Lumiracoxib (COX189)

Background Document

for Novartis Presentation to

FDA Advisory Committee

(February 16-18, 2005)

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| ##### Release date: {#re   | 13 January 2005                         |
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Property of Novartis Pharmaceuticals Corporation

All Rights Reserved

**AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION**

Table of contents

List of tables [4](#list-of-tables)

List of figures [6](#list-of-figures)

1 Meta-analysis of lumiracoxib CV safety
[8](#meta-analysis-of-lumiracoxib-cv-safety)

1.1 Meta-analysis of all lumiracoxib data: Methods
[8](#meta-analysis-of-all-lumiracoxib-data-methods)

1.1.1 Characteristics of trials, patients and interventions
[8](#characteristics-of-trials-patients-and-interventions)

1.1.2 Meta-analysis statistical methodology
[12](#meta-analysis-statistical-methodology)

1.2 Results of meta-analysis for APTC and MIs
[13](#results-of-meta-analysis-for-aptc-and-mis)

1.2.1 APTC endpoint [13](#aptc-endpoint)

1.2.2 Myocardial infarctions [14](#myocardial-infarctions)

1.2.3 Evidence from a cumulative stratified meta-analysis for APTC and
MIs
[14](#evidence-from-a-cumulative-stratified-meta-analysis-for-aptc-and-mis)

1.2.4 Meta-analysis of all lumiracoxib data for stroke
[16](#meta-analysis-of-all-lumiracoxib-data-for-stroke)

1.2.5 Meta-analysis of all lumiracoxib data for peripheral vascular risk
[17](#meta-analysis-of-all-lumiracoxib-data-for-peripheral-vascular-risk)

1.2.6 Meta-analysis of all lumiracoxib data for MI / strokes /
peripheral vascular events -- combined
[19](#meta-analysis-of-all-lumiracoxib-data-for-mi-strokes-peripheral-vascular-events-combined)

1.2.7 Summary of lumiracoxib meta-analysis data
[20](#summary-of-lumiracoxib-meta-analysis-data)

2 TARGET design: Rationale for selecting two different traditional non
steroidal anti‑inflammatory drugs (NSAIDs) as comparators
[21](#target-design-rationale-for-selecting-two-different-traditional-non-steroidal-antiinflammatory-drugs-nsaids-as-comparators)

3 TARGET: Comparison of lumiracoxib and ibuprofen
[23](#target-comparison-of-lumiracoxib-and-ibuprofen)

3.1 APTC endpoint - lumiracoxib vs ibuprofen
[23](#aptc-endpoint---lumiracoxib-vs-ibuprofen)

3.2 Clinical and silent MIs - lumiracoxib vs ibuprofen
[27](#clinical-and-silent-mis---lumiracoxib-vs-ibuprofen)

3.3 Lumiracoxib has a CV adverse event profile that is no different from
ibuprofen for all adjudicated thrombotic events
[27](#lumiracoxib-has-a-cv-adverse-event-profile-that-is-no-different-from-ibuprofen-for-all-adjudicated-thrombotic-events)

3.4 Lumiracoxib showed a significantly better blood pressure profile
than ibuprofen for de novo and aggravated hypertension, and numerically
less edema and congestive heart failure (CHF).
[28](#lumiracoxib-showed-a-significantly-better-blood-pressure-profile-than-ibuprofen-for-de-novo-and-aggravated-hypertension-and-numerically-less-edema-and-congestive-heart-failure-chf.)

3.4.1 Blood pressure -- least squares mean change from baseline
[28](#blood-pressure-least-squares-mean-change-from-baseline)

3.4.2 *De novo* hypertension -- lumiracoxib compared to ibuprofen
[29](#de-novo-hypertension-lumiracoxib-compared-to-ibuprofen)

3.4.3 Severe *de novo* hypertension -- lumiracoxib compared to ibuprofen
[30](#severe-de-novo-hypertension-lumiracoxib-compared-to-ibuprofen)

3.4.4 *Severe* aggravation of hypertension
[32](#severe-aggravation-of-hypertension)

3.4.5 Congestive heart failure (CHF), edema and weight gain
[33](#congestive-heart-failure-chf-edema-and-weight-gain)

3.4.6 Cases of edema reported as SAEs or leading to premature
discontinuation
[34](#cases-of-edema-reported-as-saes-or-leading-to-premature-discontinuation)

3.5 Analysis of upper gastro-intestinal events: lumiracoxib vs ibuprofen
[34](#analysis-of-upper-gastro-intestinal-events-lumiracoxib-vs-ibuprofen)

3.6 Low dose aspirin population -- hemoglobin changes: Lumiracoxib vs
ibuprofen and naproxen:
[35](#low-dose-aspirin-population-hemoglobin-changes-lumiracoxib-vs-ibuprofen-and-naproxen)

3.7 Combined GI and CV endpoint -- lumiracoxib vs ibuprofen
[37](#combined-gi-and-cv-endpoint-lumiracoxib-vs-ibuprofen)

3.8 Summary: Lumiracoxib does not increase CV adverse events compared to
ibuprofen and has a positive benefit to risk profile compared to
ibuprofen.
[38](#summary-lumiracoxib-does-not-increase-cv-adverse-events-compared-to-ibuprofen-and-has-a-positive-benefit-to-risk-profile-compared-to-ibuprofen.)

4 TARGET: Lumiracoxib compared to naproxen
[39](#target-lumiracoxib-compared-to-naproxen)

4.1 APTC endpoint - lumiracoxib vs naproxen
[39](#aptc-endpoint---lumiracoxib-vs-naproxen)

4.2 TARGET study: Clinical and silent MIs - lumiracoxib vs naproxen
[41](#target-study-clinical-and-silent-mis---lumiracoxib-vs-naproxen)

4.3 Lumiracoxib has a CV adverse event profile that is no different from
naproxen for other adjudicated CV events.
[41](#lumiracoxib-has-a-cv-adverse-event-profile-that-is-no-different-from-naproxen-for-other-adjudicated-cv-events.)

4.4 Lumiracoxib has a significantly better blood pressure profile than
naproxen, and numerically less congestive heart failure and weight gain.
[42](#lumiracoxib-has-a-significantly-better-blood-pressure-profile-than-naproxen-and-numerically-less-congestive-heart-failure-and-weight-gain.)

4.4.1 Blood pressure -- Least Square Means change from baseline
[42](#blood-pressure-least-square-means-change-from-baseline)

4.4.2 Congestive cardiac failure (CHF) and weight gain
[42](#congestive-heart-failure-chf-and-weight-gain)

4.5 Combined GI and CV endpoint -- lumiracoxib vs naproxen
[43](#combined-gi-and-cv-endpoint-lumiracoxib-vs-naproxen)

4.6 Summary: Lumiracoxib compared to naproxen
[43](#summary-lumiracoxib-compared-to-naproxen)

5 TARGET: high CV risk patients -- analysis of APTC and MI (silent and
clinical events)
[44](#target-high-cv-risk-patients-analysis-of-aptc-and-mi-silent-and-clinical-events)

5.1 Patients with a previous MI: repeat CV events
[45](#patients-with-a-previous-mi-repeat-cv-events)

5.2 Peripheral vascular events -- ASA population
[46](#peripheral-vascular-events-asa-population)

5.3 All thrombotic events (MI --clinical and silent, stroke, DVT and PE)
--ASA population
[46](#all-thrombotic-events-mi-clinical-and-silent-stroke-dvt-and-pe-asa-population)

5.4 Relationship between hypertension and subsequent thrombotic events
[47](#relationship-between-hypertension-and-subsequent-thrombotic-events)

6 NDA database of long-term studies
[48](#nda-database-of-long-term-studies)

6.1 Updated NDA long-term safety dataset: CV events
[48](#updated-nda-long-term-safety-dataset-cv-events)

6.1.1 Serious cardiac events (SAEs) regardless of study drug
relationship
[49](#serious-cardiac-events-saes-regardless-of-study-drug-relationship)

6.1.2 Thrombotic ADRs and relationship to dose
[49](#thrombotic-adrs-and-relationship-to-dose)

6.1.3 Thrombotic ADRs and relationship to duration of treatment
[50](#thrombotic-adrs-and-relationship-to-duration-of-treatment)

6.2 Updated NDA long-term safety dataset -- hypertension adverse events
[52](#updated-nda-long-term-safety-dataset-hypertension-adverse-events)

6.3 Updated NDA long-term safety dataset -- edema adverse events
[52](#updated-nda-long-term-safety-dataset-edema-adverse-events)

7 How do lumiracoxib CV data compare with rofecoxib?
[53](#how-do-lumiracoxib-cv-data-compare-with-rofecoxib)

7.1 VIGOR vs TARGET (naproxen substudy and non ASA population)
[53](#vigor-vs-target-naproxen-substudy-and-non-asa-population)

7.1.1 APTC endpoint [53](#aptc-endpoint-1)

7.1.2 Myocardial Infarcts [54](#myocardial-infarcts)

7.1.3 Venous thrombosis (deep vein thrombosis and pulmonary embolism)
[55](#venous-thrombosis-deep-vein-thrombosis-and-pulmonary-embolism)

7.1.4 Hypertension, edema and congestive heart failure (CHF)
[55](#hypertension-edema-and-congestive-heart-failure-chf)

7.2 Summary: VIGOR vs TARGET (naproxen substudy and non ASA population)
[57](#summary-vigor-vs-target-naproxen-substudy-and-non-asa-population)

8 Celecoxib in the CLASS study compared to lumiracoxib in TARGET
[58](#celecoxib-in-the-class-study-compared-to-lumiracoxib-in-target)

8.1 CLASS vs TARGET: differences that could impact CV results
[58](#class-vs-target-differences-that-could-impact-cv-results)

8.2 TARGET and CLASS: CV data summary
[58](#target-and-class-cv-data-summary)

9 Possible explanations for the specific rofecoxib CV profile
[61](#possible-explanations-for-the-specific-rofecoxib-cv-profile)

9.1 Structure [62](#structure)

9.2 Half--life [62](#halflife)

9.3 PK/PD (Distribution kinetics) [62](#pkpd-distribution-kinetics)

9.4 Inhibition of the vasoprotective prostaglandin PGI~2~
[62](#inhibition-of-the-vasoprotective-prostaglandin-pgi2)

10 Summary [63](#summary)

References [64](#references)

##  {#section .TOC-Entry}

## List of tables {#list-of-tables .TOC-Entry}

Table 1-1 Trials included in meta-analysis
[9](#table-1-1-trials-included-in-meta-analysis)

Table 1-2 Relative risk of APTC endpoint with lumiracoxib and
comparators from a stratified meta-analysis
[13](#table-1-2-relative-risk-of-aptc-endpoint-with-lumiracoxib-and-comparators-from-a-stratified-meta-analysis)

Table 1-3 Relative risk of MI with lumiracoxib and comparators from a
stratified meta-analysis
[14](#table-1-3-relative-risk-of-mi-with-lumiracoxib-and-comparators-from-a-stratified-meta-analysis)

Table 1-4 Relative risk of stroke with lumiracoxib and comparators from
a stratified meta-analysis
[17](#table-1-4-relative-risk-of-stroke-with-lumiracoxib-and-comparators-from-a-stratified-meta-analysis)

Table 1-5 Relative risk of peripheral vascular event with lumiracoxib
and comparators from a stratified meta-analysis
[18](#table-1-5-relative-risk-of-peripheral-vascular-event-with-lumiracoxib-and-comparators-from-a-stratified-meta-analysis)

Table 1-8 Relative risk for MI / all strokes / peripheral vascular
events -- combined, with lumiracoxib and comparators from a stratified
meta-analysis
[19](#table-1-8-relative-risk-for-mi-all-strokes-peripheral-vascular-events-combined-with-lumiracoxib-and-comparators-from-a-stratified-meta-analysis)

Table 3-1 Confirmed or probable APTC endpoint: treatment comparisons
using COX proportional hazards model (safety population)
[24](#table-3-1-confirmed-or-probable-aptc-endpoint-treatment-comparisons-using-cox-proportional-hazards-model-safety-population)

Table 3-2 Lumiracoxib vs ibuprofen -- confirmed/probable clinical and
silent myocardial infarctions
[27](#table-3-2-lumiracoxib-vs-ibuprofen-confirmedprobable-clinical-and-silent-myocardial-infarctions)

Table 3-3 Adjudicated confirmed or probable thrombotic events (MI
--clinical and silent, stroke, DVT and PE)
[27](#table-3-3-adjudicated-confirmed-or-probable-thrombotic-events-mi-clinical-and-silent-stroke-dvt-and-pe)

Table 3-4 Adjudicated Confirmed or probable peripheral vascular events
(DVT or PE)
[28](#table-3-4-adjudicated-confirmed-or-probable-peripheral-vascular-events-dvt-or-pe)

Table 3-5 TARGET study -- lumiracoxib vs ibuprofen. Incidence of edema,
CHF and weight gain (overall safety population).
[33](#table-3-5-target-study-lumiracoxib-vs-ibuprofen.-incidence-of-edema-chf-and-weight-gain-overall-safety-population.)

