trials, **aspirin use did seem to influence the gastrointestinal results
in this trial**. For example, as seen in Table 13, it appears that use
of aspirin tended to increase the overall CSUGIE event rate for
celecoxib and diclofenac but not for the ibuprofen group. This same
differential pattern also seems evident in the CSUGIE event rate for the
entire study (Table 14). While it would be clinically useful to
understand whether UGI events are more problematic when added to one
treatment regimen versus another, this trial was not able to address
(i.e. issues of powering, etc.) the issue of aspirin co-administration
in any great detail. Once again, it may be that specific trials need to
be designed and conducted to understand these important interactions.

# Cardiovascular events {#cardiovascular-events .unnumbered}

*(More details of cardiovascular events are found in the review by
Douglas Throckmorton, M.D.)*

When considering the deaths and other serious adverse events that
occurred in this trial, they appear to be consistent in nature and
frequency with those that would be expected in a long-term trial in this
patient population. For example, most patients enrolled had several
concomitant illnesses or significant medical histories, and many were
elderly. As noted (Table 5) the median age was approximately 61 years,
with about 11% of patients in each group ≥ 75 years. Approximately 40%
of patients in each treatment group had a self-reported history of
cardiovascular disease and approximately 20% took ASA prophylactically.

While serious adverse events and deaths related to cardiovascular
disorders were not unexpected, was there evidence in the CLASS trial
that any treatment group had an excess of these types of events relative
to the other groups? For example, concerns have been raised about the
possibility that COX-2 selective agents may predispose to thromboembolic
events (i.e. myocardial infarction, deep venous thrombosis, pulmonary
emboli, cerebrovascular accidents, etc.) owing to their preferential
inhibition of endothelial prostacyclins relative to platelet
thromboxanes. Further, literature reports of trials (i.e. VIGOR) of
other COX-2 selective agents have also raised this possibility.

In the original NDA, myocardial infarction was noted to occur at a
higher rate in celecoxib-treated as compared to placebo-treated
patients. In the long-term trial (Trial 024) that was included in the
NDA submission, the predominate (\>90%) cause of death for patients
taking celecoxib at any dose was cardiovascular. The majority of these
deaths were felt to represent progression of previously known
cardiovascular disease. Examination of Kaplan-Meier survival curves for
both the controlled and long-term trials in the NDA did not support the
conclusion that there was a relationship between any given duration of
exposure to celecoxib and increased mortality. There were suggestions of
a dose-response relationship (Table 60, NDA 20-998; 100 mg BID
celecoxib, 0% crude mortality rate vs. 400 mg BID celecoxib, 0.64% crude
mortality rate) between cardiovascular mortality and celecoxib use that
could not be adequately addressed by the data. However, the
cardiovascular mortality rates with celecoxib were lower than those seen
with the active controls employed in the NDA, which confounded
interpretation of these data. Of note, there was no suggestion, in the
original NDA, of any rare or unusual cardiac toxicities.

In the CLASS trial, it is not possible to examine any dose-response
relationships, rather, only comparisons of drugs at the doses employed
and in the population studied. Given these caveats, there was no
apparent, consistent adverse effect of celecoxib in the reported
parameters of cardiovascular safety when compared to either diclofenac
or ibuprofen (Table 52). When these events were examined with or without
aspirin use, these relationships did not appear to change (Table 53) in
any significant way. However, as expected since they are at higher risk,
patients taking aspirin had a higher incidence of cardiac ischemic
events in all three treatment groups as compared to those not taking
aspirin. Of note, discontinuations for thrombotic cardiac events were
not significantly different in the treatment groups (Table T41.1, sNDA
and 2.1.d.1, Cardiorenal Consult).

When cardiac adverse events (Table 54) or serious cardiac adverse events
(Table 55) and the relationship of **aspirin use** are analyzed in more
detail, some differences appear to emerge. For example, examination of
selected cardiac adverse events (Table 54) reported during the trial
suggests that anginal disorders (especially the combined disorders) was
numerically higher in those patients receiving celecoxib, regardless of
aspirin use. In the patients not receiving aspirin, the rate of
myocardial infarction was also slightly higher in the celecoxib group
(0.2%) compared with the other two drugs (0.1%). Of note, for edema and
hypertension, there appears to be a trend toward more events in those
patients receiving ibuprofen regardless of aspirin use.

For serious cardiac adverse events (Table 55) in the non-aspirin users,
there appears to be a trend toward more events in those patients
receiving celecoxib for atrial events and anginal disorders, especially
when combined; this does not appear to be the case for aspirin users.
The importance of any of these differences are difficult to interpret
especially since the trial randomization was not stratified for aspirin
use, any comparisons of the aspirin or non-aspirin users has limited
power to detect only large differences between these groups. This
difficulty in interpretation is also evident in considering
cardiovascular mortality rates (Table 39 and comment). Overall though,
these findings would not seem to support a conclusion that celecoxib has
a large adverse effect on cardiovascular mortality compared to the
non-selective NSAIDs. If the incidence rates for adverse events
(including serious) is confirmed in trials designed to specifically
address these important issues, it may be that the degree of loss of
blood flow may be a factor in understanding these events, compared to
mortality.

# Renal events {#renal-events .unnumbered}

*(More details of renal events are found in the review by Douglas
Throckmorton, M.D.)*

As noted in the original NDA, the overall findings with celecoxib were
that renal events were more like the comparator NSAIDs than the placebo
controls. For example, there was an association between celecoxib
administration and the development of clinically significant edema (i.e.
peripheral), sodium retention, worsened hypertension in susceptible
individuals, hypophosphatemia, hyperchloremia, and elevations of serum
creatinine and BUN with proteinuria as was noted in the comparator
NSAIDs. There were not clear signals, however, for serious renal events
such as bony fractures (suggesting significant acid-base changes), renal
stone formation, nephrotic syndrome, acute renal failure requiring
dialysis, papillary necrosis, or interstitial nephritis. However, there
were patients on celecoxib that were withdrawn from the long-term,
open-label trial (Trial 024) because of renal adverse events, including
acute renal failure. One outstanding issue was whether celecoxib altered
the acid-base balance since no measurements (e.g. serum bicarbonate,
arterial pH) were performed as part of the original NDA.

Regarding the issue of acid-base balance, serum HCO~3~ was measured in
the CLASS trial and adverse events possibly related to changes in
acid-base balance were collected. Between 1 and 2% of the subjects in
all three treatment groups had a measured HCO~3~ \<20 meq/dl during the
study after starting with a normal baseline \>25 mg/dl. The rate for
celecoxib, however, was less than that of the two comparator drugs. In
addition, there was no increase in reported clinical adverse events
related to changes in acid-base balance (such as bony fractures which
could indicate chronic acidosis with demineralization, Table T41.1,
sNDA) in the celecoxib group although such adverse events were quite
rare in the database for all three drugs. Overall, then, the rate of
clinically-relevant changes in acid-base balance was similar for
celecoxib, diclofenac and ibuprofen.

Regarding the comparative incidence of reported clinical renal adverse
events between the three treatment groups, there was no consistent
adverse effect of celecoxib in the reported parameters of renal safety
when compared with either diclofenac or ibuprofen. In particular, the
reported rates of uremia, nephrotic syndrome and severe hyperkalemia in
CLASS were all less than 1 per 1000 patient-years of exposure for all
three drugs. Celecoxib use was also not apparently associated with an
increase in hypertension or edema compared with diclofenac and ibuprofen
(Table 50).

When renal adverse events related to laboratory measurements were
examined, celecoxib did not appear to have a striking adverse effect
with regard to any renal parameter measured, compared with diclofenac or
ibuprofen (Tables 47, 50). The incidence of hyperkalemia, assessed as
clinical events and as changes in lab measurements, was consistently
more common in the celecoxib group than in either of the comparators,
although the difference did not achieve nominal statistical significance
for any measure (Table T 41.1 sNDA and 2.1.c.1 and 2.1.c.2, Cardiorenal
Consult).

Regarding changes in renal laboratory parameters, **when examined as
mean changes** from baseline, no clinically relevant differences between
the three treatment groups were seen at any time point for the changes
in mean BUN, serum creatinine, phosphate, bicarbonate and chloride. The
reported differences, some of which achieved nominal statistical
significance, were quite small and of no apparent clinical relevance
(Table T44.1, sNDA). Use or not of aspirin did not seem to influence
these particular results.

Of note, it does appear that patients who used **aspirin** in all three
treatment groups had a higher incidence of increases in BUN than
patients who did not use aspirin. Hyperkalemia as an AE was somewhat
higher in the celecoxib group, regardless of aspirin use (Table T 41.2
and T41.3, sNDA and 2.1.c.2, Cardiorenal Consult). For the renal SAEs
(Table T43, sNDA and 2.1.b.1, Cardiorenal Consult), too few (i.e. none
in any treatment group for hyper- or hypokalemia, acidosis, nephrotic
syndrome, edema, uremia-1 case for ibuprofen, or renal calculus-4 cases
for celecoxib, 2 for ibuprofen) were reported to analyze according to
the use of aspirin.

#  {#section-5 .unnumbered}

#  {#section-6 .unnumbered}

# Hepatic events {#hepatic-events .unnumbered}

In the original NDA, it was noted that celecoxib did not appear to
significantly alter liver or biliary function as determined primarily by
elevations of enzymes and other laboratory measurements (i.e. ALT, AST,
bilirubin, alkaline phosphatase). Serious adverse events were rare.
However, cases of liver failure have been reported in post-marketing
data.

The data in the CLASS trial appear to confirm that long-term use of high
doses of celecoxib is not associated with significant elevations of
enzymes or serious hepatic adverse events. However, diclofenac was
associated with significant elevations of liver enzymes requiring
withdrawal of approximately half of these patients. Of interest, there
were no deaths from hepatobiliary causes in any treatment group in the
CLASS trial.

# Dermatologic events {#dermatologic-events .unnumbered}

In the original NDA, it was noted that rashes and related cutaneous
reactions were among the more frequently noted adverse events associated
with celecoxib treatment. The rashes were generally mild in severity,
and often associated with urticaria or pruritis. Rash was the single
most common reason for withdrawal from study treatment. There was an
increase in incidence of rash at higher celecoxib doses (the highest
being the dose used in this trial) that suggested a dose-response
relationship. Importantly, there were no serious cutaneous reactions
associated with celecoxib treatment.

In the CLASS database, the results appear to be similar to those of the
original NDA. The incidence of rash (generally mild or moderate, none
were serious) was statistically significantly higher for celecoxib than
for either diclofenac or ibuprofen. The incidence of pruritis was also
statistically significantly higher for celecoxib than ibuprofen, but not
diclofenac. The incidence of clinically significant rash with celecoxib
was estimated to be 0.13%. The percentage of patients withdrawing for
either rash or pruritis was generally higher in the celecoxib group. Of
note, there were no cases of Stevens Johnson syndrome, toxic epidermal
necrosis or erythema multiforme noted for any of the treatment groups in
this trial.

**Overall Safety of Celebrex**

The results presented in this sNDA with celecoxib at the
supratherapeutic doses studied, support the overall safety of celecoxib.
While adverse events for celecoxib during the entire study period were
statistically greater than those of the comparator drugs (Table 42),
this did not seem to translate into more withdrawals for celecoxib
versus ibuprofen or diclofenac (Table 3). Also, although serious adverse
events were numerically higher for celecoxib (Table 41), there were no
obvious trends to suggest any specific safety risks. Similarly, the
death rate and pattern (Tables 38 and 39) did not suggest any obvious
safety risks for celecoxib. Interestingly, no deaths in the celecoxib
group occurred for GI, hepatic, renal or dermatologic causes, but the
same was true for the comparators.

**Conclusions:**

As noted earlier, the CLASS trial was a robust testing of the safety of
Celebrex at doses 2-4 times those currently labeled for RA or OA,
respectively. The NSAID comparators, ibuprofen and diclofenac, were
given at their commonly prescribed (not maximum) doses. Therefore, any
conclusions regarding the relative safety or efficacy of Celebrex needs
to be viewed in this context. However, the following are some
conclusions from this CLASS trial:

1.  Celecoxib does not appear to be more effective for treating the
    signs and symptoms of OA or RA than the NSAID comparators.

2.  Celecoxib did not demonstrate statistical superiority to NSAIDs
    (pooled) or either comparator (diclofenac and ibuprofen) with
    regards to the primary safety endpoint of CSUGIEs at any point in
    the trial although there were trends that favored celecoxib.
    However, when the use of aspirin was considered or the definition of
    the UGI endpoints was expanded to include ulcer events not deemed to
    be CSUGIEs (i.e. GDUs), celecoxib did demonstrate statistical
    superiority to pooled NSAIDs, and to ibuprofen, during this trial.
    However, celecoxib did not demonstrate statistical superiority to
    diclofenac regardless of selection of endpoint or aspirin use during
    any point in the trial.

3.  Aspirin use appears to influence event rates for gastrointestinal,
    renal and possibly cardiac outcomes. However, owing to the nature of
    this trial, particularly that use of aspirin would indicate a higher
    level of pre-existing cardiovascular disease and aspirin use was not
    stratified, it is unclear how aspirin impacts these outcomes among
    the treatment groups evaluated in this trial.

4.  The CLASS trial contains no evidence for an adverse effect of
    celecoxib on acid-base balance relative to either diclofenac or
    ibuprofen. All groups rarely had changes in this renal parameter.

5.  The CLASS trial data do not support a large adverse effect of
    celecoxib on cardiovascular mortality or on serious adverse events
    related to thrombosis relative to either diclofenac or ibuprofen.
    The data do not exclude a less apparent effect, reflected in the
    relative rates of cardiac adverse events related to ischemia.

6.  The CLASS trial data do not support a large adverse effect of
    celecoxib on renal or cardiac adverse events relative to either
    diclofenac or ibuprofen. This includes adverse events reported by
    investigators (*e.g.*, hypertension, uremia) and those detected
    through routine laboratory or blood pressure measurements (*e.g.*,
    increased BUN/ serum creatinine or systolic blood pressure).

7.  Hyperkalemia, however measured, was consistently more frequent in
    patients taking celecoxib than for diclofenac or ibuprofen, but
    these differences were small and not reflected in an increase in
    serious adverse events related to hyperkalemia.

8.  The CLASS trial data do not support the conclusion that serious
    hepatic adverse events are more frequent in those patients taking
    celecoxib than diclofenac or ibuprofen. In fact, hepatic enzyme
    elevations and withdrawals for these elevations were significantly
    and consistently reduced compared to diclofenac.

9.  The incidence of rash (generally mild or moderate, none were
    serious) was statistically significantly higher for celecoxib than
    for either diclofenac or ibuprofen. The incidence of pruritis was
    also statistically significantly higher for celecoxib than
    ibuprofen, but not diclofenac. The incidence of clinically
    significant rash with celecoxib was estimated to be 0.13%. The
    percentage of patients withdrawing for either rash or pruritis was
    generally higher in the celecoxib group.

10. There were no deaths from gastrointestinal, hepatic, renal or
    dermatologic causes in any treatment group during the time period of
    the CLASS trial.

11. No new safety issues were apparent regarding respiratory,
    endocrine/metabolic, CNS/PNS or infectious disease safety.

12. Celecoxib was generally safe and well tolerated at the
    supratherapeutic doses employed in this CLASS trial.

**Appendix (CSUGIEs)**

A narrative summary was prepared for each CSUGIE and symptomatic ulcer.
The data for these summaries were derived from the CRFs and any
additional medical records resulting from the work-up. The narrative
summaries for all CSUGIEs that occurred at any time during study
participation are included below. These are sorted by case number (case
numbers were

assigned chronologically in order of the reporting of potential
CSUGIEs).

**Case 1000**

**Patient US0293-035-10579** was a 69-year-old female with a history of
hypertension, right-sided mastectomy, hysterectomy,
non-insulin-dependent diabetes mellitus, and OA. Concomitant medications
included atenolol, enalapril, and trazadone. The patient was enrolled in
protocol N49-98-02-035 and randomized to **ibuprofen 800 mg TID**.

After 13 days of treatment the patient began experiencing intermittent
black stools followed by frank blood in the toilet for two days with
associated epigastric discomfort. On day 18 of treatment the patient
presented to the emergency room after an episode of uncertain
hematemesis; **study medication was discontinued at this time**.
Significant findings at this time included melena and a hemoglobin of
8.8 g/dL compared with a baseline hemoglobin of 14.1 g/dL and a
hematocrit of 25.4% compared with a baseline hematocrit of 41%. The
patient was admitted to the hospital and an endoscopy performed the
following day revealed an actively oozing ulcer in the gastric cardia
with blood emanating from the ulcer margins and from friable underlying
mucosa. Hemostasis was achieved using multiple injections of epinephrine
in and around the ulcer. Antral biopsies revealed chronic gastritis but
were negative for *H. pylori,* although the patient had been *H. pylori*
positive at baseline. The patient ultimately received 3 units of packed
red blood cells and was discharged from the hospital 48 hours later. The
patient was to be treated with acid suppression and undergo a repeat
endoscopy in 4 to 5 weeks to document healing. This event was classified
as: **gastric ulcer; GI bleed (traditional, 1B; alternate, 1F).**

**Case 1016**

**Patient US0242-035-11377** was a 51-year-old female with a history of
intermittent stress headaches, dizziness, hysterectomy, bilateral
salpingo-oophorectomy, stress incontinence, L4-5 spinal fusion with
Harrington rod insertion, skin fibroids, dermatitis, thyroidectomy, and
OA. A GI history was significant for peptic ulcer disease and esophageal
reflux. Concomitant medications included levothyroxine, acetaminophen,
and conjugated estrogens. The patient was enrolled in protocol
N49-98-02-035 and randomized to **ibuprofen 800 mg TID.**

After 4 days of treatment the patient began to complain of epigastric
pain and nausea. **Study medication was discontinued on day 7**. On
study day 8, the patient reported a black stool and was admitted to the
hospital. Significant findings at this time included Hemoccult-positive
stools and a hemoglobin of 14.9 g/dL compared with a baseline hemoglobin
of 16.2 g/dL and a hematocrit of 44.8%, compared with a baseline
hematocrit of 49.0%. An endoscopy performed on the following day
revealed a tiny ulcer in the gastric cardia and multiple antral ulcers,
the largest measuring 0.75 cm in diameter. Specific locations for these
ulcers were noted to be at the angularis, antrum, and prepyloric area.
There was adherent clot in the prepyloric region that could not be
washed off. This area was injected with 6 mL of epinephrine and no
active bleeding was noted. Two additional ulcers, the larger of which
measured 0.5 cm in diameter, were identified in the duodenal bulb.
CLOtest was reported as negative although the patient had a positive *H.
pylori* serology at baseline. The patient was discharged from the
hospital on the same day and was to be treated with acid suppression and
undergo a repeat endoscopy in 6 to 8 weeks. Follow-up endoscopy was
performed and revealed healing antral ulcers of 0.5 cm and 0.2 cm in
diameter. The duodenal bulb appeared normal. At this time the patient
reported that she had not completed a full course of acid suppression
and additionally reported a small amount of hematochezia. Colonoscopy
was recommended and acid suppression was restarted. This event was
classified as: **gastric ulcer; GI bleed and duodenal ulcer
(traditional, 1B; alternate, 1F).**

**Case 1018**

**Patient US0330-035-11159** was an 85-year-old female with a history of
cataract surgery, herpes zoster, multiple arthralgias, hypertension,
chronic pedal edema, obesity, and OA. Concomitant medications included
multivitamin, Equate, and Tums. Voltaren was discontinued one day prior
to start of study drug. The patient was enrolled in protocol
N49-98-02-035 and randomized to **celecoxib 400 mg BID**.

After 43 days of treatment the patient began experiencing abdominal pain
and dyspepsia. On study day 48 the patient was seen in the clinic and
she continued to report dyspepsia and lower abdominal pain. Stool
hemoccults on days 51, 52, and 53 were negative, and a hemoglobin on day
54 was 12.4 g/dL compared with a baseline hemoglobin of 13.6 g/dL and a
hematocrit on day 54 was unchanged from a baseline of 38.0%. Study
medication was discontinued on day 62 because of progressively worsening
symptoms and an outpatient UGI endoscopy was scheduled for study day 63.
The patient, however, presented to the emergency room later on study day
62 with dyspnea and melena. Nasogastric lavage produced dark maroon
material and a hematocrit was now 16.0%. An endoscopy was done as an
inpatient on day 63 revealing a 1.5 x 1.5 x 1.0-cm ulcer in the duodenal
bulb with adherent clot. After the procedure the patient developed
hematemesis and was transferred to the intensive care unit. Repeat
endoscopy was performed on day 64, again revealing the large, deep ulcer
in the apex of the duodenal bulb. On this exam a visible vessel was
identified in the ulcer base which was injected with epinephrine.
Immediate re-bleeding required repeat injections of epinephrine, and
tenuous hemostasis was ultimately achieved. Baseline serology for *H.
pylori* had been negative. On study day 66 the patient had a surgical
oversew of the lesion and ultimately recovered. She received a total of
9 units of packed red blood cells during the hospitalization. This event
was classified as: **duodenal ulcer; GI bleed (traditional, 1B;
alternate, 1F).**

**Case 1022**

**Patient US0268-102-10193** was a 73-year-old female with a history of
sinusitis, hyperopia, myopia, migraines, hypertension, colon polyps,
cholecystectomy, inflamed ovary, breast cancer with no recurrence, leg
cramps, intermittent elevation of liver enzymes, allergy to penicillin,
and OA. Concomitant medications included hydrochlorothiazide, potassium,
and calcium carbonate. The patient was enrolled in protocol
N49-98-02-102 and randomized to **diclofenac 75 mg BID.**

After 8 days of treatment the patient began experiencing melena,
abdominal pain and distention, nausea, dyspnea, and syncope. On study
day 10 the patient was found to have a hemoglobin of 12.8 g/dL compared
with a baseline hemoglobin of 13.4 g/dL and a hematocrit of 37.5%
compared with a baseline hematocrit of 40.0%. **Study medication was
discontinued on day 10**. Baseline serology for *H. pylori* had been
positive. On study day 15 an endoscopy was performed revealing two
gastric ulcers in the antrum measuring 0.3 cm and 0.2 cm. Also seen were
superficial gastric erosions and streaking erythema in the distal body
and one duodenal bulb erosion. This event was classified as: **gastric
ulcer; GI bleed (traditional, 1C; alternate, none).**

**Case 1025**

**Patient US0425-035-11153** was an 85-year-old female with a history of
sleep disorder due to chronic pain, mild Parkinson's disease, diastolic
dysfunction, upper respiratory infection/sinusitis,
restrictive/obstructive lung disease, bleeding secondary to
constipation, colon cancer, rectal bleeding due to constipation,
diverticulosis, gastroesophageal reflux disease, hiatal hernia, urinary
tract infection, bladder dysfunction, hysterectomy, osteoporosis, low
back pain, excision of basal cell carcinoma, hypothyroidism,
hyperlipidemia, anemia, intermittent mild thrombocytopenia, allergy to
metoclopramide hydrochloride, and OA. Concomitant medications included
levothyroxine, atorvastatin, diltiazem, aspirin, Darvocet N-100,
oxybutynin, alendronate, multivitamin, and Citrucel. The patient was
enrolled in protocol N49-98-02-035 and randomized to **celecoxib 400 mg
BID**.