Table 3-6 TARGET study - definite or probable UGIT complications (POBs)
[35](#table-3-6-target-study---definite-or-probable-ugit-complications-pobs)

Table 3-7 Hemoglobin (g/l) LS means for end-of-study value and its
change from baseline
[36](#table-3-7-hemoglobin-gl-ls-means-for-end-of-study-value-and-its-change-from-baseline)

Table 3-8 Hemoglobin \[g/L\] LS means for 12-month value and its change
from baseline
[36](#table-3-8-hemoglobin-gl-ls-means-for-12-month-value-and-its-change-from-baseline)

Table 3-9 TARGET -- GI and CCV (APTC) combined endpoint
[37](#table-3-9-target-gi-and-ccv-aptc-combined-endpoint)

Table 4-1 Confirmed or probable APTC endpoint: treatment comparisons
using COX proportional hazards model (safety population)
[39](#table-4-6-confirmed-or-probable-aptc-endpoint-treatment-comparisons-using-cox-proportional-hazards-model-safety-population)

Table 4-2 Incidence of confirmed or probable myocardial infarction
(clinical and silent) -- lumiracoxib vs naproxen
[41](#table-4-7-incidence-of-confirmed-or-probable-myocardial-infarction-clinical-and-silent-lumiracoxib-vs-naproxen)

Table 4-3 TARGET study: lumiracoxib vs naproxen. Incidence of confirmed
or probable cardiovascular and cerebrovascular events (overall safety
population).
[42](#table-4-3-target-study-lumiracoxib-vs-naproxen.-incidence-of-confirmed-or-probable-cardiovascular-and-cerebrovascular-events-overall-safety-population.)

Table 4-4 TARGET study: lumiracoxib vs naproxen. Incidence of CHF and
weight gain (overall safety population).
[42](#table-4-4-target-study-lumiracoxib-vs-naproxen.-incidence-of-chf-and-weight-gain-overall-safety-population.)

Table 4-5 GI and CCV (APTC) combined endpoint
[43](#table-4-5-gi-and-ccv-aptc-combined-endpoint)

Table 5-1 TARGET patient characteristics -- high CV risk patients
[44](#table-5-1-target-patient-characteristics-high-cv-risk-patients)

Table 5-2 Patients with history of CV disease: APTC and MIs (clinical
and silent)
[44](#table-5-2-patients-with-high-cv-risk-aptc-and-mis-clinical-and-silent)

Table 5-3 Patients with history of coronary heart disease (Framingham
risk patients excluded): APTC and MIs (clinical and silent)
[45](#table-5-3-patients-with-history-of-coronary-artery-disease-framingham-risk-patients-excluded-aptc-and-mis-clinical-and-silent)

Table 5-4 Peripheral vascular events (DVT or PE) - (Safety Population) -
Aspirin use: Yes
[46](#table-5-4-peripheral-vascular-events-dvt-or-pe---safety-population---aspirin-use-yes)

Table 5-5 Thrombotic events (MI --clinical and silent, stroke, DVT and
PE) - (Safety Population) - Aspirin use: Yes
[47](#table-5-5-thrombotic-events-mi-clinical-and-silent-stroke-dvt-and-pe---safety-population---aspirin-use-yes)

Table 5-6 TARGET: Incidence of confirmed or probable APTC events in
patient categories with hypertension
[48](#table-5-6-target-incidence-of-confirmed-or-probable-aptc-events-in-patient-categories-with-hypertension)

Table 6-1 Incidence of cardiovascular events
[48](#table-6-1-incidence-of-cardiovascular-events)

Table 6-2 Crude incidence of APTC endpoint by dose
[50](#table-6-2-crude-incidence-of-aptc-endpoint-by-dose)

Table 6-3 Crude incidence of APTC endpoint by duration
[51](#table-6-3-crude-incidence-of-aptc-endpoint-by-duration)

Table 6-5 Hypertension adverse events by category and preferred term
(safety patients- all non acute pain studies)
[52](#table-6-5-hypertension-adverse-events-by-category-and-preferred-term-safety-patients--all-non-acute-pain-studies)

Table 6-6 Edema adverse events by category and preferred term (safety
patients -- all non acute pain studies)
[52](#table-6-6-edema-adverse-events-by-category-and-preferred-term-safety-patients-all-non-acute-pain-studies)

Table 7-1 APTC events: VIGOR vs TARGET (non aspirin population --
naproxen vs lumiracoxib)
[54](#table-7-8-aptc-events-vigor-vs-target-non-aspirin-population-naproxen-vs-lumiracoxib)

Table 7-2 MI events: VIGOR vs TARGET (non aspirin population -- naproxen
vs lumiracoxib)
[54](#table-7-9-mi-events-vigor-vs-target-non-aspirin-population-naproxen-vs-lumiracoxib)

Table 7-3 Serious venous thrombotic events: VIGOR vs TARGET (non aspirin
population -- naproxen vs lumiracoxib)
[55](#table-7-10-serious-venous-thrombotic-events-vigor-vs-target-non-aspirin-population-naproxen-vs-lumiracoxib)

Table 7-4 VIGOR: Results of pre-specified safety analyses
[55](#table-7-11-vigor-results-of-pre-specified-safety-analyses)

Table 7-5 Edema discontinuations data in TARGET
[56](#table-7-12-edema-discontinuations-data-in-target)

Table 7-6 Hypertension discontinuations data in TARGET
[56](#table-7-13-hypertension-discontinuations-data-in-target)

Table 7-7 TARGET -- lumiracoxib vs naproxen: Incidence of edema, CHF as
an AE and weight increase (no aspirin population)
[57](#table-7-14-target-lumiracoxib-vs-naproxen-incidence-of-edema-chf-as-an-ae-and-weight-increase-no-aspirin-population)

Table 8-1 TARGET vs CLASS comparison for MI and APTC event rates
[59](#table-8-15-target-vs-class-comparison-for-mi-and-aptc-event-rates)

## List of figures {#list-of-figures .TOC-Entry}

Figure 1-1 Cumulative stratified meta-analysis of APTC events in
randomized trials comparing lumiracoxib with controls
[15](#figure-1-1-cumulative-stratified-meta-analysis-of-aptc-events-in-randomized-trials-comparing-lumiracoxib-with-controls)

Figure 1-2 Cumulative stratified meta-analysis of MI in randomized
trials comparing lumiracoxib with controls
[15](#figure-1-2-cumulative-stratified-meta-analysis-of-mi-in-randomized-trials-comparing-lumiracoxib-with-controls)

Figure 1-3 Cumulative meta-analysis of MI in randomized trials comparing
lumiracoxib with non-naproxen NSAIDs
[16](#figure-1-3-cumulative-meta-analysis-of-mi-in-randomized-trials-comparing-lumiracoxib-with-non-naproxen-nsaids)

Figure 1-4 Cumulative stratified meta-analysis of stroke in randomized
trials comparing lumiracoxib with controls
[17](#figure-1-4-cumulative-stratified-meta-analysis-of-stroke-in-randomized-trials-comparing-lumiracoxib-with-controls)

Figure 1-5 Cumulative stratified meta-analysis of peripheral vascular
events in randomized trials comparing lumiracoxib with controls
[18](#figure-1-5-cumulative-stratified-meta-analysis-of-peripheral-vascular-events-in-randomized-trials-comparing-lumiracoxib-with-controls)

Figure 1-6 Cumulative stratified meta-analysis for MI / all strokes /
peripheral vascular events -- combined, in randomized trials comparing
lumiracoxib with controls
[20](#figure-1-6-cumulative-stratified-meta-analysis-for-mi-all-strokes-peripheral-vascular-events-combined-in-randomized-trials-comparing-lumiracoxib-with-controls)

Figure 1-7 Cumulative meta-analysis of myocardial infarctions in
randomized trials comparing rofecoxib with control
[21](#figure-1-7-cumulative-meta-analysis-of-myocardial-infarctions-in-randomized-trials-comparing-rofecoxib-with-control)

Figure 3-1 Lumiracoxib vs ibuprofen: cumulative incidence of
confirmed/probable APTC endpoint
[25](#figure-3-1-lumiracoxib-vs-ibuprofen-cumulative-incidence-of-confirmedprobable-aptc-endpoint)

Figure 3-2 Posthoc depiction of cardiovascular events in non-aspirin
users in the CLASS study (Ref: FitzGerald G)
[26](#figure-3-2-posthoc-depiction-of-cardiovascular-events-in-non-aspirin-users-in-the-class-study-ref-fitzgerald-g)

Figure 3-3 De novo hypertension- lumiracoxib compared to ibuprofen
[29](#figure-3-3-de-novo-hypertension--lumiracoxib-compared-to-ibuprofen)

Figure 3-4 Severe de novo hypertension -- lumiracoxib compared to
ibuprofen
[30](#figure-3-4-severe-de-novo-hypertension-lumiracoxib-compared-to-ibuprofen)

Figure 3-5 Aggravation of hypertension -- lumiracoxib compared to
ibuprofen
[31](#figure-3-5-aggravation-of-hypertension-lumiracoxib-compared-to-ibuprofen)

Figure 3-6 Severe aggravation of hypertension
[32](#figure-3-6-severe-aggravation-of-hypertension)

Figure 3-7 Edema reported as SAEs or requiring premature discontinuation
[34](#figure-3-7-edema-reported-as-saes-or-requiring-premature-discontinuation)

Figure 3-8 TARGET: Combined GI and CCV endpoint Kaplan -- Meier
[38](#figure-3-8-target-combined-gi-and-ccv-endpoint-kaplan-meier)

Figure 4-1 Lumiracoxib vs naproxen: cumulative incidence of
confirmed/probable APTC endpoint
[40](#figure-4-1-lumiracoxib-vs-naproxen-cumulative-incidence-of-confirmedprobable-aptc-endpoint)

Figure 8-1 APTC events in TARGET- Lumiracoxib vs ibuprofen in the no
low-dose ASA population
[59](#figure-8-2-aptc-events-in-target--lumiracoxib-vs-ibuprofen-in-the-no-low-dose-asa-population)

Figure 8-2 Posthoc depiction of thromboembolic cardiovascular events in
non-aspirin users in the CLASS study (Ref: FitzGerald G)
[60](#figure-8-3-posthoc-depiction-of-thromboembolic-cardiovascular-events-in-non-aspirin-users-in-the-class-study-ref-fitzgerald-g)

# Meta-analysis of lumiracoxib CV safety

## Meta-analysis of all lumiracoxib data: Methods

Rofecoxib was withdrawn worldwide from the market on 30 September 2004
due to an increased risk of adverse cardiovascular events observed in
the Adenomatous Polyp Prevention on Vioxx® (APPROVe) study. This
significant difference was seen beginning after 18 months of treatment
and raised the question of whether these findings are associated with
other drugs in the class. However a recent publication in the Lancet
(Jüni et al 2004) questioned whether the cardiovascular signal was
evident earlier and argued using cumulative meta-analysis methodology
that the increase in myocardial infarctions with rofecoxib was evident
as early as 2000, after 14,247 patients had been randomized in rofecoxib
studies and 44 myocardial infarcts (MI) had occurred. The meta-analysis
included only therapeutic doses of rofecoxib (12.5 mg to 50 mg od). The
authors suggested that if adverse events were cumulatively analyzed,
this would allow for earlier detection of clinically significant safety
signals.

Novartis has performed a standard and cumulative meta-analysis of the
cardiovascular safety of lumiracoxib for all doses, including
supratherapeutic doses (100 mg to 1200mg od), of all completed
randomized controlled trials of lumiracoxib ≥ 1 week duration.

### Characteristics of trials, patients and interventions

All randomized, controlled studies that involved administration of
lumiracoxib (≥1 week in duration) in chronic indications were included
in the analysis (Table 1-1). Trials in acute pain models (e.g. pain due
to dental surgery, arthroplasty, dysmenorrhea), drug-drug interaction
studies of short duration, clinical pharmacology studies in healthy
volunteers or special populations were not included on the basis that
they would add little to overall patient exposure (44 patient -- years
compared with 9796 patient-years for patients taking lumiracoxib for
treatment of the signs and symptoms of either osteoarthritis or
rheumatoid arthritis). It is noteworthy that the vast majority of these
studies have already been published.