On study day 67 the patient presented to the clinic with a one-day
history of passing melenic stools and complaints of lightheadedness and
abdominal pain that had begun on that day. Findings at this time
included hemoccult-negative stool, significant orthostatic changes in
both systolic and diastolic blood pressure, and a hemoglobin of 12.0
g/dL compared with a baseline of 15.0 g/dL and a hematocrit of 36%
compared with a baseline of 45%. The patient was admitted to the
hospital and subsequently transferred to the intensive care unit after
she became more hypotensive and tachycardia. The patient was transfused
2 units of packed red blood cells and an endoscopy was performed on
study day 68. Endoscopic findings included a deep gastric ulcer with a
visible vessel in the antrum measuring 0.5 cm in its longest length,
duodenitis with multiple areas of submucosal hemorrhaging, and a
superficial duodenal bulb ulcer measuring 1.5 cm at its longest length.
Due to mechanical failure, thermal coagulation of the visible vessel was
unsuccessful. On study day 70 the patient's hemoglobin had fallen to 8.9
g/dL and the hematocrit had fallen to 26.9%. A repeat endoscopy was
performed. This exam revealed similar findings to the previous endoscopy
with the additional finding of a 1.0-cm clean-based postbulbar ulcer.
Again, no active bleeding was present and the gastric ulcer with visible
vessel was treated with several applications of Gold Probe coagulation.
Biopsies obtained for *H. pylori* from the antrum were negative, as was
the baseline serology. Over the next several days the patient stabilized
and was discharged on study day 73; **study medication had been
discontinued on day 62**. This event was classified as: **gastric ulcer;
GI bleed and duodenal ulcer (traditional, 1B; alternate, 1F).**

**Case 1026**

**Patient US0080-035-12446** was a 75-year-old female with a history of
splenectomy, hysterectomy, onychomycosis of both feet, water retention,
hypothyroidism, and OA. Concomitant medications included estradiol,
levothyroxine, and spironolactone hydrochlorothiazide. The patient was
enrolled in protocol N49-98-02-035 and randomized to **ibuprofen 800 mg
TID**.

After 5 days of treatment the patient developed melenic stools. Black,
tarry stools continued into study day 6 and on study 7 the patient was
seen in the investigator's office. Significant findings at this time
included hemoccult-positive stools and a hemoglobin of 14.2 g/dL
compared with a baseline of 15.0 g/dL and a hematocrit of 42.1% compared
with a baseline of 45.0%. On study day 8 an endoscopy was performed
revealing mild esophagitis, a 2.0-cm hiatal hernia, and a 1.0 x 1.0-cm
ulcer on the superior wall of the duodenal bulb with adherent clot. An
antral biopsy was negative for pathology and *H. pylor*i; Baseline
serology for *H. pylori* had also been negative**. Study medication had
been discontinued on day 6**. This event was classified as: **duodenal
ulcer; GI bleed (traditional, 1B; alternate, none).**

**Case 1027**

**Patient US0415-035-21191** was a 53-year-old female with a history of
asthma, fluid retention, hypertension, and RA. Concomitant medications
included methotrexate, folic acid, albuterol, and hydrochlorothiazide.
The patient was enrolled in protocol N49-98-02-035 and randomized to
**ibuprofen 800 mg TID**.

On day 17 of treatment the patient developed emesis, abdominal cramping,
nausea, diarrhea, and dizziness. At this time she **discontinued her
study medication**. She also reported experiencing ongoing nonspecific
fatigue over the previous 9 days. On study day 18 she presented to the
clinic with strongly hemoccult-positive black stools. At this time a
hemoglobin was 10.3 g/dL compared with a baseline of 13.3 g/dL and a
hematocrit was 30.3% compared with a baseline of 41%. An endoscopy was
performed on study day 19 revealing approximately 12 petechial lesions
in the body and three linear erosions, each measuring approximately 0.6
cm, in the antrum. Hemoccult-positive black stools persisted at least
through study day 22 and the hematocrit fell to 27.6% at this time. The
patient was treated for *H. pylor*i; the baseline serology had been
positive This event was classified as: **gastric erosion (traditional,
1C; alternate, 1G).**

**Case 1028**

**Patient US0144-035-20966** was an 80-year-old female with a history of
sleep disturbance, hypertension, left foot bunion, peptic ulcer disease,
and RA. Concomitant medications included Tylenol PM, glucosamine, and
metoprolol. The patient was enrolled in protocol N49-98-02-035 and
randomized to **celecoxib 400 mg BID**.

On study day 41 the patient reported that she had experienced a near
syncopal episode and "fell over a sofa." Paramedics responding to her
call were not informed of the near syncope and evaluated her for a fall.
Because of stable vital signs and no other symptoms reported, the
paramedics did not transport the patient to the hospital. Later in the
day the patient experienced coffee ground-like emesis which she
attributed to tea that she had previously consumed. At approximately
6:00 pm the patient began to feel weak and dizzy and passed a large
black/burgundy colored diarrheal stool. Paramedics were again called and
this time transported her to the emergency room. Significant findings in
the emergency room included postural changes in blood pressure,
specifically 113/65 mm Hg, 80 bpm (supine) and 105/64 mm Hg, 102 bpm
(standing). Laboratory tests revealed a hemoglobin of 9.0 g/dL compared
with a baseline of 12.1 g/dL and a hematocrit of 26.2% compared with a
baseline of 37.0%. Baseline serology for *H. pylori* had been positive.
The patient was transfused with 2 units of packed red blood cells. An
endoscopy performed on study day 42 revealed antral linear erosions in
the stomach and a 1.0 x 2.0-cm inferior duodenal ulcer without active
bleeding or visible vessel. Study medication had been discontinued on
day 40. The patient was treated with acid-suppressive therapy and was
**discontinued from the study**. This event was classified as:
**duodenal ulcer; GI bleed (traditional, 1C; alternate, 1G).**

**Case 1029 (Censored)**

**Patient US0417-035-20397** was a 67-year-old female with a history of
tonsillectomy, adenoidectomy, fatigue, depression, hypertension,
hemorrhoidectomy, hematuria, fractured toes, basal cell carcinoma,
psoriasis, hypercholesterolemia and RA. Concomitant medications included
Prempro, triamterene/hydrochlorothiazide, methotrexate, aspirin,
multivitamins, folic acid, cod liver oil, vitamin E, vitamin C, and
calcium. The patient was enrolled in protocol N49-98-02-035 and
randomized to **ibuprofen 800 mg TID** which started 12/4/98**.**

\[On the second day 12/5/98\] of treatment, the patient complained of
stomach "churning," nausea, and "not feeling right." Study medication
was discontinued on day 3 \[12/6/98\]. On study day 6 \[12/9/98\] the
patient noticed black stools for the first time and a rectal examination
detected hemoccult-positive stool. Additional significant findings at
this time included a hematocrit of 41.8% compared with a baseline
hematocrit of 43.0%. On study day \[7, 12/11/98\] the patient had an
upper endoscopy performed revealing three gastric ulcers and a hiatal
hernia. Two of these ulcers were located near the gastroesophageal
junction and measured 0.5 x 0.1 cm and 1.0 x 0.1 cm, respectively. A
third ulcer, 1.0 cm in diameter, was found in the prepyloric area. None
of the ulcers had stigmata of recent bleeding and no fresh blood was
seen. Finally, the gastric mucosa appeared generally inflamed and the
antrum was described as "abnormal." A CLOtest biopsy was negative for
*H. pylor*i, as was the baseline serology. The **patient was terminated
from the study and treated with acid suppression**. A follow-up
endoscopy done approximately six weeks later revealed a 0.5-cm antral
ulcer approximately 3 to 4 cm from the pylorus. CLOtest was again
negative. This event was classified as: **gastric ulcer; GI bleed
(traditional, 1C; alternate, none).**

***Reviewer's comment: The dates/comments in this summary that appear
in* \[\] *were added after review of the CRF.***

**Case 1036**

**Patient US0017-102-10032** was an 80-year-old male with a history of
impaired hearing, cataracts in right and left eyes, Parkinson's disease,
anxiety, right carotid endarterectomy, hypertension, bilateral common
carotid angiography, appendectomy, peptic ulcer in 1988, heartburn, rash
under right breast, and OA. Concomitant medications included enalapril
maleate, Darvocet-N, amantadine hydrochloride, isradipine, and
clonazepam. The patient was enrolled in protocol N49-98-02-102 and
randomized to **diclofenac 75 mg BID.**

After 66 days of treatment the patient began experiencing diarrhea and
very dark black stool. Significant findings at this time included
hemoccult-positive stool and a hemoglobin of 14.3 g/dL compared with a
baseline of 14.5 g/dL and a hematocrit of 44% compared with a baseline
of 43%. On study day 72, an upper endoscopy revealed fewer than 25 red-
and white-based erosions scattered in the gastric body and antrum, but
most prominently located in the prepyloric area. There was also a
white-based linear ulceration measuring 0.3 cm in length on the
posterior wall of the pylorus. The duodenal bulb and sweep were
remarkable for patchy areas of inflammation. Also seen was a small
sliding hiatal hernia. There was no evidence of esophagitis. Serology
for *H. pylori* was negative, as was the baseline serology. **Study
medication was discontinued on day 66.** This event was classified as:
**gastric ulcer; GI bleed (traditional, 1C; alternate, none).**

#### Case 1037

**Patient US0386-102-10294** was a 71-year-old female with a history of
a right wrist ganglion, migraine headaches and intermittent headaches,
dizziness, transient ischemic attack, hypertension, carotid artery
stenosis, peripheral vascular disease, aortofemoral bypass, emphysema,
dyspepsia, duodenal ulcer, gastric ulcer, esophagitis, chronic
constipation, hemorrhoids, intermittent rectal bleeding, cystocele
repair, hysterectomy, compound fracture of the 4th lumbar vertebra, back
pain, left small toe fracture, hypercholesterolemia, osteoporosis, and
OA. Concomitant medications included nifedipine slow release,
lisinopril, dipyridamole, and hydrochlorothiazide. The patient was
enrolled in protocol N49-98-02-102 and randomized to **diclofenac 75 mg
BID.**

After nine days of treatment the patient began experiencing epigastric
pain, nausea, and heartburn. At this time the patient was found to have
hemoccult-positive stool. Endoscopic evaluation performed on study day
30 revealed a 1.0-cm duodenal bulb ulcer with a clot**. Study medication
was discontinued** at this time. Serology for *H. pylori* was negative,
as was the Baseline serology. This event was classified as: **duodenal
ulcer; GI bleed (traditional, 1B; alternate, none).**

**Case 1040**

**Patient US0024-102-20702** was a 73-year-old male with a history of
hearing loss, tonsillectomy, chronic sinusitis, septal deviation, concha
bullosa deformities of both middle turbinates, arcuate defects of both
eyes, numbness and tingling in left leg, appendectomy, hemorrhoids,
benign prostatic hyperplasia, muscle weakness, low back pain, fracture
of the right ankle, shrapnel scars, bruising easily, lips burning,
anemia, hepatitis, hyperuricemia, hypercholesterolemia, OA, and RA.
Concomitant medications included hydrocodone bitartrate with
acetaminophen, prednisone, methotrexate, hydrochlorothiazide with
triamterene, diphenhydramine hydrochloride cream, aspirin, Tums,
multivitamins, and Folic acid. The patient was enrolled in protocol
N49-98-02-102 and randomized to **celecoxib 400 mg BID.**

After 17 days of treatment the patient began experiencing heartburn,
mild epigastric pain, black vomitus, and black tarry stool. **Study
medication was discontinued** at this time. Significant findings at this
time included a hemoglobin of 9.4 g/dL compared with a baseline of 12.7
g/dL, a hematocrit of 27.2% compared with a baseline of 38.0%, and

hemoccult-positive stool. Because of these findings the patient
underwent an upper endoscopy. This revealed approximately 5.0 to 6.0 cm
of Barrett's esophagus and a deep posterior duodenal bulb ulcer with a
large clot in its base. The ulcer measured approximately 2.0 cm and was
identified as the source of bleeding. The ulcer base was injected with
6.5 mL of epinephrine. Serology for *H. pylori* was negative, as was the
baseline serology. The patient ultimately received 1 unit of packed red
blood cells. This event was classified as: **duodenal ulcer; GI bleed
(traditional, 1B; alternate, 1F).**

**Case 1041**

**Patient US0112-035-10077** was an 81-year-old male with a history of a
tonsillectomy, hypertension, heart murmur, hyperlipidemia,
diverticulitis, cholecystectomy, benign prostatic hypertrophy, back
pain, gout, right inguinal hernia repair, skin cancer, and OA.
Concomitant medications included allopurinol, gemfibrozil, lisinopril,
and hydrochlorothiazide. The patient was enrolled in protocol
N49-98-02-035 and randomized to **ibuprofen 800 mg TID.**

After 85 days of treatment the patient was found to have a a hemoglobin
of 12.1 g/dL compared with a baseline of 15.8 g/dL and a hematocrit of
36.0% compared with a baseline of 48.0%. **Study medication was
discontinued on day 104**. On study day 105 a UGI endoscopy was
performed revealing multiple superficial and full thickness ulcers

measuring from 0.3 to 0.8 cm. One or two of the lesions appeared to have
been oozing around the edge. Antral biopsies for *H. pylori* were
positive, as was the baseline serology. This event was classified as:
**gastric ulcer; GI bleed (traditional, 1B; alternate, 1F).**

**Case 1052**

**Patient US0544-102-20398** was a 66-year-old male with a history of
right hearing loss, coronary artery disease with six-vessel bypass,
hyperlipidemia, GI intolerance to NSAIDs, right knee surgery, OA, and
RA. Concomitant medications included Lipitor, procardia, atenolol, gold
injections, multivitamins, and aspirin. The patient was enrolled in
protocol N49-98-02-102 and randomized to **diclofenac 75 mg BID**.

On the first day of treatment the patient began taking Maalox every
other day for heartburn. Between study days 8 and 41 the patient only
used Maalox nightly at bedtime; however after day 41 this frequency was
increased to BID due to increasingly symptomatic heartburn. **Study
medication was discontinued on day 48**. On study day 49 the patient
experienced several episodes of melena that recurred on day 50 but had
stopped by day 51. A UGI endoscopy was performed on study day 56,
revealing a 5.0-cm hiatal hernia, mild nonerosive duodenitis, and a 1.0
to 1.5-cm duodenal bulb ulcer with moderate surrounding erythema and
edema. A biopsy for *H. pylori* was negative, as was the baseline
serology. A rectal examination produced hemoccult-positive stool.
Laboratory evaluation performed on study day 57 revealed a hemoglobin of
7.5 g/dL compared with a baseline of 13.3 g/dL and a hematocrit of 21.9%
compared with a baseline of 41.0%. The patient was treated for *H.
pylori* and with acid suppression and **discontinued from the study**.
This event was classified as: **duodenal ulcer; GI bleed (traditional,
1C; alternate, 1G).**

**Case 1055**

**Patient US0279-102-12815** was a 66-year-old male with a history of
hiatal hernia and gastric ulcer (1991), hypertension, congestive heart
failure, gout, cardiomegaly, obesity, hypercholesterolemia, esophageal
reflux, angina, rhinitis, psoriasis, bronchitis, arteriosclerotic
cardiovascular disease, peptic ulcer disease (1988), esophagitis,
chronic renal insufficiency, degenerative joint disease (right hip and
bilateral shoulder replacement), seasonal allergies, OA, and RA.
Concomitant medications included digoxin, isosorbide, sublingual
nitroglycerin, aspirin, furosemide, lisinopril, metoprolol, prazosin,
diphenhydramine, cetrizine, colchicine, probenecid, calcium carbonate,
Maalox, hydrocortisone, Thymol, triamcinolone, and Entex-LA. The patient
was enrolled in protocol N49-98-02-102 and randomized to **diclofenac 75
mg BID**.

After 7 days of treatment the patient began experiencing nausea and
epigastric and abdominal pain. **Study medication was discontinued at
this time**. On study day 11 the patient was seen in the clinic and
reported multiple episodes of black tarry stools, which had begun that
day. Significant findings at this time included hemoccult-positive stool
and an orthostatic change in pulse rate from 83 bpm in a sitting
position to 104 bpm in a standing position. The patient was admitted to
the hospital and an upper endoscopy was performed on study day 12
revealing a duodenal bulb ulcer. Biopsy was negative for *H. pylori,* as
was a Baseline serology. The patient was treated with acid suppression
and was **discontinued from the study.** This event was classified as:
**duodenal ulcer; GI bleed (traditional, 1C; alternate, 1G).**

Case 1056 (Censored)

**Patient US0114-035-11573** was a 72-year-old female with a history of
myopia, hyperopia, sinus infection, glaucoma, tonsillitis, temporal
mandibular joint dysfunction, stress headaches, depression, migraines,
hypertension, hypercholesterolemia, pneumonia, bronchitis, hiatal
hernia, urinary tract infection, menorrhagia, benign bilateral breast
cysts, shattered humerus, dehydration and OA. Concomitant medications
included Levo Bunolol, medroxyprogesterone acetate, conjugated estrogen,
triamterene, verapamil hydrochloride, fluoxetine hydrochloride,
Fioricet, Calcium with Vitamin D, Darvocet, Vitamin C, and loratadine.
The patient was enrolled in protocol N49-98-02-035 and randomized to
**celecoxib 400 mg BID**.

\[The patient started therapy on 12/11/98. This may also be the last day
of her prior naproxen sodium therapy\]. After 2 \[rash was noted first
on study day 9-12/19/98 or study day 11-12/21/98\] days of treatment the
patient developed itching, a whole body rash, and black stools \[melena
was first noted by the patient 12-19-98 at which time she was found to
be heme +, a typed addition to the CRF states that "it is believed
patient began having black stools on 12/12.98"\]. From study day 10
through study day 16 the patient complained of GI upset. **Study
medication was discontinued on day 10 \[day 11-12/21/98\]**. At this
time the patient was given a prescription for cimetidine and a steroid
dose pack. She refused further work-up until "after the holidays" and
ultimately returned for a termination visit on day 27 \[1/6/99\].
Significant findings at this time included a hemoglobin of 10.2 g/dL
compared with a baseline of 12.3 g/dL, a hematocrit of 29.0% compared
with a baseline of 37.0%, and hemoccult-positive stool. A UGI endoscopy
was performed on day 50 \[1/29/99\] revealing 0.5-cm and 0.3-cm
clean-based antral ulcers, and an erosion on the greater curve in the
mid-body of the stomach. A biopsy for *H. pylori* was negative, as was
the baseline serology. Of note, the patient did not take any NSAIDs
between study drug discontinuation and the endoscopy. This event was
classified as: **gastric ulcer; GI bleed (traditional, 1C; alternate,
1G).**

***Reviewer's comment: The dates/ comments in this summary that appear
in* \[\] *were added after review of the CRF.***

**Case 1057**

**Patient US0268-102-10196** was a 60-year-old male with a history of
tinnitus, decreased hearing in right ear, hypertension, mild restrictive
lung disease, hiatal hernia, colon polyps, rotator cuff injury of the
right shoulder, bilateral ankle and groin rash secondary to dermatitis,
and OA. Concomitant medications included amlodipine besylate,
levothyroxine sodium, diazepam, Tylenol PM, fluoxetine hydrochloride,
Tylenol with Codeine, and nizatidine. The patient was enrolled in
protocol N49-98-02-102 and randomized to **celecoxib 400 mg BID.**

After 56 days of treatment the patient began experiencing severe
epigastric pain. **Study medication was discontinued on day 62.** On
study day 65 the patient underwent an UGI endoscopy revealing a large
hiatal hernia and a 1.0 to 1.2-cm duodenal bulb ulcer with adherent clot
in the base. Serology for *H. pylori* was negative, as was the baseline
serology. The patient was **discontinued from the study** and treated
with acid suppression.

This event was classified as: **duodenal ulcer; GI bleed (traditional,
1B; alternate, 1F).**

#### Case 1058

**Patient US0118-102-20035** was a 56-year-old female with a history of
hysterectomy, multiple fractures as a result of an automobile accident,
*Staphylococcus* infection, and RA. Concomitant medications included
hydroxychloroquine sulfate, conjugated estrogens, and sulfasalazine. The
patient was enrolled in protocol N49-98-02-102 and randomized to
**diclofenac 75 mg BID**.