###### Table 1-1 Trials included in meta-analysis {#table-1-1-trials-included-in-meta-analysis .unnumbered}

+--------------+-----+------+---------------+-------------+-----+----+
| Reference    | St  | Tre  | Lumiracoxib   | Control     | Du  | J  |
|              | udy | ated | dose (number  | (number of  | rat | ad |
|              | num | diso | of patients   | patients    | ion | ad |
|              | ber | rder | rando         | randomi     |     | s  |
|              |     | (nu  | mized/safety) | zed/safety) |     | co |
|              |     | mber |               |             |     | re |
|              |     | of   |               |             |     | ^3 |
|              |     | p    |               |             |     | 1^ |
|              |     | atie |               |             |     |    |
|              |     | nts) |               |             |     |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Schnitzer,   | 104 | OA   | 50 mg bid     | placebo     | 4   | 5  |
| 2004^12^     |     | (n=  | (n=98/98)     | (n=97/97)   | we  |    |
|              |     | 583) |               |             | eks |    |
|              |     |      | 100 mg bid    | diclofenac  |     |    |
|              |     |      | (n=96/96)     | 75 mg bid   |     |    |
|              |     |      |               | (n=94/94)   |     |    |
|              |     |      | 200 mg bid    |             |     |    |
|              |     |      | (n=99/99)     |             |     |    |
|              |     |      |               |             |     |    |
|              |     |      | 400 mg od     |             |     |    |
|              |     |      | (n=99/99)     |             |     |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Schnitzer in | 105 | RA   | 50 mg bid     | placebo     | 4   | 5  |
| press^13^    |     | (n=  | (n=102/102)   | (n=99/99)   | we  |    |
|              |     | 571) |               |             | eks |    |
|              |     |      | 100 mg bid    | diclofenac  |     |    |
|              |     |      | (n=98/97)     | 75 mg bid   |     |    |
|              |     |      |               | (n=91/91)   |     |    |
|              |     |      | 200 mg bid    |             |     |    |
|              |     |      | (n=94/94)     |             |     |    |
|              |     |      |               |             |     |    |
|              |     |      | 400 mg od     |             |     |    |
|              |     |      | (n=87/87)     |             |     |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Fleischmann, | 109 | OA   | 200 mg od     | placebo     | 13  | 5  |
| 2003^14^     |     | (n=1 | (n=462/462)   | (n=231/231) | we  |    |
|              |     | 600) |               |             | eks |    |
|              |     |      | 400 mg od     | celecoxib   |     |    |
|              |     |      | (n=463/463)   | 200 mg od   |     |    |
|              |     |      |               | (n=444/444) |     |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Kivitz,      | 110 | RA   | 400 mg od     | celecoxib   | 13  | 4  |
| 2004^15^     |     | (n=  | (n=227/227)   | 200 mg bid  | we  |    |
|              |     | 893) |               | (n=223/223) | eks |    |
|              |     |      | 800 mg od     |             |     |    |
|              |     |      | (n=227/227)   | ibuprofen   |     |    |
|              |     |      |               | 800 mg tid  |     |    |
|              |     |      |               | (n=216/216) |     |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Geusens,     | 111 | RA   | 200 mg od     | placebo     | 26  | 5  |
| 200316       |     | (n=1 | (n=280/280)   | (n=284/284) | we  |    |
|              |     | 124) |               |             | eks |    |
|              |     |      | 400 mg od     | naproxen    |     |    |
|              |     |      | (n=281/281)   | 500 mg bid  |     |    |
|              |     |      |               | (279/279)   |     |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Tannenbaum,  | 112 | OA   | 200 mg od     | placebo     | 13  | 5  |
| 2004^17^     |     | (n=1 | (n=487/487)   | (n=243/243) | we  |    |
|              |     | 702) |               |             | eks |    |
|              |     |      | 400 mg od     | celecoxib   |     |    |
|              |     |      | (n=491/491)   | 200 mg od   |     |    |
|              |     |      |               | (n=481/481) |     |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Reference    | St  | Tre  | Lumiracoxib   | Control     | Du  | J  |
|              | udy | ated | dose (number  | (number of  | rat | ad |
|              | num | diso | of patients   | patients    | ion | ad |
|              | ber | rder | rando         | randomi     |     | s  |
|              |     | (nu  | mized/safety) | zed/safety) |     | co |
|              |     | mber |               |             |     | re |
|              |     | of   |               |             |     | ^3 |
|              |     | p    |               |             |     | 1^ |
|              |     | atie |               |             |     |    |
|              |     | nts) |               |             |     |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Schell,      | 1   | OA   | 200 mg od     | celecoxib   | 39  | 4  |
| 2003^18^     | 12E | (n=1 | (n=411/411)   | 200 mg od   | we  |    |
|              | (39 | 235) |               | (405/405)   | eks |    |
|              | w   |      | 400 mg od     |             |     |    |
|              | eek |      | (n=419/419)   |             |     |    |
|              | ext |      |               |             |     |    |
|              | ens |      |               |             |     |    |
|              | ion |      |               |             |     |    |
|              | to  |      |               |             |     |    |
|              | 01  |      |               |             |     |    |
|              | 12) |      |               |             |     |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Data on file | 114 | RA   | 200 mg od     | placebo     | 13  | 5  |
| ^19^         |     | (n=1 | (n=315/315)   | (n=309/309) | we  |    |
|              |     | 239) |               |             | eks |    |
|              |     |      | 400 mg od     | celecoxib   |     |    |
|              |     |      | (n=313/313)   | 200 mg bid  |     |    |
|              |     |      |               | (n=302/302) |     |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Hawkey,      | 126 | OA   | 200 mg od     | celecoxib   | 13  | 4  |
| 2004^20^     |     | (n=1 | (n=264/264)   | 200 mg od   | we  |    |
|              |     | 042) |               | (n=258/258) | eks |    |
|              |     |      | 400 mg od     |             |     |    |
|              |     |      | (n=260/260)   | ibuprofen   |     |    |
|              |     |      |               | 800 mg tid  |     |    |
|              |     |      |               | (n=260/260) |     |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Berenbaum in | 128 | OA   | 400 mg od     | placebo     | 13  | 5  |
| press^21^    |     | (n=  | (n=205/205)   | (n=204/204) | we  |    |
|              |     | 511) |               |             | eks |    |
|              |     |      |               | rofecoxib   |     |    |
|              |     |      |               | 25 mg od    |     |    |
|              |     |      |               | (n=102/102) |     |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Wittenberg,  | 2   | OA   | 400 mg od     | placebo     | 1   | 5  |
| 2003^22^     | 301 | (n=  | (n=144/144)   | (n=75/75)   | w   |    |
|              |     | 364) |               |             | eek |    |
|              |     |      |               | celecoxib   |     |    |
|              |     |      |               | 200 mg bid  |     |    |
|              |     |      |               | (n=145/145) |     |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Berenbaum in | 2   | OA   | 200 mg od     | placebo     | 1   | 5  |
| press^21^    | 303 | (n=  | (n=105/105)   | (n=103/103) | w   |    |
|              |     | 408) |               |             | eek |    |
|              |     |      | 400 mg od     | celecoxib   |     |    |
|              |     |      | (n=99/99)     | 200 mg bid  |     |    |
|              |     |      |               | (n=101/101) |     |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Hawkey in    | 2   | OA   | 400 mg od     | rofecoxib   | 6   | 4  |
| press^23^    | 307 | (n=  | (n=154/154)   | 25 mg od    | we  |    |
|              |     | 309) |               | (n=155/155) | eks |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Scott*.,*    | 2   | RA   | 800 mg od     | naproxen    | 4   | 4  |
| 2003^24^     | 312 | (n=  | (n=38/38)     | 500 mg bid  | we  |    |
|              |     | 120) |               | (n=41/41)   | eks |    |
|              |     |      | 1200 mg od    |             |     |    |
|              |     |      | (n=41/41)     |             |     |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Ben          | 2   | OA   | 100 mg od     | placebo     | 4   | 5  |
| evolenskaya, | 316 | (n=  | (n=122/122)   | (n=122/122) | we  |    |
| 2003^25^     |     | 244) |               |             | eks |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Reference    | St  | Tre  | Lumiracoxib   | Control     | Du  | J  |
|              | udy | ated | dose (number  | (number of  | rat | ad |
|              | num | diso | of patients   | patients    | ion | ad |
|              | ber | rder | rando         | randomi     |     | s  |
|              |     | (nu  | mized/safety) | zed/safety) |     | co |
|              |     | mber |               |             |     | re |
|              |     | of   |               |             |     | ^3 |
|              |     | p    |               |             |     | 1^ |
|              |     | atie |               |             |     |    |
|              |     | nts) |               |             |     |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Grifka,      | 2   | OA   | 200 mg od     | placebo     | 4   | 5  |
| 2004^26^     | 319 | (n=  | (n=205/205)   | (n=196/196) | we  |    |
|              |     | 594) |               |             | eks |    |
|              |     |      | 400 mg od     |             |     |    |
|              |     |      | (n=193/193)   |             |     |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Pavelka,     | 2   | RA   | 200 mg od     | placebo     | 13  | 5  |
| 200427       | 335 | (n=1 | (n=458/458)   | (n=465/465) | we  |    |
|              |     | 151) |               |             | eks |    |
|              |     |      |               | naproxen    |     |    |
|              |     |      |               | 500 mg bid  |     |    |
|              |     |      |               | (n=228/228) |     |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Data on file | 23  | RA   | 200 mg od     | naproxen    | 39  | 4  |
| ^28^         | 35E | (n=  | (n=376/376)   | 500 mg bid  | we  |    |
|              | (39 | 647) |               | (n=271/271) | eks |    |
|              | w   |      |               |             |     |    |
|              | eek |      |               |             |     |    |
|              | ext |      |               |             |     |    |
|              | ens |      |               |             |     |    |
|              | ion |      |               |             |     |    |
|              | to  |      |               |             |     |    |
|              | 23  |      |               |             |     |    |
|              | 35) |      |               |             |     |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Beaulieu,    | 2   | OA   | 100 mg od     | placebo     | 13  | 5  |
| 2004^29^     | 360 | (n=1 | (n=391/391)   | (n=382/382) | we  |    |
|              |     | 551) |               |             | eks |    |
|              |     |      | 100 mg od     | celecoxib   |     |    |
|              |     |      | with 2-week   | 200 mg od   |     |    |
|              |     |      | loading dose  | (n=393/393) |     |    |
|              |     |      | of 200 mg od  |             |     |    |
|              |     |      | (n=385/385)   |             |     |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Lehmann*,*   | 2   | OA   | 100 mg od     | placebo     | 13  | 5  |
| 2004 ^30^    | 361 | (n=1 | (n=420/420)   | (n=424/424) | we  |    |
|              |     | 684) |               |             | eks |    |
|              |     |      | 100 mg od     | celecoxib   |     |    |
|              |     |      | with 2-week   | 200 mg od   |     |    |
|              |     |      | loading dose  | (n=420/420) |     |    |
|              |     |      | of 200 mg od  |             |     |    |
|              |     |      | (n=420/420)   |             |     |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Data on file | 23  | OA   | 100 mg od     | celecoxib   | 39  | 4  |
|              | 61E | (n=1 | (n=853/853)   | 200 mg od   | we  |    |
|              | (39 | 310) |               | (n=457/457) | eks |    |
|              | w   |      |               |             |     |    |
|              | eek |      |               |             |     |    |
|              | ext |      |               |             |     |    |
|              | ens |      |               |             |     |    |
|              | ion |      |               |             |     |    |
|              | to  |      |               |             |     |    |
|              | 23  |      |               |             |     |    |
|              | 61) |      |               |             |     |    |
+--------------+-----+------+---------------+-------------+-----+----+
| Schnitzer,   | TAR | OA   | 400 mg od     | naproxen    | 52  | 4  |
| 2004^8^ and  | GET | (    | (n=9156/9117) | 500 mg bid  | we  |    |
| Farkouh      |     | n=18 |               | (n          | eks |    |
| 2004^9^      |     | 325) |               | =4754/4730) |     |    |
|              |     |      |               |             |     |    |
|              |     |      |               | ibuprofen   |     |    |
|              |     |      |               | 800 mg tid  |     |    |
|              |     |      |               | (n          |     |    |
|              |     |      |               | =4415/4397) |     |    |
+--------------+-----+------+---------------+-------------+-----+----+

A total of 22 trials in the database met the meta-analysis inclusion
criteria. All studies were randomized, double-blind, controlled studies.
A total of 33,933 patients were included in the safety population used
for the analyses; of these, 17339 patients (9796.4 patient-years
exposure) were randomized to lumiracoxib and 16594 patients were
allocated to controls (8824.5 patient-years exposure). Prospective
adjudication for the components of Antiplatelet Trialist's Collaboration
(APTC) endpoint occurred for 15,678.7 of the total 18,620.9
patient-years exposure. This well-established endpoint included
confirmed silent (electrocardiogram detected) myocardial infarctions,
confirmed or probable myocardial infarction, stroke (ischemic and
hemorrhagic), and cardiovascular death. All trials except two had an
active comparator. Of the 14 placebo-controlled trials, the majority had
a duration of 13 weeks. Four trials continued for one year (TARGET, and
trials 112, 2335, and 2361 with their extensions) totaling 22,781 safety
patients (16,526.1 patient-years exposure).

Fifteen trials (13 trials plus 2 extension trials) were performed in
patients with osteoarthritis, with the remaining 7 trials (including 1
extension) were performed in patients with rheumatoid arthritis.
Patients with osteoarthritis contributed most to patient exposure, which
was driven by the large number of patients in TARGET (18,325 patients
(18,244 safety patients); 13,505.8 patient-years).

Over 70% of patients were female and the majority of patients were over
55 years of age. Low-dose aspirin use for CV prophylaxis was generally
allowed and greater in TARGET (24%, stratified) than the other studies
(approximately 10%), while five of the smaller studies (≤ 4 weeks) did
not recruit any patients on low-dose aspirin (104, 105, 2301, 2303 and
2312). Over 30% of patients had baseline hypertension (45% in TARGET)
and approximately 5% had diabetes (8% in TARGET).

### Meta-analysis statistical methodology

Meta-analytic models were used to analyze the APTC and myocardial
infarction endpoints from the Novartis Clinical Trial Database. These
models included a random effect for trial and assumed a Poisson model
for the outcomes. Meta-analytic models were used to investigate the
effect of type of comparator, indication, duration, external
adjudication, and dose of lumiracoxib on odds ratio of treatment effect.
Likelihood ratio tests were used to assess the significance of the above
interaction factors. Exact Poisson methods were used to estimate the
odds ratio and corresponding 95% confidence interval (CI) for each trial
between the treatment groups under comparison. Estimates were not made
when one or both of the treatment groups being compared had zero events;
the addition of 0.5 to all cells leads to biased and imaginary estimates
when the observed event counts are low. The cumulative meta-analysis was
performed by fitting a series of meta-analytic models of the type
described above. At each step in the cumulation, defined by chronologic
dates of database lock in the development program, a random-effect
meta-analysis model was fit to the data that had accumulated by that
date. Meta-analytic models were fit using SAS, odds ratios and CIs per
study were calculated using StatExact, and consistency of model results
were tested assuming binomial, Bayes, and GEE models of the same nature
in SAS, WinBugs, and S-Plus. In trials that also have an extension with
no placebo group, results for lumiracoxib versus placebo are obtained
from the placebo-controlled phase only.