After 6 days of treatment the patient began experiencing nausea and
moderate to severe abdominal pain. **Study medication was discontinued
on day 19.** On study day 20 the patient underwent an upper endoscopy
revealing six antral ulcers, the largest measuring 0.6 x 0.2 cm with a
small overlying clot. The remaining five ulcers measured 0.2 to 0.4 cm.
A small hiatal hernia, ulcerative esophagitis, and duodenitis were also
reported. A biopsy for *H. pylori* was positive, as was the baseline
serology. The patient was **discontinued from the study** and treated
with acid suppression. This event was classified as: **gastric ulcer; GI
bleed (traditional, 1B; alternate, none).**

**Case 1060**

**Patient US0253-035-20258** was a 58-year-old male with a history of
hypertension, hiatal hernia, gastroesophageal reflux disease, UGI
bleeding, vasectomy, carpal tunnel release of left wrist, anemia, and
RA. Concomitant medications included lisinopril and ferrous sulfate. The
patient was enrolled in protocol N49-98-02-035 and randomized to
**ibuprofen 800 mg TID.**

After 92 days of treatment, at the scheduled week 13 visit, the patient
was found to have a hemoglobin of 12.2 g/dL compared with a baseline of
14.5 g/dL and a hematocrit of 39.0% compared with a baseline of 45.0%.
On study day 94 a stool sample was found to be hemoccult-positive and a
repeat hematocrit was 34.0%. **Study medication was discontinued on day
100**. A UGI endoscopy was performed on study day 101 revealing a hiatal
hernia, ulcerative esophagitis, severe erosive gastritis with multiple
deep linear erosions in the upper body of the stomach, minor antral
petechiae and edema, and scant coffee ground material. The erosions were
further characterized as 1.0 to 2.0 cm in length with a depth of 0.1 to
0.2 cm. A CLOtest was negative for *H. pylori* as was a baseline
serology. This event was classified as: **gastric erosion; GI bleed
(traditional, 1D1; alternate, 1H).**

**Case 1073**

**Patient US0066-035-13004** was a 70-year-old male with a history of
mild hypertension, hypercholesterolemia, mild benign prostatic
hyperplasia, GI-related NSAID intolerance, and OA. Concomitant
medications included aspirin, atorvastatin, niacin, vitamin E and C,
glucosamine, and chondroitin. The patient was enrolled in protocol
N49-98-02-035 and randomized to **celecoxib 400 mg BID**.

After 65 days of treatment the patient reported having a formed black
stool. Formed black stool recurred on study day 66 and the patient
presented to the clinic. **Study medication was discontinued at this
time.** Significant findings at this time included hemoccult-positive
stool and a hemoglobin of 15.2 g/dL compared with a baseline of15.8 g/dL
and a hematocrit of 44.0%, compared with a baseline of 47.0%. The
patient was admitted to the hospital and a follow-up hemoglobin done at
midnight of study day 66 was 13.3 g/dL with a hematocrit of 39.3%. A UGI
endoscopy was performed on study day 66 revealing two 0.5-cm stellate,
clean-based ulcers on the angularis, a 1.3-cm antral ulcer oozing bright
red blood, and a normal duodenum. Hemostasis was achieved using both
epinephrine injection and bicap cautery. A CLOtest was positive for *H.
pylori,* as was the baseline serology. The patient was treated with acid
suppression and discontinued from the study. This event was classified
as: **gastric ulcer; GI bleed (traditional, 1B; alternate, 1F).**

**Case 1075**

**Patient US0585-102-11251** was a 79-year-old female with a history of
peripheral vascular atherosclerotic disease with claudication,
hypercholesterolemia, bradycardia, ulcers, and OA. Concomitant
medications included atrovastin, cimetidine, aspirin, and
hydrochlorothiazide with triamterene. The patient was enrolled in
protocol N49-98-02-102 and randomized to **celecoxib 400 mg BID**.

After 34 days of treatment the patient began experiencing epigastric
pain. On day 36 the pain became more severe and the patient took
cimetidine. On study day 37 the patient went to the emergency room after
experiencing two episodes of tarry black stool and coffee ground emesis.
**Study medication was discontinued at this time**. She also reported
orthostatic symptoms at this time. A nasogastric lavage produced 600 mL
of coffee ground material and fresh blood. Significant laboratory
findings at this time included hemoccult-positive stool and a hematocrit
of 34.9% compared with a baseline hematocrit of 45.0%. The patient was
admitted to the hospital and an UGI endoscopy was performed revealing a
0.8 x 1.0-cm pyloric channel ulcer with a pulsatile, actively bleeding
visible vessel in its base. Additional ulcers were seen in the pyloric
channel and duodenal bulb as well. Hemostasis was achieved using
epinephrine injection and monopolar electrocautery. Biospy for *H.
pylori* was positive, as was the baseline serology. Ultimately, the
patient received 4 units of packed red blood cells and was treated with
acid suppression. She was **discontinued from the study**. This event
was classified as: **gastric ulcer; GI bleed; duodenal ulcer
(traditional, 1B; alternate, 1F).**

**Case 1078**

**Patient US0387-102-10181** was a 60-year-old male with a history of
left lower leg reconstruction with left total knee replacement, left leg
reconstruction with metal plate insertion, and OA. Concomitant
medications included aspirin, darvocet, calcium, and multiple vitamins.
The patient was enrolled in protocol N49-98-02-102 and randomized to
**celecoxib 400 mg BID.**

After 107 days of treatment the patient began experiencing dyspnea on
exertion, diaphoresis, hematochezia, and melena. **Study medication was
discontinued** on day 108. On study day 113 the patient presented to the
clinic and was admitted to the hospital. Significant findings at this
time included a hematocrit of 25.3% compared with a baseline hematocrit
of 38.0%. The patient received 2 units of packed red blood cells. Upper
GI endoscopy performed the next day, study day 114, revealed a deep
linear ulcer in the prepyloric antrum with surrounding edema. There was
also a deep, round duodenal bulb ulcer 1.0 cm in diameter. Both ulcers
had an exudative base without stigmata of recent bleeding. A CLOtest was
negative for *H. pylori,* as was the baseline serology. The patient was
treated with acid suppression. This event was classified as: **gastric
ulcer, duodenal ulcer; GI bleed (traditional, 1C; alternate, 1G).**

**Case 1084**

**Patient US0052-102-10549** was an 84-year-old female with a history of
dry eyes secondary to Sjogren's syndrome, appendectomy, flatulence,
irritable bowel syndrome, lysis of intestinal adhesions, incontinence,
hysterectomy, chronic urinary tract infections, osteoporosis, left
shoulder tendonitis, right hip replacement, bilateral hammertoe repair,
hair loss, and OA. Concomitant medications included conjugated
estrogens, multivitamins, calcium carbonate, loperamide, and aspirin.
The patient was enrolled in Study N49-98-02-102 and randomized to
**diclofenac 75 mg BID.**

After 93 days of treatment the patient was seen in the clinic for a
scheduled week 13 visit and found to have a hemoglobin of 9.6 g/dL
compared with a baseline of 11.9 g/dL and a hematocrit of 28.0% compared
with a baseline of 37.0%. On study day 97 a stool sample was found to be
hemoccult-positive. **Study medication was discontinued at this time.**
On study day 98 a UGI endoscopy was performed revealing four very
shallow erosions in the prepyloric antrum and a 1.0-cm shallow to
moderately deep ulcer in the distal duodenal bulb. The ulcer had a clean
base but a small amount of blood was noted to ooze from the periphery of
the lesion. A biopsy for *H. pylori* was negative despite a positive
baseline serology. The patient was treated with acid suppression and
**discontinued from the study.** This event was classified as:
**duodenal ulcer; GI bleed (traditional, 1B;**

**alternate, 1F).**

#### Case 1085

**Patient US0110-035-11139** was a 67-year-old male with a history of
Meniere's disease, hyperlipidemia, chronic obstructive pulmonary
disease, cerebrovascular accident, asthma, anserine bursitis of right
knee, central laminectomy, type II diabetes mellitus, thoracic outlet
syndrome, rib resection, right knee arthroscopy, right tennis elbow,
seasonal and environmental allergies, allergy to penicillin, and OA.
Concomitant medications included pravastatin, meclizine, metformin,
Asthmacort, albuterol, aspirin, methylprednisolone, and loratadine. The
patient was enrolled in protocol N49-98-02-035 and randomized to
**ibuprofen 800 mg TID**.

After 168 days of treatment the patient called the principal
investigator because he was feeling weak and dizzy. He also reported
black stools and leg cramps. Because the patient felt too sick to see
the investigator, he presented to the emergency room. The patient
repeated his concerns about orthostatic symptoms and reported persistent
melena.

Significant findings at this time included pallor, tachycardia with a
heart rate of approximately 130 to 140 bpm, and black,
hemoccult-positive stool. A nasogastric lavage produced "coffee ground"
material. A hemoglobin was 13.0 g/dL compared with a baseline 15.3 g/dL
and a hematocrit was 40.1% compared with a baseline of 45.0%. The
patient was admitted to the hospital and a UGI endoscopy performed that
evening revealed old blood but no active bleeding, a linear distal
esophageal ulcer, a group of shallow antral ulcers, and a pyloric
channel ulcer with a visible vessel. The visible vessel was cauterized
with a heater probe. No *H. pylori* testing was done, but the baseline
serology had been positive for *H. pylor*i. **Study medication was
discontinued** and the patient was treated with acid suppression. This
event was classified as: **gastric ulcer; GI bleed (traditional, 1B;
alternate, 1F).**

**Case 1113**

**Patient US0112-035-10235** was an 84-year-old female with a history of
coronary artery bypass graft secondary to coronary artery disease,
hypertension, benign heart murmur, hiatal hernia, colon resection
secondary to infection, hysterectomy, osteoporosis, left knee
replacement, psoriasis, and OA. Concomitant medications included
alendronate sodium, diltiazem hydrochloride, aspirin, furosemide,
vitamin B12, vitamin D, fluvastatin sodium, isoxsuprine hydrochloride,
calcium carbonate, and potassium chloride. The patient was enrolled in
protocol N49-98-02-035 and randomized to **celecoxib 400 mg BID.**

After 209 days of treatment the patient developed nausea, anorexia, and
right upper quadrant pain. On study day 210 the patient presented to her
primary care physician and a work-up including an abdominal ultrasound
and abdominal CT was performed. The ultrasound revealed a small amount
of fluid in Morrison's pouch and the CT revealed a prominent gallbladder
with pericholecystic fluid. An x-ray revealed free air in the right
upper quadrant and an exploratory laparotomy revealed a perforated
pyloric channel ulcer. A Graham closure was performed and the patient
recovered without incident. The baseline serology had been negative for
*H. pylor*i. **Study medication was discontinued** on day 211. This
event was classified as: **gastric ulcer; perforation (traditional, 2;
alternate, 2).**

**Case 1122**

**Patient US0448-035-11767** was a 68-year-old female with a history of
bilateral cataract removal with lens implants, heartburn, back and neck
pain, arthroscopic right knee surgery, psoriasis, sun sensitivity, and
OA. Concomitant medications included conjugated estrogen,
medroxyprogesterone acetate, carisoprodol, calcium, vitamins, Pain Free
herbal supplement, acetaminophen, and l-lysine. The patient was enrolled
in protocol N49-98-02-035 and randomized to **ibuprofen 800 mg TID**.