There were 34,349 patients randomized to the studies. Of these, 33,933
were confirmed to have received study medication and constitute the
safety population used for the analyses of safety outcomes. In the
extension studies (0112E, 2361E and 2335E; Table 2-1), patients were
re-randomized between the core and extension phases. Because the
extension phases were conducted as separate studies with separate study
protocols, patients enrolled in the extensions studies enter the
meta-analyses twice, once each for the core and extension treatment
groups, making a total of 34,668 effective patients used in the
meta-analyses.

## Results of meta-analysis for APTC and MIs

### APTC endpoint

Of the 22 randomized controlled trials identified from the Novartis
lumiracoxib clinical database, the meta-analyses found no significantly
increased risk of CV events for the APTC endpoint comparing lumiracoxib
with placebo, naproxen and non--naproxen NSAIDs (Table 1-2 below). As
seen in TARGET, the relative risks differed directionally when
lumiracoxib was compared to naproxen and non-naproxen NSAIDs. However
the significance of the results was unchanged regardless of comparator,
dose, prospective expert adjudication or study duration.

###### Table 1-2 Relative risk of APTC endpoint with lumiracoxib and comparators from a stratified meta-analysis {#table-1-2-relative-risk-of-aptc-endpoint-with-lumiracoxib-and-comparators-from-a-stratified-meta-analysis .unnumbered}

  ------------------------------------------------------------------------------
  Comparisons    Contrasts                  Risk\   95% CI for\   Interaction\
                                            ratio   risk ratio    p-value
  -------------- -------------------------- ------- ------------- --------------
  All            all Lumiracoxib - all      1.14    ( 0.83,1.57)  
  comparators    control                                          

                                                                  

  Type of        Lumiracoxib - placebo      0.88    ( 0.34,2.25)  0.6172
  control                                                         

                 Lumiracoxib - Non Naproxen 0.83    ( 0.46,1.51)  
                 NSAID                                            

                 Lumiracoxib - Naproxen     1.49    ( 0.94,2.36)  

                                                                  

  Duration       \>3 months: Lumiracoxib -  1.18    ( 0.84,1.67)  0.6121
                 control                                          

                 \<=3 months: Lumiracoxib - 0.93    ( 0.38,2.29)  
                 control                                          

                                                                  

  External       external: Lumiracoxib -    1.08    ( 0.75,1.54)  0.5562
  Adjudication   control                                          

                 no external: Lumiracoxib - 1.36    ( 0.66,2.80)  
                 control                                          

                                                                  

  Dose\*         Lumiracoxib high dose      1.17    ( 0.84,1.65)  0.5379
                 -control                                         

                 Lumiracoxib low dose       0.99    ( 0.57,1.71)  
                 -control                                         
  ------------------------------------------------------------------------------

\* Low dose is defined as up to 200 mg daily. High dose is 400 mg daily
and above.

### Myocardial infarctions

None of the comparisons was statistically significant. However as was
seen in TARGET, the relative risks for myocardial infarction differed
directionally when lumiracoxib was compared to non-naproxen NSAIDs and
naproxen (Table 1-3). The significance of the results was unchanged
regardless of comparator, dose, prospective expert adjudication or study
duration.

###### Table 1-3 Relative risk of MI with lumiracoxib and comparators from a stratified meta-analysis {#table-1-3-relative-risk-of-mi-with-lumiracoxib-and-comparators-from-a-stratified-meta-analysis .unnumbered}

  -------------------------------------------------------------------------------
  Comparisons    Contrasts                  Risk\    95% CI for\   Interaction\
                                            ratio    risk ratio    p-value
  -------------- -------------------------- -------- ------------- --------------
  All            all Lumiracoxib -all       1.28     ( 0.78, 2.12) 
  comparators    control                                           

                                                                   

  Type of        Lumiracoxib - placebo      1.06     ( 0.20, 6.69) 0.7484
  control                                                          

                 Lumiracoxib - Non Naproxen 0.80     ( 0.28, 2.25) 
                 NSAID                                             

                 Lumiracoxib - Naproxen     1.69     ( 0.82, 3.48) 

                                                                   

  Duration       \>3 months: Lumiracoxib -  1.30     ( 0.75, 2.27) 0.9191
                 control                                           

                 \<=3 months: Lumiracoxib - 1.39     ( 0.41, 4.72) 
                 control                                           

                                                                   

  External       external: Lumiracoxib -    1.20     ( 0.67, 2.16) 0.7152
  Adjudication   control                                           

                 no external: Lumiracoxib - 1.48     ( 0.54, 4.05) 
                 control                                           

                                                                   

  Dose           Lumiracoxib high dose      1.34     ( 0.79, 2.29) 0.5799
                 -control                                          

                 Lumiracoxib low dose       1.07     ( 0.46, 2.49) 
                 -control                                          
  -------------------------------------------------------------------------------

\* Low dose is defined as up to 200 mg daily. High dose is 400 mg daily
and above.

### Evidence from a cumulative stratified meta-analysis for APTC and MIs

Although the direction of the relative risks for the APTC endpoint and
MI for lumiracoxib compared to naproxen and non-naproxen NSAIDs diverge
in a consistent manner, we performed a cumulative meta-analysis
comparing lumiracoxib with all comparators over time from 2001 to 2004.
The cumulative meta-analysis analyzed more than 34 000 patients with a
total of 161 APTC events including 66 myocardial infarctions. This
analysis also found no significant difference at any time point (Figures
1-1 and 1-2 below). In fact, there was a trend over time from 2003 to
2004 towards a decrease in the relative risk of the APTC endpoint and
myocardial infarctions as more events and patients were included.

####### Figure 1-1 Cumulative stratified meta-analysis of APTC events in randomized trials comparing lumiracoxib with controls {#figure-1-1-cumulative-stratified-meta-analysis-of-aptc-events-in-randomized-trials-comparing-lumiracoxib-with-controls .unnumbered}

![](media/image2.wmf){width="6.290972222222222in"
height="3.472916666666667in"}

####### Figure 1-2 Cumulative stratified meta-analysis of MI in randomized trials comparing lumiracoxib with controls {#figure-1-2-cumulative-stratified-meta-analysis-of-mi-in-randomized-trials-comparing-lumiracoxib-with-controls .unnumbered}

![](media/image3.wmf){width="6.290972222222222in"
height="3.495833333333333in"}

When the analysis was done excluding naproxen, the risk decreased to
1.09 (95 % CI 0.56 -- 2.12) which supports our assertion that naproxen
at the high dose of 500 mg bid may have a antithrombotic effect (Figure
1-3 below)

####### Figure 1-3 Cumulative meta-analysis of MI in randomized trials comparing lumiracoxib with non-naproxen NSAIDs {#figure-1-3-cumulative-meta-analysis-of-mi-in-randomized-trials-comparing-lumiracoxib-with-non-naproxen-nsaids .unnumbered}

![](media/image4.wmf){width="6.299305555555556in"
height="3.667361111111111in"}

### Meta-analysis of all lumiracoxib data for stroke

None of the comparisons was statistically significant. This was
unchanged regardless of comparator, dose, prospective expert
adjudication or study duration (see Table 1-4 below). The cumulative
meta-analysis did not reveal a statistically significant difference at
any point in time (see Figure 1-4 below).

###### Table 1-4 Relative risk of stroke with lumiracoxib and comparators from a stratified meta-analysis {#table-1-4-relative-risk-of-stroke-with-lumiracoxib-and-comparators-from-a-stratified-meta-analysis .unnumbered}

  ------------------------------------------------------------------------------
  Comparisons    Contrasts                  Risk\   95% CI for\   Interaction\
                                            ratio   risk ratio    p-value
  -------------- -------------------------- ------- ------------- --------------
  All            all Lumiracoxib - all      1.20    ( 0.70, 2.07) 
  comparators    control                                          

                                                                  

  Type of        Lumiracoxib - placebo      0.89    ( 0.15, 5.08) 0.3174
  control                                                         

                 Lumiracoxib - Non Naproxen 0.91    ( 0.35, 2.35) 
                 NSAID                                            

                 Lumiracoxib - Naproxen     1.46    ( 0.70, 3.07) 

                                                                  

  Duration       \>3 months: Lumiracoxib -  1.18    ( 0.68, 2.06) 
                 control                                          

                 \<=3 months: Lumiracoxib -         not estimable 
                 control                                          

                                                                  

  External       external: Lumiracoxib -    1.06    ( 0.59, 1.88) 0.1424
  Adjudication   control                                          

                 no external: Lumiracoxib - 4.44    ( 0.51, 38.9) 
                 control                                          

                                                                  

  Dose           Lumiracoxib high dose -    1.19    ( 0.67, 2.11) 0.8955
                 control                                          

                 Lumiracoxib low dose -     1.12    ( 0.43, 2.92) 
                 control                                          
  ------------------------------------------------------------------------------

\* Low dose is defined as up to 200 mg daily. High dose is 400 mg daily
and above.

####### Figure 1-4 Cumulative stratified meta-analysis of stroke in randomized trials comparing lumiracoxib with controls {#figure-1-4-cumulative-stratified-meta-analysis-of-stroke-in-randomized-trials-comparing-lumiracoxib-with-controls .unnumbered}

![](media/image5.wmf){width="6.290972222222222in"
height="1.8215277777777779in"}

### Meta-analysis of all lumiracoxib data for peripheral vascular risk

None of the comparisons was statistically significant. This was
unchanged regardless of comparator, dose, prospective expert
adjudication or study duration (see Table 1-5 below). The cumulative
meta-analysis did not reveal a statistically significant difference at
any point in time (see Figure 1-5 below).

###### Table 1-5 Relative risk of peripheral vascular event with lumiracoxib and comparators from a stratified meta-analysis {#table-1-5-relative-risk-of-peripheral-vascular-event-with-lumiracoxib-and-comparators-from-a-stratified-meta-analysis .unnumbered}

  -------------------------------------------------------------------------------
  Comparisons    Contrasts                   Risk\   95% CI for\   Interaction\
                                             ratio   risk ratio    p-value
  -------------- --------------------------- ------- ------------- --------------
  All            all Lumiracoxib -all        1.10    ( 0.56, 2.16) 
  comparators    control                                           

                                                                   

  Type of        Lumiracoxib - placebo       0.99    ( 0.25, 3.97) 0.1631
  control                                                          

                 Lumiracoxib - Non Naproxen  1.82    ( 0.44, 7.53) 
                 NSAID                                             

                 Lumiracoxib - Naproxen      0.79    ( 0.26, 2.42) 

                                                                   

  Duration       \>3 months: Lumiracoxib -   1.36    ( 0.62, 2.95) 0.3967
                 control                                           

                 \<=3 months: Lumiracoxib -  0.68    ( 0.16, 2.95) 
                 control                                           

                                                                   

  External       external: Lumiracoxib -     1.01    ( 0.45, 2.26) 0.7378
  Adjudication   control                                           

                 no external: Lumiracoxib -  1.30    ( 0.37, 4.57) 
                 control                                           

                                                                   

  Dose           Lumiracoxib high dose -     0.98    ( 0.46, 2.09) 0.3570
                 control                                           

                 Lumiracoxib low dose -      1.55    ( 0.61, 3.95) 
                 control                                           
  -------------------------------------------------------------------------------

\* Low dose is defined as up to 200 mg daily. High dose is 400 mg daily
and above.

####### Figure 1-5 Cumulative stratified meta-analysis of peripheral vascular events in randomized trials comparing lumiracoxib with controls {#figure-1-5-cumulative-stratified-meta-analysis-of-peripheral-vascular-events-in-randomized-trials-comparing-lumiracoxib-with-controls .unnumbered}

![](media/image6.wmf){width="6.280555555555556in"
height="3.2868055555555555in"}

### Meta-analysis of all lumiracoxib data for MI / strokes / peripheral vascular events -- combined

For the combined endpoint of MIs/ strokes/ peripheral vascular events,
none of the comparisons was statistically significant. This was
unchanged regardless of comparator, dose, prospective expert
adjudication or study duration (see Table 1-8 below). The cumulative
meta-analysis did not reveal a statistically significant difference at
any point in time (see Figure 1-6 below).

This analysis combines definite MIs (as analyzed in section 1.2.2),
definite strokes (as analyzed in section 1.2.4), and peripheral events
(as analyzed in section 1.2.5).

This endpoint differs from the APTC endpoint (CV death, non-fatal
stroke, non-fatal MI) analyzed in section 1.2.1 in that it does not
include CV deaths that were not also adjudicated as stroke or MI, and in
that it does include peripheral events which are not considered for the
standard CV APTC endpoint.