After 123 days of treatment the patient began experiencing abdominal
pain. She reported that on study day 124 she vomited for 5 hours but
obtained some relief from Mylanta. On study day 126 the patient
presented to her physician and was found to be hemoccult-positive.
**Study medication was discontinued** at this time. A hemoglobin at this
time was 11.3 g/dL compared with a baseline of 12.3 g/dL and a
hematocrit was 33.7% compared to a baseline of 37.0%. On study day 129
the patient underwent UGI endoscopy revealing four posterior wall antral
ulcers, the largest of which was 0.8 cm x 1.0 cm, three proximal antral
ulcers between 0.3 cm and 0.6 cm located along the lesser curvature, a
0.2 x 1.5-cm greater curvature erosion, multiple punctate erosions, a
0.6-cm to 0.7-cm pyloric channel ulcer, and a normal duodenum to the
third portion. The endoscopist felt that there was no evidence of outlet
obstruction but that the pyloric channel ulcer may have contributed to a
partial outlet obstruction. Biopsy for *H. pylori* was negative, as was
the baseline serology. This event was classified as: **gastric ulcer; GI
bleed (traditional, 1D1; alternate, none).**

**Case 1132**

**Patient US0371-035-12217** was a 78-year-old female with a history of
cataract removal with lens implant, memory loss, internal hemorrhoids,
colo-vesicular fistula, gastroesophageal reflux, appendectomy, coronary
artery disease, angina pectoris, family history of colon carcinoma,
sigmoid resection for chronic diverticulitis, hiatal hernia, urinary
incontinence, degenerative joint disease, right inguinal hernia repair,
fibrocystic breast disease, obesity, allergy to eggs, and OA.
Concomitant medications included Centrum vitamins. The patient was
enrolled in protocol N49-98-02-035 and randomized to **ibuprofen 800 mg
TID.**

After 25 days of treatment the patient began experiencing epigastric
pain and reflux. She was found to have a hemoglobin of 10.2 g/dL
compared with a baseline of 12.3 g/dL and a hematocrit of 30.0% compared
with a baseline of 36.0%. Stool hemoccults were negative and on study
day 30 a UGI series revealed a large hiatal hernia with reflux. The
patient remained in the study and on study day 81 she had a colonoscopy
revealing hemorrhoids, an anastomotic stricture and diverticulosis. On a
routine study visit on study day 92 the patient was found to have a
persistently low hemoglobin of 9.7 g/dL with a hematocrit of 31.0% and
on study day 99 the stool was hemoccult-positive for the first time.
**Study medication was discontinued** on day 141 and on study day 149 a
UGI endoscopy revealed a hiatal hernia and a 0.3 to 0.4-cm gastric ulcer
in the proximal body with associated black spot or blood clot. Biopsy
for *H. pylori* was positive, as was the baseline serology. The patient
was treated with antibiotics and acid suppression. This event was
classified as: **gastric ulcer; GI bleed (traditional, 1B; alternate,
1F).**

**Case 1133**

**Patient US0182-102-11142** was a 66-year-old female with a history of
angina, heart attack, hypertension, constipation, hemorrhoid,
hysterectomy, osteoporosis, total right and left hip arthroplasty,
redone total left hip arthroplasty, and OA. Concomitant medications
included lisinopril, diltiazem hydrochloride, conjugated estrogens,
vitamin supplement, Vitamin C, Vitamin E, and docusate sodium. The
patient was enrolled in protocol N49-98-02-102 and randomized to
**celecoxib 400 mg BID.**

After 96 days of treatment the patient returned for a scheduled visit
and was found to have a hemoglobin of 11.3 g/dL compared with a baseline
of 14.0 g/dL and a hematocrit of 35.0% compared with a baseline of
41.0%. Follow-up stool hemoccults were found to be positive on study
days 106, 108, and 118. **Study medication was discontinued** on day
127. Upper GI endoscopy was performed on study day 131, revealing three
non-bleeding superficial antral ulcers with distinct depth. The largest
lesion had a diameter of 0.6 cm in its longest axis. A biopsy for *H.
pylori* was negative, as was the baseline serology. The patient was
**discontinued from the study** and treated with acid suppression. This
event was classified as: **gastric ulcer; GI bleed (traditional, 1D1;
alternate, 1H).**

**Case 1145**

**Patient US0448-035-11011** was an 81-year-old female with a history of
cataract removal, hypercholesterolemia, duodenal ulcer disease (1976),
heartburn, nocturia, postmenopausal hormone replacement therapy,
occasional constipation, chronic low back pain, osteoporosis, sciatica,
and OA. Concomitant medications included glucosamine,

conjugated estrogens, medroxyprogesterone acetate, unspecified
multivitamins, calcium, vitamins B, C, and E, iron, and acetaminophen.
The patient was enrolled in protocol N49-98-02-035 and randomized to
**ibuprofen 800 mg TID.**

After approximately 124 days of treatment the patient began experiencing
sporadic epigastric pain and heartburn. On study day 158 the patient was
found to have a hemoglobin of 11.1 g/dL compared with a baseline of 14.1
g/dL and a hematocrit of 34.0% compared with a baseline of 44.0%.
Follow-up hemoglobin and hematocrit on study day 183 were again low at
11.1 g/dL and 33.0%, respectively. Stools were hemoccult-negative at
this time. **Study medication was discontinued** on day 189. On study
day 196 the patient underwent UGI endoscopy and colonoscopy. The
colonoscopy revealed a 1.0-cm sessile sigmoid polyp and the endoscopy
was remarkable for a hiatal hernia and esophageal erosions, an edematous
pyloric channel, and a 1.5 x 2.0-cm duodenal bulb ulcer with a "dirty"
necrotic base. The area around the ulcer was described as friable and
bled with minimal manipulation. Because of surrounding edema and
friability, the endoscope could not be passed into the descending
duodenum. Biopsy for *H. pylori* was negative, as was the baseline
serology. This event was classified as: **duodenal ulcer; GI bleed
(traditional, 1B; alternate, 1F).**

**Case 1146**

**Patient US0595-102-12252** was an 84-year-old male with a history of
heart murmur, macular degeneration, ankle edema, left total knee surgery
(twice), left carpal tunnel release, left lower leg cramps, right thumb
lock, angina with exertion, bilateral cataract surgery, vitrectomy,
scleral buckle, chronic obstructive pulmonary disease, gallstones,

coronary artery disease, atrial fibrillation (nonrecurrent since 1993),
arteriosclerotic cardiovascular disease, benign prostatic hypertrophy,
polymyalgia rheumatica (nonrecurrent since 1989), aortic sclerosis,
degenerative disc disease, partial tear of the right rotator cuff, and
OA. Concomitant medications included diltiazem hydrochloride,
bumetanide, aspirin, ocuflox, and Pred Forte. The patient was enrolled
in protocol N49-98-02-102 and randomized to **diclofenac 75 mg BID.**

After 11 days of treatment the patient began experiencing heartburn and
chest pain that was relieved with antacids. Later that day he developed
severe epigastric burning and tightness with radiation to the chest.
After medicating himself with three aspirin, one Prilosec, four
nitroglycerin and an unknown medication and experiencing no relief, he
presented to the hospital and was admitted. **Study medication was
discontinued** at this time. Significant findings at this time included
hemoccult-positive stool and a hemoglobin of 11.3 g/dL compared with a
baseline of 13.2 g/dL and a hematocrit of 33.0% compared with a baseline
of 38.0%. Additionally, a troponin level was 1.2 ng/mL. Myocardial
infarction was ruled out and on study day 15 a UGI endoscopy revealed
two to three small nonbleeding gastric antral ulcers and antral
gastritis. A biopsy for *H. pylori* was negative, as was the baseline
serology. On study day 18 the patient underwent a cardiac
catheterization that demonstrated triple vessel disease. The patient
elected medical management of his cardiovascular disease and was treated
with acid suppression for his ulcer disease. This event was classified
as: **gastric ulcer; GI bleed (traditional, 1D1 alternate, none).**

**Case 1148**

**Patient US0279-102-12965** was a 78-year-old male with a history of
dizziness, cerebrovascular accident, hypertension, atrial fibrillation,
cardiovascular disease, cardiac dysrhythmia, congestive heart failure,
tobacco use, diverticulosis, hyperacidity, benign prostatic hypertrophy,
rotator cuff sprain, lumbago, non-insulin-dependent diabetes mellitus,
obesity, constipation, total right hip replacement (twice), and OA.
Concomitant medications included aspirin, sublingual nitroglycerin,
topical nitroglycerin, docusate sodium, albuterol, glyburide,
levofloxacin, quinidine, terazosin, furosemide, lisinopril, metoprolol,
and ipratropium. The patient was enrolled in protocol N49-98-02-102 and
randomized to **diclofenac 75 mg BID.**

After 82 days of treatment the patient was hospitalized for dyspnea. A
cardiac work-up was initiated and ultimately led to a cardiac
catheterization and subsequent coronary artery bypass grafting on study
day 92. **Study medication was discontinued on day 91**. Upon admission
to the hospital on study day 82, the patient was found to have
hemoglobin of 13.2 g/dL compared with a baseline of 15.1 g/dL and a
hematocrit of 38.4% compared to a baseline of 46.0%, although a **GI
work-up was not performed**. The patient was discharged from the
hospital on study day 99 after an uneventful postoperative recovery. On
study day 102, however, the patient was readmitted to the hospital after
he presented to the emergency room with recurrent dyspnea and chest
pain. He was transferred to another hospital and subsequently developed
hypotension and melena and was placed in the intensive care unit. Upper
GI endoscopy revealed a large amount of blood in the fundus and a 1.0 x
2.0-cm duodenal bulb ulcer with an adherent clot. No active bleeding was
noted. The patient received 6 units of packed red blood cells as the
hemoglobin and hematocrit had fallen to 8.0 g/dL and 23.0% by midnight
of study day 102. At approximately this time the patient developed
hematemesis and underwent a second endoscopy. On this examination
pulsatile bleeding was noted from the duodenal ulcer. Heater probe
cautery and injection sclerotherapy was unsuccessful and the patient
required emergency surgery consisting of vessel ligation and vagotomy.
He received an additional 3 units of packed red blood cells and
ultimately stabilized and was discharged from the hospital. Biopsy for
*H. pylori* was negative, despite a positive baseline serology.
Medications included his cardiac regimen as well as acid suppression.
This event was classified as: **duodenal ulcer: GI bleed (traditional,
1B; alternate, 1F).**

#### Case 1149

**Patient US0134-035-20749** was a 60-year-old male with a history of
ventral hernia repair and RA. Concomitant medications included
methotrexate, hydrocodone, Cosamin DS, and acetaminophen. The patient
was enrolled in protocol N49-98-02-035 and randomized to **ibuprofen 800
mg TID.**

After 31 days of treatment the patient was asymptomatic but noted to
have a hemoglobin of 11.2 g/dL compared with a baseline of 12.3 g/dL and
a hematocrit of 34.0% compared with a baseline of 39.0%. On study day
43, the patient was still asymptomatic but found to have a hemoglobin
and hematocrit of 9.6 g/dL and 29.0%, respectively. Study **medication
was discontinued** at this time and on study day 46 the patient was
found to have a hemoccult-positive stool. Upper GI endoscopy was
performed on study day 47 revealing greater than 25 gastric petechiae
and 7 gastric erosions 0.2 to 0.3 cm in diameter predominantly located
in the pre-pyloric antrum. The pylorus was also noted to be edematous
and the duodenal bulb was remarkable for petechiae and edema. Baseline
serology for *H. pylori* had been positive. This event was classified
as: **gastric erosions; GI bleed (traditional, 1D1; alternate, 1H).**

**Case 1186**

**Patient US0421-035-10266** was a 74-year-old male with a history of
atrial arrhythmia, hypertension, nocturia, benign prostatic hypertrophy,
appendectomy, and OA. Concomitant medications included verelan and "baby
aspirin." The patient was enrolled in protocol N49-98-02-035 and
randomized to **celecoxib 400 mg BID.**