###### Table 1-8 Relative risk for MI / all strokes / peripheral vascular events -- combined, with lumiracoxib and comparators from a stratified meta-analysis {#table-1-8-relative-risk-for-mi-all-strokes-peripheral-vascular-events-combined-with-lumiracoxib-and-comparators-from-a-stratified-meta-analysis .unnumbered}

  -------------------------------------------------------------------------------
  Comparisons    Contrasts                   Risk\   95% CI for\   Interaction\
                                             ratio   risk ratio    p-value
  -------------- --------------------------- ------- ------------- --------------
  All            all Lumiracoxib -all        1.24    ( 0.89, 1.71) 
  comparators    control                                           

                                                                   

  Type of        Lumiracoxib - placebo       0.97    ( 0.39, 2.41) 0.5519
  control                                                          

                 Lumiracoxib - Non Naproxen  1.05    ( 0.56, 1.98) 
                 NSAID                                             

                 Lumiracoxib - Naproxen      1.40    ( 0.88, 2.23) 

                                                                   

  Duration       \>3 months: Lumiracoxib -   1.29    ( 0.9, 1.83)  0.6445
                 control                                           

                 \<=3 months: Lumiracoxib -  1.04    ( 0.43,2.50)  
                 control                                           

                                                                   

  External       external: Lumiracoxib -     1.12    ( 0.78, 1.62) 0.3034
  Adjudication   control                                           

                 no external: Lumiracoxib -  1.69    ( 0.82, 3.50) 
                 control                                           

                                                                   

  Dose           Lumiracoxib high dose       1.22    ( 0.86, 1.73) 0.9485
                 -control                                          

                 Lumiracoxib low dose        1.24    ( 0.73, 2.11) 
                 -control                                          
  -------------------------------------------------------------------------------

\* Low dose is defined as up to 200 mg daily. High dose is 400 mg daily
and above.

####### Figure 1-6 Cumulative stratified meta-analysis for MI / all strokes / peripheral vascular events -- combined, in randomized trials comparing lumiracoxib with controls {#figure-1-6-cumulative-stratified-meta-analysis-for-mi-all-strokes-peripheral-vascular-events-combined-in-randomized-trials-comparing-lumiracoxib-with-controls .unnumbered}

![](media/image7.wmf){width="6.290972222222222in"
height="3.4520833333333334in"}

### Summary of lumiracoxib meta-analysis data

The meta-analysis did not reveal a statistically significant difference
between lumiracoxib and NSAIDs for:

1.  Myocardial infarcts (MI)

2\. Stroke (ischemic and hemorrhagic)

3\. APTC Cardiovascular (CV) composite endpoint, combining CV deaths,
non-fatal MIs, non-fatal strokes (ischemic and hemorrhagic)

4\. Pulmonary embolism (PE) and deep vein thrombosis (DVT)

5\. All thrombotic events, combining MIs, strokes, PE and DVT

In contrast, Juni et al found an increased risk for myocardial
infarctions in patients taking therapeutic doses of rofecoxib (12.5 --
50 mg od) (Figure 1-7 below).

####### Figure 1-7 Cumulative meta-analysis of myocardial infarctions in randomized trials comparing rofecoxib with control {#figure-1-7-cumulative-meta-analysis-of-myocardial-infarctions-in-randomized-trials-comparing-rofecoxib-with-control .unnumbered}

![](media/image8.png){width="6.304166666666666in"
height="4.688888888888889in"}

In the VIGOR study, there was a 4-5 fold statistically significant
increase in MIs in patients taking rofecoxib compared to patients on
naproxen. There was no statistically significant difference found in the
larger TARGET outcomes study for lumiracoxib vs NSAIDs combined or vs
the individual comparators (naproxen and ibuprofen) (see section below).

# TARGET design: Rationale for selecting two different traditional non steroidal anti‑inflammatory drugs (NSAIDs) as comparators

The study design for the Therapeutic Arthritis Research and
Gastrointestinal Event Trial (TARGET) was presented to the FDA Arthritis
Advisory Committee on December 7, 2001, after the Vioxx GI Outcomes
Research (VIGOR) study (Bombardier C et al. 2000) had been published.
Input from the FDA and the Arthritis Advisory Committee was integrated
into the final study design.

In VIGOR the COX--2 selective inhibitor rofecoxib given 50 mg od was
compared to naproxen 500 mg bid in approximately 8000 rheumatoid
arthritis (RA) patients. While the study succeeded in showing a
significant decrease in symptomatic and complicated ulcers in favor of
rofecoxib, there was a difference in the rate of the composite endpoint
of non-fatal myocardial infarction (MI), non‑fatal stroke, and sudden
death between the two groups favoring naproxen (0.8% for rofecoxib vs
0.4% for naproxen, p \< 0.05). This was driven mainly by the difference
in MIs in favor of naproxen (0.4% vs 0.1%, p \< 0.01).

It was argued by the sponsor that a plausible hypothesis to explain this
difference was that naproxen had an anti-platelet effect via COX‑1
activity and was therefore antithrombotic. This antiplatelet activity
was thought to be a unique feature of naproxen at the 500 mg dose when
given twice daily over a long period, compared to other NSAIDs which did
not have significant antiplatelet activity. The other possible
hypotheses for the VIGOR findings were that they were due to a unique
prothrombotic mechanism of rofecoxib or a combination of the above.

Therefore, it became of paramount public health importance to the larger
scientific community, as Novartis discussed the design of the TARGET
study with the FDA and the Arthritis Advisory Committee, that two NSAIDs
with different COX 1 and COX 2 activity be selected to compare to
lumiracoxib. This was thought then to be of importance with regard to
the effect on upper gastrointestinal complications, as celecoxib in the
CLASS study had failed to show a significant difference compared to
ibuprofen and diclofenac combined as a primary endpoint.

It must be noted that before the VIGOR and the Celecoxib Long Term
Arthritis Safety Study (CLASS) (Silverstein FE et al. 2000) were
performed, traditional NSAIDs had not been studied in a rigorous
clinical study of substantial duration in an arthritis patient
population. CLASS and VIGOR had a median duration of 6-9 months, while
TARGET had a fixed term design of 12 months and included more patients
(18000 plus) than CLASS (8000 plus) and VIGOR (8000 plus) combined. As
such, the TARGET study provides, to date, the largest and longest
database examining the CV and other organ effects of naproxen (3534
patient-years exposure) and ibuprofen (3090 patient-years exposure) in
an OA population.

Prior to these outcome studies, NSAIDs had been studied for short
periods of time in randomized control trials and most of the data came
from epidemiological, observational studies which have significant
potential methodological bias. Besides patients using a plethora of over
the counter drugs (NSAIDs), outside a clinical trial situation patients
are less compliant and unlikely to take NSAIDs daily on a long term
basis; rather patients typically treat themselves symptomatically. And
since only aspirin binds irreversibly to the platelet COX 1 receptor,
NSAIDs are unlikely to have a significant effect on platelet function if
taken intermittently or at low doses.

Therefore, the contribution to the understanding of the CV and other
organ systems profiles of the naproxen and ibuprofen arms from TARGET is
of significant clinical and scientific value for the discussion of NSAID
CV safety. The TARGET data provide and allow meaningful discussion and
interpretation of the CV profile of ibuprofen compared to lumiracoxib
and naproxen compared to lumiracoxib.

Finally, as we discuss the CV data, it is important to recall that
COX-2s were introduced to decrease NSAID induced ulcer complications. To
that end, lumiracoxib is the only remaining COX-2 that has demonstrated
a reduction in complicated ulcers (79% reduction in non aspirin
population) compared to NSAIDs as a primary endpoint in an outcomes
study.

# TARGET: Comparison of lumiracoxib and ibuprofen

Because TARGET consists of two identically designed studies conducted in
parallel (Protocol 0117 compared lumiracoxib 400 mg with naproxen 500 mg
bid and Protocol 2332 compared lumiracoxib 400 mg with ibuprofen 800 mg
tid), we can examine the CV profile of lumiracoxib 400 mg and compare it
separately to ibuprofen and to naproxen. It must be noted though that
TARGET was not powered to show a difference in CV adverse events, but
rather was powered for detection of the more frequent upper
gastro-intestinal complications. However, the TARGET study has numerous
methodological strengths that give importance to the CV data generated.
These strengths include:

> 1\. TARGET is the largest GI outcome study comparing a COX 2 selective
> inhibitor and NSAIDs published to date (N= 18 325);

2.  TARGET had a fixed term design that ensured that more than 60% of
    patients completed 12 months treatment;

3.  patients taking low dose aspirin were included (24% of the total
    population) and were stratified to treatment groups. This allowed
    the effect of low dose ASA on upper GI ulcer complications and CV
    thrombotic events to be examined and;

4.  an external, blinded cardio- and cerebrovascular committee
    prospectively defined and adjudicated all cases of MI (silent and
    clinical), strokes, CV deaths, deep vein thrombosis and pulmonary
    embolism. The rigor of CV disease ascertainment and analysis equals
    that normally found in CV outcomes studies.

## APTC endpoint - lumiracoxib vs ibuprofen

The table below (Table 3-1) shows that there is a consistent trend
towards numerically less adjudicated APTC events with lumiracoxib
compared to ibuprofen. Although the confidence interval crosses 1 and
the p values are not significant, [all]{.underline} the hazard ratios
(HR) are consistently less than one. The figure below (Figure 3-1)
illustrates the time course of APTC occurrences. Although the
differences are not significant, it is noteworthy that the Kaplan-Meier
curves appear to separate over time in favor of lumiracoxib. It is also
again worth noting that the ibuprofen substudy itself was at least the
same size and had a mean duration of exposure that was longer than
either CLASS or VIGOR.

######  {#section-1 .unnumbered}

###### Table 3-1 Confirmed or probable APTC endpoint: treatment comparisons using COX proportional hazards model (safety population) {#table-3-1-confirmed-or-probable-aptc-endpoint-treatment-comparisons-using-cox-proportional-hazards-model-safety-population .unnumbered}

  --------------------- ---------- ------------ --------- ----------- -------------
                        **Number   **Number (%) **HR**    **95% CI**  **P-value**
                        at risk**  with                               
                                   events**                           

  Overall TARGET                                                      
  population                                                          

  Lumiracoxib           4376       19 (0.43)    0.76      0.41-1.40   0.3775

  Ibuprofen             4397       23 (0.52)                          

  Non ASA population                                                  

  Lumiracoxib           3401       13 (0.38)    0.94      0.44-2.04   0.8842

  Ibuprofen             3431       13 (0.38)                          

  Low dose ASA                                                        
  population                                                          

  Lumiracoxib           975        6 (0.62)     0.56      0.20-1.54   0.2603

  Ibuprofen             966        10 (1.04)                          
  --------------------- ---------- ------------ --------- ----------- -------------

Source: TARGET study report

####### Figure 3-1 Lumiracoxib vs ibuprofen: cumulative incidence of confirmed/probable APTC endpoint {#figure-3-1-lumiracoxib-vs-ibuprofen-cumulative-incidence-of-confirmedprobable-aptc-endpoint .unnumbered}

![](media/image9.wmf){width="6.291666666666667in"
height="4.7243055555555555in"}

Source: TARGET study report

This may be contrasted with the CLASS study, where for celecoxib vs
ibuprofen in the non-ASA population (Figure 3-2 below), patients taking
celecoxib had a non-significant higher rate of serious thromboembolic
events (1.4%) compared to patients on ibuprofen (0.7%). Importantly, the
ibuprofen APTC cumulative rate at one year of 0.7% in TARGET is greater
than the lumiracoxib rate (Figure 3-1 above) and the same as the
ibuprofen rate in the CLASS study.

####### Figure 3-2 Posthoc depiction of cardiovascular events in non-aspirin users in the CLASS study (Ref: FitzGerald G) {#figure-3-2-posthoc-depiction-of-cardiovascular-events-in-non-aspirin-users-in-the-class-study-ref-fitzgerald-g .unnumbered}

![](media/image10.wmf){width="6.003472222222222in"
height="4.696527777777778in"}

##  Clinical and silent MIs - lumiracoxib vs ibuprofen

The number of MIs are few and although the p values are not significant,
it is worth noting again (as with the APTC endpoint above) that the
hazard ratios (HR) are consistently less than 1, in a direction favoring
lumiracoxib (Table 3-2).

###### Table 3-2 Lumiracoxib vs ibuprofen -- confirmed/probable clinical and silent myocardial infarctions {#table-3-2-lumiracoxib-vs-ibuprofen-confirmedprobable-clinical-and-silent-myocardial-infarctions .unnumbered}

  --------------------- ---------- ------------------ -------- ----------- -------------
                        **Number   **Number of        **HR**   **95% CI**  **P-value**
                        at risk**  patients with                           
                                   event (rate per                         
                                   100                                     
                                   patient-years)**                        

  Overall TARGET                                                           
  population                                                               

  Lumiracoxib           4376       5 (0.15)           0.66     0.21-2.09   0.4833

  Ibuprofen             4397       7 (0.23)                                

  Non ASA population                                                       

  Lumiracoxib           3401       4 (0.16)           0.75     0.20-2.79   0.6669

  Ibuprofen             3431       5 (0.21)                                

  Low dose ASA                                                             
  population                                                               

  Lumiracoxib           975        1 (0.14)           0.47     0.04-3.93   0.5328

  Ibuprofen             966        2 (0.30)                                
  --------------------- ---------- ------------------ -------- ----------- -------------

Source: Farkouh M *et al*. 2004 (Table 4)

## Lumiracoxib has a CV adverse event profile that is no different from ibuprofen for all adjudicated thrombotic events

A similar number of adjudicated thrombotic events occurred with
lumiracoxib (19 events) compared to ibuprofen (18 events) (Table 3-3).