After 292 days of treatment the patient passed two black stools followed
by profuse red diarrhea. The patient also described one episode of
hematemesis. Because of these symptoms and a feeling of weakness, the
patient presented to the emergency room. **Study medication was
discontinued**, and significant findings at this time included
orthostatic symptoms, resting tachycardia to 110 bpm, hemoccult-positive
stools, and a hemoglobin of 11.3 g/dL compared with a baseline of 14.4
g/dL and a hematocrit of 32.4% compared with a baseline of 42.0%. The
patient was hydrated and admitted to the intensive care unit. Shortly
thereafter, he had recurrent hematemesis of fresh blood and clots.
Emergent UGI endoscopy revealed a 1.0-cm prepyloric ulcer with two
visible vessels. The ulcer base and vessels were injected with
epinephrine with apparently adequate hemostatic effect. The patient
ultimately received 2 units of packed red blood cells and was discharged
from the hospital on study day 295 with a hemoglobin and hematocrit of
8.7 g/dL and 25.6%. Biopsy for *H. pylori* was positive, as was the
baseline serology. This event was classified as: **gastric ulcer; GI
bleed (traditional, 1B; alternate, 1F).**

**Case 1189**

**Patient US0147-102-11341** was an 84-year-old female with a history of
sinusitis, epistaxis, cataract, depression, atrial fibrillation,
coronary artery disease, abdominal aortic aneurysm, angioplasty, asthma,
cholecystectomy, bilateral inguinal hernia repair, constipation, anal
incontinence, hiatal hernia, sigmoid diverticulitis, pyloric channel
gastritis, duodenitis, hysterectomy, urinary incontinence, uterine
prolapse, left renal cyst mass, osteoporosis, vertebral compression
fracture, rib fracture, incisional hernia repair, lichen planus of the
lip, mouth ulcers, hypertriglyceridemia, and OA. Concomitant medications
included valsartan, calcium, felodipine, hydrocodone, nitroglycerine,
and aspirin. The patient was enrolled in protocol N49-98-02-102 and
randomized to **celecoxib 400 mg BID.**

After 150 days of treatment the patient began experiencing intermittent
nausea, vomiting, and abdominal pain. On study day 163, because of
progression of these symptoms, the patient presented to the emergency
room. Significant findings at this time included a blood pressure of
78/46 mm Hg and a hemoglobin of 11.7 g/dL compared with a baseline of
12.5 g/dL and a hematocrit of 35.3% compared with a baseline of 39.0%.
After a prolonged emergency room stay and intravenous hydration, the
patient was discharged. **Study medication was discontinued on day
171.** The patient continued to have abdominal pain and intermittent
nausea and vomiting. On study day 178 she was found to have a hemoglobin
of 9.4 g/dL and a hematocrit of 29.0%. On day 179 she was treated in the
emergency room for severe constipation. On study day 183 the patient
underwent an UGI endoscopy revealing presbyesophagus with a mild
stricture and ulceration at the gastroesophageal junction, and a 6.0 to
8.0-cm hiatal hernia. There were also five smaller gastric ulcers in the
body of the stomach and a 3.0-cm ulcer on the lesser curvature with
hemosiderin type lesions in the base, and two to five gastric erosions.
Biopsies of the large lesion were negative for malignancy and biopsies
were negative for *H. pylor*i, as was the baseline serology. The patient
was treated with acid suppression and **discontinued from the study**.
This event was classified as: **gastric ulcer; GI bleed**

**(traditional, 1B; alternate, 1F).**

**Case 1201 (Censored)**

**Patient US0039-035-21235** was a 74-year-old female with a history of
seasonal allergies, spinal stenosis, peripheral neuropathy, dependent
edema, left carpal tunnel surgery, first degree atrioventricular block,
chronic bronchitis, right kidney surgery, left medial malleolus skin
ulcer, gastroesophageal reflux disease, hemorrhoidal bleeding, asthma,

hypertension, diverticulosis, cholelithiasis, oral carcinoma, rhinitis,
tonsillectomy, appendectomy, hemorrhoidectomy, hysterectomy, benign
breast cysts, sinus surgery, left eye cataract, anemia, and RA.
Concomitant medications included prednisone, conjugated estrogens, "baby
aspirin," lisinopril, pentoxyfylline, Tylox, famotodine, ipatropium,
aurothioglucose, nedocromil sodium, fish oil, calcium carbonate, and
fexofenadine. The patient was enrolled in protocol N49-98-02-035 and
randomized to **celecoxib 400 mg BID.** Study medication was
discontinued on day 29 because the patient began taking high-dose
prednisone (day 23) for vasculitic toe lesions.

On approximately study day 42, the patient began experiencing weakness,
polyuria, and fatigue. On day 48 she presented to the emergency room
with significant findings included hyperglycemia, anemia, and
hemoccult-positive stool. Specifically, her blood glucose was 317 g/dL
and her hemoglobin was 9.8 g/dL compared with a baseline of 10.6 g/dL
and a hematocrit was 31.8% compared with a baseline of 36.0%. She was
admitted to the hospital and a UGI endoscopy performed on day 52
revealed a 1.0 x 1.0-cm "punched-out" appearing ulcer with edematous
margins located on the posterior wall of the antrum. Biopsies were
negative for *H. pylori,* as was the baseline serology. Her hemoglobin
fell to a low of 8.9 g/dL and her hematocrit fell to 27.7% but she was
not transfused. The patient was treated with acid suppression and
discharged. This event was classified as: **gastric ulcer; GI bleed
(traditional, 1D1; alternate, none).**

**Case 1206**

**Patient US0518-102-20349** was a 69-year-old male with a history of
ear surgery, recurrent headaches, hypertension, diverticulosis,
cholecystectomy, duodenal polyp, GI NSAID intolerance, strained back,
adult-onset diabetes, thrombocytopenia with transfusion, and RA.
Concomitant medications included prednisone, penicillamine, nifedipine,
and folic acid. The patient was enrolled in protocol N49-98-02-102 and
randomized to **celecoxib 400 mg BID**.

After 199 days of treatment the patient began experiencing loose melenic
stools and left-sided abdominal pain. On study day 200 the patient was
admitted to the hospital. **Study medication was discontinued**, and
significant findings at this time included melena and a hemoglobin of
14.6 g/dL compared with a baseline of 15.8 g/dL and a hematocrit of
44.0% compared with a baseline of 46.0%. On study day 202 the hemoglobin
and hematocrit had fallen to 12.5 g/dL and 35.5%, respectively. The
patient underwent both upper endoscopy and colonoscopy. The upper
endoscopy revealed a 1.5-cm ulcer on the posterior wall of the duodenal
bulb without stigmata of recent bleeding. A CLOtest was negative for *H.
pylori* despite positive baseline serology. The colonoscopy revealed
marked sigmoid diverticulosis. The patient was **discontinued from the
study** and treated with acid suppression. This event was classified as:
**duodenal ulcer; GI bleed (traditional, 1C; alternate, 1G).**

**Case 1242**

**Patient US0304-102-12176** was a 76-year-old female with a history of
eye infection, fluid behind the eyes, myocardial infarction,
arteriosclerotic heart disease, peripheral vascular disease, congestive
heart disease, hyperlipidemia, diverticulitis, sigmoid colectomy, peptic
ulcer disease, colon polyps, colorectal anastomosis, chronic low back
pain, lumbar stenosis, lumbosacral spine fusion, onychomycosis,
non-insulin-dependent diabetes mellitus, GI-related NSAID intolerance,
and OA. Concomitant medications included chlorpropamide, lisinopril,
potassium chloride, furosemide, "baby aspirin," multivitamins, and
propoxyphene hydrochloride. The patient was enrolled in protocol
N49-98-02-102 and randomized to **celecoxib 400 mg BID.**

After 139 days of treatment the patient began experiencing heartburn,
epigastric pain, diarrhea, and dark stools. The patient interrupted
study medication on days 143 through 145. On study day 145, the patient
was examined in the office and diagnosed with viral gastroenteritis.
Significant findings at this time were limited to a 28 mm Hg orthostatic
change in systolic blood pressure. On day 153, the patient was again
evaluated for persistent diarrhea and several episodes of emesis. On day
159 the patient was admitted to the hospital for persistent epigastric
pain, nausea, and vomiting. Work-up on the day of admission included an
ultrasound of the gallbladder with normal results. A hemoglobin at this
time was 12.1 g/dL compared with a baseline of 15.2 g/dL and a
hematocrit was 35.6% compared with a baseline of 43.0%. Stools remained
hemoccult-negative.

An endoscopy performed on study day 161 revealed an enlarged stomach,
abnormal duodenal mucosa, and a stricture of the duodenum just beyond
the bulb. The stricture did not allow passage of the endoscope into the
distal duodenum. Duodenal biopsies of the strictured area revealed mild
acute duodenitis with slight villous blunting. Following the endoscopy,
on the same day, the patient underwent a UGI series that revealed a
slight narrowing of the second portion of the duodenum possibly
representing a nonobstructive stricture. Additional work-up included a
negative stool culture for *Clostridium difficil*e. Biopsy for *H.
pylori* was negative, as was the baseline serology. Treatment medication
included Unasyn, meperidine hydrochloride, promethazine hydrochloride,
and famotidine. **Study medication was discontinued at the time of
hospital admission on day 159.** The patient was discharged from the
hospital on study day 162 with a diagnosis of "duodenal stricture -
probably peptic." At a follow up visit on day 177, the patient offered
no GI complaints and was placed on **rofecoxib 25 mg QD**. At an office
visit on day 191 the patient reported having intermittent diarrhea. A
follow-up endoscopy was performed on day 264 demonstrating a
significantly improved duodenal stricture. The scope was able to pass
and there was no evidence of mucosal abnormality other than some
structural distortion consistent with prior duodenal ulcer disease. It
was the endoscopist's impression that the stricture had been caused by
an ulcer. This event was classified as: **gastric outlet obstruction
(traditional, 3; alternate, 3).**

**Case 1245 (Censored)**

**Patient US0328-102-11895** was a 75-year-old male with a history of
angioplasty, hypertension, cardiovascular disease, prostate biopsy,
removal of skin lesions, hyperlipidemia, transient ischemic attacks,
inguinal herniorrhaphy, ear surgery, peptic ulcer disease (in his 20s),
colon polyps, and OA. Concomitant medications included atenolol,
aspirin, nitroglycerin, vitamin C, and Maxzide. The patient was enrolled
in protocol N49-98-02-102 and randomized to **celecoxib 400 mg BID**.