###### Table 3-3 Adjudicated confirmed or probable thrombotic events (MI --clinical and silent, stroke, DVT and PE) {#table-3-3-adjudicated-confirmed-or-probable-thrombotic-events-mi-clinical-and-silent-stroke-dvt-and-pe .unnumbered}

  ----------------------------------------------------------------------------------------------------------
                                                  Cox proportional hazards model                  
  -------------------- ------------ ------------- -------------------------------- -------------- ----------
                                                  \_\_\_\_                                        

  Contrast             Number of\   Number of\    Hazard\                          95% CI for\    p-value
                       subjects\    subjects\     ratio                            hazard ratio   
                       at risk      with events                                                   

  \- Study 2332 -                                                                                 

  Lumiracoxib          4376         19 (0.43)                                                     

  Ibuprofen            4397         18 (0.41)                                                     

  Lumiracoxib vs                                  0.99                             0.52 - 1.88    0.9732
  Ibuprofen                                                                                       
  ----------------------------------------------------------------------------------------------------------

Source: TARGET study report

Similarly, although the number of peripheral vascular events was low,
there was no significant difference between lumiracoxib and ibuprofen
(Table 3-4).

###### Table 3-4 Adjudicated Confirmed or probable peripheral vascular events (DVT or PE) {#table-3-4-adjudicated-confirmed-or-probable-peripheral-vascular-events-dvt-or-pe .unnumbered}

  ----------------------------------------------------------------------------------------------------------
                                                  Cox proportional hazards model                  
  -------------------- ------------ ------------- -------------------------------- -------------- ----------
                                                  \_\_\_\_                                        

  Contrast             Number of\   Number of\    Hazard\                          95% CI for\    p-value
                       subjects\    subjects\     ratio                            hazard ratio   
                       at risk      with events                                                   

  \- Study 2332 -                                                                                 

  Lumiracoxib          4376         6 (0.14)                                                      

  Ibuprofen            4397         3 (0.07)                                                      

  Lumiracoxib vs                                  1.92                             0.48 - 7.68    0.3558
  Ibuprofen                                                                                       
  ----------------------------------------------------------------------------------------------------------

Source: TARGET study report

## Lumiracoxib showed a significantly better blood pressure profile than ibuprofen for de novo and aggravated hypertension, and numerically less edema and congestive heart failure (CHF).

### Blood pressure -- least squares mean change from baseline

In the TARGET study blood pressure (BP) measurements were done at every
study visit. In the ibuprofen substudy at study end, 4312 patients
taking lumiracoxib versus 4331 taking ibuprofen had BP measurements. For
systolic BP, least squares mean change from baseline to study end was
+ 0.7 mmHg for lumiracoxib and + 2.7 mmHg for ibuprofen (p \< 0.0001).
For diastolic BP, least squares mean change from baseline to study end
was + 0.0 mmHg for lumiracoxib and + 0.9 mmHg for ibuprofen
(p \< 0.0001). In TARGET, 4219 patients (46.3%) on lumiracoxib and 4061
(44.5%) patients in the NSAIDs groups (TARGET study report) were
hypertensive at baseline.

Further analyses within the TARGET study assessing differences between
lumiracoxib and ibuprofen for the following are presented using Kaplan
-- Meier curves;

1.  *De novo* hypertension

2.  Severe *de novo* hypertension (hypertension defined as SAEs or AEs
    leading to premature discontinuation)

3.  Aggravation (worsening) of baseline hypertension

4.  Hypertension-related AEs which are serious or lead to premature
    discontinuation from the study

### *De novo* hypertension -- lumiracoxib compared to ibuprofen

Patients taking lumiracoxib 400 mg od had significantly less new onset
of hypertension compared to patients allocated to ibuprofen 800 mg tid
(Figure 3-3 (p\<0.0001)

####### Figure 3-3 De novo hypertension- lumiracoxib compared to ibuprofen {#figure-3-3-de-novo-hypertension--lumiracoxib-compared-to-ibuprofen .unnumbered}

![](media/image11.png){width="6.298611111111111in"
height="4.7243055555555555in"}

### Severe *de novo* hypertension -- lumiracoxib compared to ibuprofen

There were few cases of severe de novo hypertension as defined above.
However, more patients taking ibuprofen had such events compared to
patients taking lumiracoxib (p=0.6177) (Figure 3-4).

####### Figure 3-4 Severe de novo hypertension -- lumiracoxib compared to ibuprofen {#figure-3-4-severe-de-novo-hypertension-lumiracoxib-compared-to-ibuprofen .unnumbered}

![](media/image12.png){width="6.298611111111111in"
height="4.7243055555555555in"}

Patients taking ibuprofen were significantly more likely to have
aggravation of hypertension compared to patients taking lumiracoxib
(p=0.0005) (Figure 3-5).

####### Figure 3-5 Aggravation of hypertension -- lumiracoxib compared to ibuprofen {#figure-3-5-aggravation-of-hypertension-lumiracoxib-compared-to-ibuprofen .unnumbered}

![](media/image13.png){width="6.298611111111111in"
height="4.7243055555555555in"}

###  *Severe* aggravation of hypertension

Significantly more patients taking ibuprofen had cases of severe
aggravation of their hypertension compared to patients taking
lumiracoxib (p=0.01) (Figure 3-6).

####### Figure 3-6 Severe aggravation of hypertension {#figure-3-6-severe-aggravation-of-hypertension .unnumbered}

![](media/image14.png){width="6.298611111111111in"
height="4.7243055555555555in"}

This statistically significant difference in BP may have significant
clinical benefits for lumiracoxib when compared to ibuprofen over the
long-term, since over 45% of patients in the TARGET study were found to
be hypertensive. This is in keeping with other demographic studies in OA
(Singh G et al. 2002). In fact, a recent study of OA patients found that
increases in systolic BP of 1-5 mmHg were associated with 7100 - 35700
additional ischemic heart disease and stroke events over one year with
corresponding costs (Year 2000 USD) of 114-569 million USD per year.
They concluded that relatively small changes in systolic BP associated
with use of common arthritis medications could have a significant effect
on the cardiovascular profile (Singh G et al. 2003). This was confirmed
in an even more recent analysis by Grover et al (2005) that modeled data
from a rofecoxib study (SUCCESS VI), concluding that maintaining BP
control could result in 668,000 person years of life saved with over
\$2.4 billion (USD) in direct health care cost savings (Grover et al,
Hypertension 45:92-97, 2005).

### Congestive heart failure (CHF), edema and weight gain

Lumiracoxib in TARGET was associated with numerically less edema and CHF
compared to ibuprofen (Table 3-5).

###### Table 3-5 TARGET study -- lumiracoxib vs ibuprofen. Incidence of edema, CHF and weight gain (overall safety population). {#table-3-5-target-study-lumiracoxib-vs-ibuprofen.-incidence-of-edema-chf-and-weight-gain-overall-safety-population. .unnumbered}

  ----------------------------- -------------------- --------------------
                                **Lumiracoxib        **Ibuprofen
                                (N=4376)**           (N=4397)**

                                **n (%)**            **n (%)**

  Edema AEs - prespecified      217 (5.0)            245 (5.6)
  terms                                              

  CHF (post hoc analysis)       12 (0.27)            15 (0.34)

                                **Lumiracoxib        **Ibuprofen
                                (N=4129)**           (N=4120)**

  Increase in weight from       353 (8.5)            352 (8.5)
  baseline \> 5%                                     
  ----------------------------- -------------------- --------------------

Source: TARGET study report

### Cases of edema reported as SAEs or leading to premature discontinuation

More patients taking ibuprofen reported "severe" cases of edema compared
to patients allocated to lumiracoxib (p=0.0560) (Figure 3-7).

####### Figure 3-7 Edema reported as SAEs or requiring premature discontinuation {#figure-3-7-edema-reported-as-saes-or-requiring-premature-discontinuation .unnumbered}

![](media/image15.png){width="6.298611111111111in"
height="4.7243055555555555in"}

## Analysis of upper gastro-intestinal events: lumiracoxib vs ibuprofen

The primary objective of the TARGET study was to determine the risk of
upper gastro-intestinal ulcer complications of lumiracoxib compared to
NSAIDs (ibuprofen and naproxen). Patients taking lumiracoxib had an 83%
reduction in upper GI ulcer complications compared to patients taking
ibuprofen in the non-aspirin population (HR 0.17, 95% CI 0.07 -- 0.45,
p=0.0003); a 71% reduction in the overall population (HR 0.29, 95% CI
0.14 -0.59, p=0.0006) and non-significant 8% decrease in the low dose
aspirin population (Table 3-6).

The four-fold reduction in magnitude of upper GI ulcer complications
seen with lumiracoxib compared to ibuprofen has important clinical
implications given the societal burden of morbidity relating to ulcer
complications from NSAID use.

###### Table 3-6 TARGET study - definite or probable UGIT complications (POBs) {#table-3-6-target-study---definite-or-probable-ugit-complications-pobs .unnumbered}

  ------------------- ---------- ---------- ------------- ------------- ---------------
                      **Number   **Number   **KM          **KM          **p-value\***
                      at risk**  with       estimate\     estimate\     
                                 events**   % (CI) at day % (CI) at day 
                                            196**         392**         

  **TARGET (0117 +                                                      
  2332)**                                                               

  **No low-dose                                                         
  aspirin group**                                                       

  Lumiracoxib         6950       14         0.15 ( 0.05 - 0.25 ( 0.12 - \<0.0001
                                            0.25)         0.39)         

  NSAIDs              6968       64         0.81 ( 0.58 - 1.09 ( 0.82 - 
                                            1.03)         1.36)         

  **Overall patient                                                     
  group**                                                               

  Lumiracoxib         9117       29         0.22 ( 0.12 - 0.40 ( 0.25 - \<0.0001
                                            0.33)         0.54)         

  NSAIDs              9127       83         0.81 ( 0.61 - 1.09 ( 0.85 - 
                                            1.00)         1.32)         

  **Low-dose aspirin                                                    
  group**                                                               

  Lumiracoxib         2167       15         0.47 ( 0.16 - 0.88 ( 0.43 - 0.4972
                                            0.78)         1.32)         

  NSAIDs              2159       19         0.82 ( 0.40 - 1.09 ( 0.60 - 
                                            1.23)         1.58)         

  **Study 2332**                                                        

  **No low-dose                                                         
  aspirin group**                                                       

  Lumiracoxib         3401       5          0.14 ( 0.00 - 0.19 ( 0.02 - \<0.0001
                                            0.28)         0.35)         

  Ibuprofen           3431       28         0.73 ( 0.42 - 1.00 ( 0.63 - 
                                            1.03)         1.38)         

  **Overall patient                                                     
  group**                                                               

  Lumiracoxib         4376       10         0.18 ( 0.05 - 0.28 ( 0.11 - 0.0003
                                            0.32)         0.46)         

  Ibuprofen           4397       33         0.69 ( 0.42 - 0.94 ( 0.61 - 
                                            0.95)         1.26)         

  **Low-dose aspirin                                                    
  group**                                                               

  Lumiracoxib         975        5          0.32 ( 0.00 - 0.64 ( 0.07 - 0.9615
                                            0.69)         1.21)         

  Ibuprofen           966        5          0.55 ( 0.01 - 0.70 ( 0.09 - 
                                            1.09)         1.31)         
  ------------------- ---------- ---------- ------------- ------------- ---------------

Modified ITT analysis excludes any event starting within 2 days of
initiation of study drug.\
\* p value for treatment comparisons, lumiracoxib vs. comparator, from
log rank test stratified by sub-study where appropriate\
Source: TARGET study report

## Low dose aspirin population -- hemoglobin changes: Lumiracoxib vs ibuprofen and naproxen:

In the patients taking low-dose aspirin, those patients allocated to
ibuprofen had significantly more hemoglobin loss at the end-of-study
compared to patients taking lumiracoxib (mean hemoglobin difference of
1.17 g/L, p=0.0012) (Table 3-7). Significant loss of hemoglobin results
in anemia, and may be caused by otherwise undetected internal bleeding
resulting from NSAID use.

###### Table 3-7 Hemoglobin (g/l) LS means for end-of-study value and its change from baseline  {#table-3-7-hemoglobin-gl-ls-means-for-end-of-study-value-and-its-change-from-baseline .unnumbered}

**LS means for end-of-study value and its change from baseline**

**General linear model with baseline value, age, and treatment as
dependent variables**

**Selected No. of Chg f Baseline**

**group Comparison patients LS Mean (95% CI) LS Mean (95% CI) p-value**

0117 Lumi 4615 136.3 (136.1,136.5) -2.40 (-2.62,-2.17) \<0.0001

Naproxen 4598 135.4 (135.1,135.6) -3.31 (-3.54,-3.08)

0117/asa Lumi 1162 135.9 (135.5,136.4) -2.96 (-3.43,-2.48) 0.3856

Naproxen 1168 135.6 (135.2,136.1) -3.25 (-3.72,-2.78)

0117/non-asa Lumi 3453 136.4 (136.1,136.7) -2.21 (-2.47,-1.95) \<0.0001

Naproxen 3430 135.3 (135.0,135.5) -3.33 (-3.59,-3.07)

2332 Lumi 4273 136.7 (136.5,136.9) -2.24 (-2.47,-2.02) \<0.0001

Ibuprofen 4295 134.6 (134.4,134.9) -4.33 (-4.56,-4.11)

2332/asa Lumi 954 136.0 (135.5,136.5) -3.00 (-3.50,-2.50) 0.0012

Ibuprofen 944 134.8 (134.3,135.3) -4.17 (-4.67,-3.67)

2332/non-asa Lumi 3319 136.9 (136.7,137.2) -2.03 (-2.28,-1.78) \<0.0001

Ibuprofen 3351 134.6 (134.3,134.8) -4.38 (-4.63,-4.13)

This difference in hemoglobin loss was even greater (1.78 g/L, p\<
0.0001) when only patients who completed the entire 12- month study were
analyzed (Table 3-8 below).

###### Table 3-8 Hemoglobin \[g/L\] LS means for 12-month value and its change from baseline {#table-3-8-hemoglobin-gl-ls-means-for-12-month-value-and-its-change-from-baseline .unnumbered}

**LS means for 12-month value and its change from baseline**

General linear model with baseline value, age, and treatment as
dependent variables

**Selected No. of Chg f Baseline**

**group Comparison patients LS Mean (95% CI) LS Mean (95% CI) p-value**

0117 Lumi 3065 136.7 (136.5,137.0) -1.98 (-2.24,-1.73) \<0.0001

Naproxen 2986 135.9 (135.6,136.1) -2.85 (-3.11,-2.59)

0117/asa Lumi 726 136.6 (136.0,137.2) -2.41 (-2.98,-1.85) 0.2499

Naproxen 764 136.1 (135.6,136.7) -2.88 (-3.43,-2.33)

0117/non-asa Lumi 2339 136.8 (136.5,137.1) -1.85 (-2.13,-1.56) \<0.0001

Naproxen 2222 135.8 (135.5,136.1) -2.84 (-3.14,-2.55)

2332 Lumi 2687 137.2 (136.9,137.5) -2.06 (-2.33,-1.80) \<0.0001

Ibuprofen 2509 134.8 (134.5,135.1) -4.45 (-4.72,-4.17)

2332/asa Lumi 585 136.4 (135.8,137.0) -2.56 (-3.16,-1.97) \<0.0001

Ibuprofen 549 134.6 (134.0,135.2) -4.33 (-4.94,-3.71)

2332/non-asa Lumi 2102 137.4 (137.1,137.7) -1.93 (-2.23,-1.63) \<0.0001

Ibuprofen 1960 134.9 (134.5,135.2) -4.48 (-4.78,-4.17)

This finding in the population taking low-dose aspirin is perhaps the
first significant gastro-intestinal data from a randomized controlled
trial showing benefit for a COX2 selective inhibitor in the presence of
low-dose aspirin. Differences in hemoglobin may represent a more
sensitive indicator of adverse GI events than the primary endpoint used
in TARGET (upper GI ulcer complications), which showed a trend in favor
of lumiracoxib in the low-dose aspirin population. A hemoglobin
difference of almost 2g/L may have a significant impact on the overall
health of an elderly OA population. Since many elderly patients are on
low dose aspirin, these patients are likely to have a high
cardiovascular risk and it is important in this population not to
increase the risk of anemia. Anemia may contribute to the development of
congestive heart failure.

## Combined GI and CV endpoint -- lumiracoxib vs ibuprofen

When the adjudicated endpoints for GI (upper GI ulcer complications) and
CV (APTC endpoint) are combined, there was a 50% reduction of these
events in favor of lumiracoxib compared to ibuprofen in the overall
population (HR 0.50, 95% CI 0.32 -- 0.79, p = 0.0025) and a 56%
reduction in the non-aspirin population (HR 0.44, 95% CI 0.26 -- 0.76, p
= 0.0032) (Table 3-9).

###### Table 3-9 TARGET -- GI and CCV (APTC) combined endpoint {#table-3-9-target-gi-and-ccv-aptc-combined-endpoint .unnumbered}

  ---------------------- ---------- ---------- ---------- --------- ---------------
                         **Number   **Number   **Hazard   **95%     **p-value\***
                         at risk**  (%) with   ratio**    CI**      
                                    events**                        

  **Overall patient                                                 
  group**                                                           

  **TARGET (0117 +                                                  
  2332)**                                                           

  Lumiracoxib            9117       89 (0.98)  0.65       0.49 -    0.0014
                                                          0.84      

  NSAIDs                 9127       133 (1.46)                      

  **Study 2332**                                                    

  Lumiracoxib            4376       30 (0.69)  0.50       0.32 -    0.0025
                                                          0.79      

  Ibuprofen              4397       56 (1.27)                       

  **No low-dose aspirin                                             
  group**                                                           

  **TARGET (0117 +                                                  
  2332)**                                                           

  Lumiracoxib            6950       50 (0.72)  0.52       0.37 -    0.0002
                                                          0.74      

  NSAIDs                 6968       91 (1.31)                       

  **Study 2332**                                                    

  Lumiracoxib            3401       19 (0.56)  0.44       0.26 -    0.0032
                                                          0.76      

  Ibuprofen              3431       41 (1.19)                       
  ---------------------- ---------- ---------- ---------- --------- ---------------

\* p value based on Wald chi-squared statistic for treatment comparison,
lumiracoxib vs. comparator, stratified by age; and also by sub-study
where appropriate.\
Source: TARGET study report

This is further illustrated by the Kaplan-Meier curve in Figure 3-8
below.

####### Figure 3-8 TARGET: Combined GI and CCV endpoint Kaplan -- Meier {#figure-3-8-target-combined-gi-and-ccv-endpoint-kaplan-meier .unnumbered}

![](media/image16.png){width="6.298611111111111in"
height="4.7243055555555555in"}

## Summary: Lumiracoxib does not increase CV adverse events compared to ibuprofen and has a positive benefit to risk profile compared to ibuprofen.

From the TARGET study, which is the largest gastrointestinal outcomes
study in arthritis to date to prospectively examine all major outcomes
including CV, there is no evidence that lumiracoxib is associated with
an increase in serious CV thrombotic events (APTC endpoint and MIs) when
compared to ibuprofen. In fact, lumiracoxib had numerically fewer events
than ibuprofen, indicating that lumiracoxib does not have a thrombotic
CV signal. Except for the theoretical possibility of an interaction
between ibuprofen and low dose aspirin, ibuprofen has not been shown to
increase CV risk. Of note is that in TARGET, lumiracoxib is associated
with numerically less edema and CHF and with a significantly lower mean
increase in BP and less hypertension.

Ibuprofen is available in the US as an over the counter drug. In TARGET,
lumiracoxib was associated with an 83% (p \< 0.0001) decrease in upper
gastrointestinal (GI) tract ulcer complications compared to ibuprofen.
Further, patients taking ibuprofen had significantly more hemoglobin
loss at the end of the study compared to patients on lumiracoxib, even
in those taking low-dose aspirin for CV prophylaxis. The immense GI
benefit gained by using lumiracoxib combined with the numerically fewer
cardiac (CV) events, provides robust evidence that lumiracoxib has a
superior benefit/risk safety profile compared to ibuprofen.

Finally, when the combined endpoint of adjudicated primary GI events and
CCV (APTC) events are assessed, patients taking lumiracoxib at 4 times
the recommended OA dose have a significant benefit (reduction) compared
to patients on ibuprofen (50% decrease in the overall population, p =
0.0025)..

# TARGET: Lumiracoxib compared to naproxen

## APTC endpoint - lumiracoxib vs naproxen

###### Table 4-6 Confirmed or probable APTC endpoint: treatment comparisons using COX proportional hazards model (safety population) {#table-4-6-confirmed-or-probable-aptc-endpoint-treatment-comparisons-using-cox-proportional-hazards-model-safety-population .unnumbered}

  ---------------------- ---------- ----------- -------- ------------ -------------
                         **Number   **Number    **HR**   **95% CI**   **P-value**
                         at risk**  (%) with                          
                                    events**                          

  Overall TARGET                                                      
  population                                                          

  Lumiracoxib            4741       40 (0.84)   1.46     (0.89 -2.37) 0.1313

  Naproxen               4730       27 (0.57)                         

  Non ASA population                                                  

  Lumiracoxib            3549       22 (0.62)   1.49     (0.76 --     0.2417
                                                         2.92)        

  Naproxen               3537       14 (0.47)                         

  Low dose ASA                                                        
  population                                                          

  Lumiracoxib            1192       18 (1.51)   1.42     (0.70 --     0.3368
                                                         2.90)        

  Naproxen               1193       13 (1.09)                         
  ---------------------- ---------- ----------- -------- ------------ -------------

Source: TARGET study report

In Table 4-1 above, although there was no statistically significant
difference for the primary endpoint (APTC) between lumiracoxib and
naproxen in all populations, fewer events occurred with naproxen. This
is in contrast to the ibuprofen sub-study. In comparison, in the VIGOR
trial rofecoxib was associated with a significant difference (OR 1.94,
95% CI 1.10 -3.44, p \< 0.05) in favor of naproxen for a similar
endpoint. Importantly, the VIGOR trial was of a shorter median duration
and had less patient exposure.

Figure 4-1 below provides time-to-event curves for the rates of serious
CV events over time (1 year) between lumiracoxib and naproxen in TARGET.

####### Figure 4-1 Lumiracoxib vs naproxen: cumulative incidence of confirmed/probable APTC endpoint {#figure-4-1-lumiracoxib-vs-naproxen-cumulative-incidence-of-confirmedprobable-aptc-endpoint .unnumbered}

![](media/image17.png){width="6.298611111111111in"
height="4.7243055555555555in"}

Source: TARGET study report

## TARGET study: Clinical and silent MIs - lumiracoxib vs naproxen

###### Table 4-7 Incidence of confirmed or probable myocardial infarction (clinical and silent) -- lumiracoxib vs naproxen {#table-4-7-incidence-of-confirmed-or-probable-myocardial-infarction-clinical-and-silent-lumiracoxib-vs-naproxen .unnumbered}

  -------------------- ---------- ------------------ -------- ----------- -------------
                       **Number   **Number of        **HR**   **95% CI**  **P-value**
                       at risk**  patients with                           
                                  event (rate per                         
                                  100                                     
                                  patient-years)**                        

  Overall TARGET                                                          
  population                                                              

  Lumiracoxib          4741       18 (0.49)          1.77     0.82-3.84   0.1471

  Naproxen             4730       10 (0.28)                               

  Non ASA population                                                      

  Lumiracoxib          3549       10 (0.36)          2.37     0.74-7.55   0.1454

  Naproxen             3537       4 (0.15)                                

  Low dose ASA                                                            
  population                                                              

  Lumiracoxib          1192       8 (0.91)           1.36     0.47-3.93   0.5658

  Naproxen             1193       6 (0.67)                                
  -------------------- ---------- ------------------ -------- ----------- -------------

Source: Farkouh M *et al.* 2004 (Table 4)

The data from Table 4-2 above show that there are numerically fewer MIs
in the naproxen group than in the lumiracoxib group. This is in contrast
to the trend in the ibuprofen substudy (less events with lumiracoxib),
but is in keeping with the evidence that naproxen 500 mg bid taken
continuously has antiplatelet activity via COX‑1 activity. Supporting
evidence for naproxen's COX-1 activity at this dose and dosing regimen
(500 mg bid) has been shown and published elsewhere (Capone *et al.*
2004, Weir *et al.* 2003, Juni *et al.* 2004).

This evidence in combination with the data from the Jüni et al.
meta-analysis and the lumiracoxib meta-analysis further supports the
hypothesis that naproxen, if given 500 mg twice daily for an extended
period of time, exerts antiplatelet effects.

Confirmation of this hypothesis is in fact provided by the TARGET study
results. If the hypothesis that naproxen has COX-1 antiplatelet activity
at the dose and regimen is correct, the addition of a drug with COX-1
activity to the naproxen vs. lumiracoxib substudy should negate this
difference in MIs (canceling the benefit of MI reduction seen in
patients taking naproxen). This is shown in Table 4-2 above when the low
dose aspirin population is considered: naproxen 6 events vs lumiracoxib
8 events.

## Lumiracoxib has a CV adverse event profile that is no different from naproxen for other adjudicated CV events.

Besides myocardial infarctions, other CV endpoints adjudicated do not
differ for naproxen vs lumiracoxib. As shown in Table 4-3 below, though
the number of events is low, there is no evidence of a CV signal when
lumiracoxib is compared to naproxen for these events.

###### Table 4-3 TARGET study: lumiracoxib vs naproxen. Incidence of confirmed or probable cardiovascular and cerebrovascular events (overall safety population). {#table-4-3-target-study-lumiracoxib-vs-naproxen.-incidence-of-confirmed-or-probable-cardiovascular-and-cerebrovascular-events-overall-safety-population. .unnumbered}

  ----------------------- ----------------------- -----------------------
                          **Lumiracoxib           **Naproxen (N=4730)**
                          (N=4741)**              

                          **n (%)**               **n (%)**

  Cardiovascular death    11 (0.23)               8 (0.17)

  Stroke                  16 (0.34)               12 (0.25)

  Transient ischemic      2 (0.04)                5 (0.11)
  attack                                          

  Unstable angina         6 (0.13)                4 (0.08)

  Deep vein thrombosis    2 (0.04)                4 (0.08)

  Pulmonary embolism      2 (0.04)                4 (0.08)
  ----------------------- ----------------------- -----------------------

Source: TARGET study report

## Lumiracoxib has a significantly better blood pressure profile than naproxen, and numerically less congestive heart failure and weight gain.

### Blood pressure -- Least Square Means change from baseline

In the TARGET study blood pressure (BP) measurements were done at every
study visit. In the naproxen substudy at study end, 4,678 patients
taking lumiracoxib versus 4,661 taking naproxen had BP measurements. For
systolic BP, mean change (LSMs) from baseline to study end was + 0.2
mmHg for lumiracoxib and + 1.4 mmHg for naproxen (p \< 0.0001). For
diastolic BP, least squares mean change from baseline to study end was -
0.3 mmHg for lumiracoxib and + 0.2 mmHg for naproxen (p = 0.0002).