After 199 days of treatment the patient began experiencing severe left
knee pain and was hospitalized for septic arthritis. **Study drug was
discontinued at this time**. On study day 200 the patient underwent
incision and drainage of the left knee and received one dose of
**ketorolac 30 mg intravenously**. Additionally, **celecoxib 200 mg QD
was apparently administered beginning on study day 205.** On study day
207 the patient experienced slight epigastric pain, witnessed melena,
and a decreased hematocrit. Specifically, the hemoglobin was 10.0 g/dL
compared with a baseline of 16.1 g/dL and a hematocrit was 29.3%
compared with a baseline of 45.0%. At this time the patient related
having dark stools for weeks prior to this event but was not able to
determine the date they began. On the same day (study day 207) the
patient underwent UGI endoscopy revealing four antral ulcers with
exudative bases. These ulcers appeared chronic and measured 0.3 to 0.5
cm with pliable margins and stigmata of recent bleeding. Biopsies of the
margins revealed chronic gastritis and no evidence of *H. pylori*
despite a positive baseline serology. The patient ultimately received a
total of 2 units of packed red blood cells and was discharged from the
hospital. This event was classified as: **gastric ulcer; GI bleed
(traditional, 1C; alternate, 1G).**

**Case 1246**

**Patient US0125-102-10012** was a 71-year-old female with a history of
right eye cataract, insomnia, hypertension, hiatal hernia, hemorrhoids,
endometriosis, left total knee replacement, dislocated right shoulder,
hypercholesterolemia, and OA. Concomitant medications included aspirin,
fluvastatin, furosemide, multivitamins, and calcium carbonate. The
patient was enrolled in protocol N49-98-02-102 and randomized to
celecoxib 400 mg BID.

After 276 days of treatment the patient was asymptomatic but was found
to have a decreased hemoglobin and hematocrit. Specifically, the
hemoglobin was 10.7 g/dL compared with a baseline of 13.8 g/dL and the
hematocrit was 36.0% compared with a baseline of 43.0%. The ensuing
work-up revealed hemocult-positive stools on study days 283, 284, 285
and, 286. **Study medication was discontinued on day 295**. Upper GI
endoscopy on study day 297 revealed a linear ulcer in the distal
esophagus, esophageal erosions, a hiatal hernia, and a 0.5 x 2.0 to
3.0-cm linear antral ulcer on the lesser curvature. The antral ulcer was
described as having some depth and slightly raised margins. A CLOtest
for *H. pylori* was negative, as was the baseline serology. The patient
was **withdrawn from the study**, treated with acid suppression, and
scheduled for a follow-up endoscopy to document healing. This event was
classified as: **gastric ulcer; GI bleed (traditional, 1D1; alternate,
1H).**

**Case 1294**

**Patient US0531-102-11559** was an 80-year-old male with a history of
tonsillectomy, constipation, insomnia, diabetes, hypertension, and OA.
Concomitant medications included aspirin, tolbutamide, fosinopril,
glucosamine sulfate, Metamucil, and Tylenol PM. The patient was enrolled
in protocol N49-98-02-102 and randomized to **diclofenac 75 mg BID.**

After approximately 253 days of treatment the patient began experiencing
intermittent abdominal bloating and flatulence. **Study medication was
discontinued on day 259**. On study day 261 the patient experienced pain
in the lower abdomen with radiation to the right shoulder, orthostatic
symptoms, and fatigue. He also reported having a dark stool. On study
day 263 the patient passed another dark stool and reported nausea
without emesis. At this point the patient was hospitalized for further
work-up. On admission the patient was found to have slight lower
abdominal tenderness and hemoccult-positive dark brown stool. Laboratory
findings revealed hemoglobin of 7.7 g/dL compared with a baseline of
10.9 and a hematocrit of 25.3% compared with a baseline of 35.0%. A
nasogastric lavage performed in the emergency room was negative for
blood. On study day 264 the patient received 2 units of packed red blood
cells. On day 268 the patient underwent an endoscopy revealing grade III
erosive esophagitis, evidence of chronic gastritis, and a single 1.0-cm
duodenal bulb ulcer without stigmata of recent hemorrhage. A biopsy
specimen was negative for *H. pylori* by CLOtest and histology despite a
positive baseline serology. The patient was treated with acid
suppression and **discontinued from the study**. This event was
classified as: **duodenal ulcer; GI bleed (traditional, 1D1; alternate,
1H).**

**Case 1297 (Censored)**

**Patient US0591-102-10168** was a 71-year-old male with a history of
atrial fibrillation, bilateral inguinal hernia repair, bilateral repair
of shoulder joints, removal of multiple basal cell carcinoma lesions,
bilateral total knee replacements, and OA. Concomitant medications
included lidocaine, propoxyphene hydrochloride, glucosamine,
chondroitin, warfarin sodium, atenolol, triamcinolone, multivitamins,
antioxidant, methylsulfanylmethane, and low-dose aspirin (initiated on
study day 253). The patient was enrolled in protocol N49-98-02-102 and
randomized to **diclofenac 75 mg BID.**

After 277 days of treatment the patient began experiencing severe
abdominal pain and was hospitalized with an acute abdomen. Of note, the
patient had previously been hospitalized on study day 265 for elective
bilateral total knee replacement and **study drug had been discontinued
on study day 242**. On study day 278 the patient underwent an
exploratory laparotomy revealing a perforated ulcer. The ulcer was noted
to be 2.0 cm in diameter and located on the anterior surface of the
prepyloric region. Also noted was an abscess in the right upper quadrant
and a large amount of dark fluid within the colon that was felt to be
old blood. Surgical repair of the lesion and appropriate drainage was
performed. Significant laboratory findings at this time included a
hemoglobin of 7.1 g/dL compared with a baseline of 13.4 g/dL and a
hematocrit of 20.5% compared with a baseline hematocrit of 41.0%. The
patient received 2 units of packed red blood cells on study days 278 and
280. On day 284 the patient had a witnessed black diarrheal stool that
was found to be hemoccult-positive. Colonoscopy performed on study day
286 revealed multiple diverticuli in the sigmoid colon and a poor
preparation in the right colon. No bleeding was identified on this
examination. Baseline serology for *H. pylori* had been positive. This
event was classified as: **gastric ulcer; perforation (traditional, 2;
alternate, 2).**

**Case 1343**

**Patient US0514-102-12391** was a 61-year-old female with a history of
nasal fracture, tonsillectomy, depression, hypercholesterolemia,
seasonal allergies, dyspnea, cholecystectomy, occasional heartburn,
hiatal hernia, esophageal sphincter stenosis surgery, gastric ulcer
oversew, surgical removal of gastric scar tissue, duodenal ulcer,
bulimia, diverticulosis (inactive), appendectomy, hysterectomy,
fibrocystic breast disease, fractured pelvis, back pain, thin dry skin
on arms, lipoma removal, chronic anemia, and OA. Concomitant medications
included vitamin B12, trazodone hydrochloride, bupropion, diazepam,
conjugated estrogens, Tylenol Sinus, St. Johns Wort, Tums, and Darvocet
N-100. The patient was enrolled in protocol N49-98-02-102 and randomized
to **celecoxib 400 mg BID.**

After 261 days of treatment, at a routine visit, she was found by the
Investigator to have epigastric tenderness and a hemoglobin of 9.8 g/dL
compared with a baseline of 12.7 g/dL and a hematocrit of 32.0%,
compared with a baseline of 41.0%. **Study medication was discontinued
at this time**. In addition, on study day 249, stool was reported as
hemoccult-positive. Baseline serology for *H. pylori* had been negative.
On study day 262 an endoscopy revealed grade II nonerosive esophagitis
and evidence of a partial gastrectomy. There was food residue in the
stomach and a high-grade strictured region with erosive, friable, and
white mucosa at the body of the stomach. The anastomotic area mucosa was
friable, but no obvious old or new bleeding was seen. The endoscope
could not be passed through the stenotic anastamosis. On study day 268,
the patient underwent repeat endoscopy for vomiting, weight loss, and
nausea. During balloon dilatation of the anastamosis a perforation
occurred in the stomach requiring discontinuation of the procedure and
hospitalization. The patient was transferred to the hospital for
management of the perforation. Computerized tomography confirmed a
perforated viscus with free peritoneal air. The patient underwent an
emergency laparotomy, lysis of adhesions, and stricturoplasty with
repair of perforation and patch. The patient received 2 units of blood
perioperatively. Postoperative recovery was uneventful. This event was

classified as: **gastric outlet obstruction (traditional, 3; alternate,
3).**

**Case 1356**

**Patient US0321-102-10761** was a 72-year-old female with a history of
cardiovascular disease, recurrent sore throat, laryngitis, hypertension,
hypercholesterolemia, II/IV systolic ejection murmur, bilateral leg
varicosities, pneumonia, external hemorrhoids, menopause, left hip and
leg pain, angioma of the right buttock, lumbar spondylosis, and OA.
Concomitant medications included atenolol, hydrochlorothiazide, and
acetaminophen. The patient was enrolled in protocol N49-98-02-102 and
randomized to **celecoxib 400 mg BID.**

After 307 days of treatment the patient began experiencing nausea,
vomiting, and diarrhea. On study day 316, the patient was admitted to
the hospital with complaints of nausea, coffee ground emesis, burning in
her throat, a bad taste in her mouth, diarrhea, and fever. **Study
medication was discontinued**, and significant findings at this time
included a hemoglobin of 9.7 g/dL compared with a baseline of 12.1 g/dL
and a hematocrit of 28.0%, compared with a baseline of 36.0%, and
hemoccult-positive stool. On study day 317, the patient developed right
upper quadrant abdominal and epigastric discomfort and a temperature
elevation to 103.7°F. On day 318, the patient underwent abdominal
ultrasound with normal results. On day 319, the patient underwent an
endoscopy that revealed a hiatal hernia, grade I esophagitis, atrophic
gastropathy, multiple dispersed erosions with stigmata of recent
bleeding, evidence of dark blood in the incisura, antrum, and prepyloric
region, two nonbleeding linear antral ulcers, and a normal duodenum. The
largest dimension of the gastric ulcers was 0.7 cm. Baseline serology
for *H. pylori* had been negative. The patient was treated with acid
suppression and **discontinued from the study** with a work-up planned
to determine the etiology of the fever. This event was classified as:
**gastric ulcer; GI bleed (traditional, 1A; alternate, 1E).**

Case 1383 (Censored)

**Patient CA0484-035-12170** was a 62-year-old male with a history of
hypertension, ischemic heart disease, tachyarrythmias, cholecystectomy,
peptic ulcer disease, elevated liver enzymes, diffuse idiopathic
skeletal hyperostosis, gout, rotator cuff surgery, headaches, renal
dysfunction, and OA. Concomitant medications included allopurinol,
atenolol, Cytotec, vitamin E, calcium, and magnesium. The patient was
enrolled in protocol N49-98-02-035 and randomized to **ibuprofen 800 mg
TID.**

After 18 days of treatment the patient began experiencing diffuse
abdominal pain, bloating, acid regurgitation, and severe retrosternal
burning. **Study medication was discontinued at this time**. After study
medication was discontinued on day 18, the patient took **indomethacin
SR 75 mg from study day 22 to day 34**. On day 21 stool was
hemoccult-negative. On study day 29 a hemoglobin was unchanged from
baseline at 14.5 g/dL and a hematocrit was 44.0% compared with a
baseline of 42.2%. On study day 36 the patient developed black tarry
stools and weakness. On study day 43 an endoscopy was performed
revealing a slight laxity at the diaphragmatic pinch, and a linear,
1.0-cm duodenal bulb ulcer. According to the endoscopist, the ulcer
appeared to be healing. A biopsy for *H. pylori* was negative, despite a
positive baseline serology. A hemoglobin and hematocrit on the day of
endoscopy was 12.4 g/dL and 36.0%, respectively. Additionally, stools
were hemoccult positive on study days 41 and 42. The patient was treated
with acid suppression and for *H. pylori* and **discontinued from the
study**. This event was classified as: **duodenal ulcer; GI bleed
(traditional, 1C; alternate, 1G).**