As shown in the HOT study (Hansson L et al, 1998) and discussed
previously, this significant difference in BP may have significant
clinical benefits for lumiracoxib when compared to naproxen in the
long-term. Naproxen, like ibuprofen, is a widely used NSAID that is
available over the counter in the US.

### Congestive heart failure (CHF) and weight gain

In TARGET, lumiracoxib was associated with numerically less congestive
heart failure and weight gain from baseline compared to naproxen (Table
4-4).

###### Table 4-4 TARGET study: lumiracoxib vs naproxen. Incidence of CHF and weight gain (overall safety population). {#table-4-4-target-study-lumiracoxib-vs-naproxen.-incidence-of-chf-and-weight-gain-overall-safety-population. .unnumbered}

  ----------------------------- -------------------- --------------------
                                **Lumiracoxib        **Naproxen
                                (N=4741)**           (N=4730)**

                                **n (%)**            **n (%)**

  CHF (post hoc analysis)       10 (0.21)            16 (0.34)

                                **Lumiracoxib        **Naproxen
                                (N=4481)**           (N=4441)**

  Increase in weight from       364 (8.1)            406 (9.1)
  baseline \> 5%                                     
  ----------------------------- -------------------- --------------------

Source: TARGET study report

## Combined GI and CV endpoint -- lumiracoxib vs naproxen

When lumiracoxib was compared to naproxen for the primary endpoint
(upper gastrointestinal ulcer complications) there was a 76% reduction
in the non-aspirin population (HR 0.24, 95% CI 0.12-0.50, p =0.0001).

For the combined endpoints GI/CCV, numerically fewer patients in the
overall population on lumiracoxib had events compared to naproxen (HR
0.75, 95% CI 0.53-1.05, p = 0.0961). Importantly, patients on
lumiracoxib and not taking low dose aspirin had a significant 41%
decrease in the combined GI/CCV events compared to patients on naproxen
(HR 0.59, 95% CI 0.38 -- 0.93, p = 0.0219). This would indicate that
notwithstanding the numerical difference in CV events, lumiracoxib has a
positive benefit-risk ratio compared to naproxen (Table 4-5).

###### Table 4-5 GI and CCV (APTC) combined endpoint {#table-4-5-gi-and-ccv-aptc-combined-endpoint .unnumbered}

  ---------------------- ---------- ---------- ---------- --------- ---------------
                         **Number   **Number   **Hazard   **95%     **p-value\***
                         at risk**  (%) with   ratio**    CI**      
                                    events**                        

  **Overall patient                                                 
  group**                                                           

  **TARGET (0117 +                                                  
  2332)**                                                           

  Lumiracoxib            9117       89 (0.98)  0.65       0.49 -    0.0014
                                                          0.84      

  NSAIDs                 9127       133 (1.46)                      

  **Study 0117**                                                    

  Lumiracoxib            4741       59 (1.24)  0.75       0.53 -    0.0961
                                                          1.05      

  Naproxen               4730       77 (1.63)                       

  **No low-dose aspirin                                             
  group**                                                           

  **TARGET (0117 +                                                  
  2332)**                                                           

  Lumiracoxib            6950       50 (0.72)  0.52       0.37 -    0.0002
                                                          0.74      

  NSAIDs                 6968       91 (1.31)                       

  **Study 0117**                                                    

  Lumiracoxib            3549       31 (0.87)  0.59       0.38 -    0.0219
                                                          0.93      

  Naproxen               3537       50 (1.41)                       
  ---------------------- ---------- ---------- ---------- --------- ---------------

\* p value based on Wald chi-squared statistic for treatment comparison,
lumiracoxib vs. comparator, stratified by age; and also by sub-study
where appropriate.\
Source: TARGET study report

## Summary: Lumiracoxib compared to naproxen

The numerical decrease in MIs seen with naproxen is observed in the
population not taking low dose aspirin. For all other adjudicated CV
endpoints including the APTC endpoint, there is no difference seen
between lumiracoxib and naproxen. Of note, in TARGET lumiracoxib was
associated with numerically less CHF and weight gain and with a
significantly lower mean increase in BP and less hypertension compared
to naproxen. Naproxen is available as an over the counter drug in the
US. Lumiracoxib in TARGET was shown to decrease ulcer complications by
76% when compared to naproxen (p \< 0.0001). Lumiracoxib is the only
remaining COX-2 inhibitor to show a significant reduction in ulcer
complications as a primary outcome compared to NSAIDs.

While the TARGET study has provided more data that supports the naproxen
anti-thrombotic hypothesis, naproxen does not have a general
cardioprotective effect. As we have discussed above, there are other
clinically relevant CV risk factors for which naproxen clearly does not
provide a benefit (CHF, weight gain, hypertension).

# TARGET: high CV risk patients -- analysis of APTC and MI (silent and clinical events)

TARGET included more than 2200 patients with a CV history or high CV
risk based on Framingham risk equations as seen in the Table 5-1 below.

###### Table 5-1 TARGET patient characteristics -- high CV risk patients {#table-5-1-target-patient-characteristics-high-cv-risk-patients .unnumbered}

+----------------------+-----------------------+-----------------------+
|                      | **Lumiracoxib (N =    | **NSAIDs (N=9127)**   |
|                      | 9117)**               |                       |
|                      |                       | **n (%)**             |
|                      | **n (%)**             |                       |
+----------------------+-----------------------+-----------------------+
| **History of CV      | **981 (10.8)**        | **899 (9.8)**         |
| disease**            |                       |                       |
+----------------------+-----------------------+-----------------------+
| Coronary artery      | 683 (7.5)             | 624 (6.8)             |
| disease              |                       |                       |
+----------------------+-----------------------+-----------------------+
| MI                   | 150 (1.6)             | 138 (1.5)             |
+----------------------+-----------------------+-----------------------+
| Cerebrovascular      | 177 (1.9)             | 172 (1.9)             |
| disease              |                       |                       |
+----------------------+-----------------------+-----------------------+
| Peripheral vascular  | 151 (1.7)             | 145 (1.5)             |
| disease              |                       |                       |
+----------------------+-----------------------+-----------------------+
| High risk Framingham | 160 (1.8)             | 167 (1.8)             |
| score                |                       |                       |
+----------------------+-----------------------+-----------------------+
| **Total High CV      | **1141 (12.5)**       | **1066 (11.7)**       |
| risk**               |                       |                       |
+----------------------+-----------------------+-----------------------+
| **Other CV risk      |                       |                       |
| factors**            |                       |                       |
+----------------------+-----------------------+-----------------------+
| Hypertension         | 4219 (46.3)           | 4061 (44.5)           |
+----------------------+-----------------------+-----------------------+
| Dyslipidemia         | 1829 (20.1)           | 1834 (20.1)           |
+----------------------+-----------------------+-----------------------+
| Diabetes             | 744 (8.2)             | 675 (7.4)             |
+----------------------+-----------------------+-----------------------+

Source: TARGET study report

###### Table 5-2 Patients with high CV risk: APTC and MIs (clinical and silent) {#table-5-2-patients-with-high-cv-risk-aptc-and-mis-clinical-and-silent .unnumbered}

\* Including silent MIs\
Source: TARGET study report

Table 5-2 shows no significant difference in the APTC endpoint or in MIs
when this high CV risk population is analyzed. The same can be seen in
patients with a history of coronary artery disease (Table 5-3 below).

###### Table 5-3 Patients with history of coronary artery disease (Framingham risk patients excluded): APTC and MIs (clinical and silent) {#table-5-3-patients-with-history-of-coronary-artery-disease-framingham-risk-patients-excluded-aptc-and-mis-clinical-and-silent .unnumbered}

  ---------------- ---------- ----------- --------- ----------- ----------
  **\              **\        **APTC\     **P       **MI\*\     **P -
  Treatment**      N**        n (%)**     value**   n (%)**     value**

  Lumiracoxib      981        13 (1.33)   1.0000    8 (0.82)    0.7925

  NSAIDs           899        11 (1.22)             6 (0.67)    

  Lumiracoxib      588        11 (1.87)   0.6469    7 (1.19)    0.7741
  (0117)                                                        

  Naproxen         559        8 (1.34)              5 (0.89)    

  Lumiracoxib      393        2 (0.51)    0.6674    1 (0.25)    1.0000
  (2332)                                                        

  Ibuprofen        340        3 (0.88)              1 (0.29)    
  ---------------- ---------- ----------- --------- ----------- ----------

\* Including silent MIs, Source: TARGET study report

The fact that TARGET included over n=2200 patients who were at high CV
risk establishes the study as providing CV safety data comparable to a
standalone high CV risk safety study in which n=1000 patients receive
lumiracoxib and n=1000 receive an active comparator. However, Novartis
acknowledges that although patients that experienced a prior MI,
congestive heart failure, unstable angina and other severe CV symptoms
were allowed into TARGET, their enrollment was predicated on the fact
that these events occurred or were diagnosed six months or more prior to
enrollment. However, 288 patients with a prior MI were enrolled in
TARGET. This very high risk group is analyzed further below.

## Patients with a previous MI: repeat CV events

Because of the debate on CV risk, we performed a post--hoc analysis of
the patients who had a myocardial infarction 6 or more months before
participating in the TARGET study. A total of 288 patients had a
previous MI (1.6% of TARGET patients) and in this group there were 10
APTC events that re-occurred during the study. There were numerically
more APTC events in the patients randomized to naproxen (6 events) than
in patients taking lumiracoxib (3 events) or ibuprofen (1 event).

Of the 10 APTC events that occurred, 4 were MIs. Numerically more MIs
occurred in patients taking naproxen (3 events) than patients taking
lumiracoxib (1 event). Patients with a previous MI represent the highest
risk group for recurrent MIs and it is this group that would be expected
to show a difference in event rates if lumiracoxib was prothrombotic.
Because the number of events is small, it is possible that the
differences are due to chance, but it is reassuring that the number of
APTC events or MIs in the lumiracoxib group was not higher than in the
patients taking naproxen.

## Peripheral vascular events -- ASA population

When peripheral vascular risk is analyzed by presence of aspirin use in
TARGET, the results are similar to those observed in the overall
population in that there is no statistical difference compared to
naproxen or ibuprofen (see Table 5-4 below).

###### Table 5-4 Peripheral vascular events (DVT or PE) - (Safety Population) - Aspirin use: Yes {#table-5-4-peripheral-vascular-events-dvt-or-pe---safety-population---aspirin-use-yes .unnumbered}

  ----------------------------------------------------------------------------------------------------------
                                                  Cox proportional hazards model                  
  -------------------- ------------ ------------- -------------------------------- -------------- ----------
  Contrast             Number of\   Number of\    Hazard\                          95% CI for\    p-value
                       subjects\    subjects\     ratio                            hazard ratio   
                       at risk      with events                                                   

  \- TARGET -                                                                                     

  Lumiracoxib          2167         3 (0.14)                                                      

  NSAIDs               2159         5 (0.23)                                                      

  Lumiracoxib vs                                  0.58                             0.14 - 2.43    0.4555
  NSAIDs (1)                                                                                      

  \- Study 0117 -                                                                                 

  Lumiracoxib          1192         1 (0.08)                                                      

  Naproxen             1193         3 (0.25)                                                      

  Lumiracoxib vs                                  0.36                             0.04 - 3.42    0.3705
  Naproxen (2)                                                                                    

  \- Study 2332 -                                                                                 

  Lumiracoxib          975          2 (0.21)                                                      

  Ibuprofen            966          2 (0.21)                                                      

  Lumiracoxib vs                                  0.94                             0.13 - 6.67    0.9491
  Ibuprofen (2)                                                                                   
  ----------------------------------------------------------------------------------------------------------

Source: TARGET study report

## All thrombotic events (MI --clinical and silent, stroke, DVT and PE) --ASA population

When all thrombotic events are analyzed by presence or absence of
aspirin use in TARGET, the results are similar to those observed in the
overall population in that there is no statistical difference compared
to naproxen or ibuprofen (Table 5-5).

###### Table 5-5 Thrombotic events (MI --clinical and silent, stroke, DVT and PE) - (Safety Population) - Aspirin use: Yes {#table-5-5-thrombotic-events-mi-clinical-and-silent-stroke-dvt-and-pe---safety-population---aspirin-use-yes .unnumbered}

  -----------------------------------------------------------------------------------------------------------
                                                   Cox proportional hazards model                  
  --------------------- ------------ ------------- -------------------------------- -------------- ----------
  Contrast              Number of\   Number of\    Hazard\                          95% CI for\    p-value
                        subjects\    subjects\     ratio                            hazard ratio   
                        at risk      with events                                                   

  \- TARGET -                                                                                      

  Lumiracoxib           2167         23 (1.06)                                                     

  NSAIDs                2159         22 (1.02)                                                     

  Lumiracoxib vs NSAIDs                            1.05                             0.58 - 1.88    0.8729

  \- Study 0117 -                                                                                  

  Lumiracoxib           1192         18 (1.51)                                                     

  Naproxen              1193         15 (1.26)                                                     

  Lumiracoxib vs                                   1.23                             0.62 - 2.44    0.5550
  Naproxen                                                                                         

  \- Study 2332 -                                                                                  

  Lumiracoxib           975          5 (0.51)                                                      

  Ibuprofen             966          7 (0.72)                                                      

  Lumiracoxib vs                                   0.67                             0.21 - 2.12    0.4980
  Ibuprofen                                                                                        
  -----------------------------------------------------------------------------------------------------------

Source: TARGET study report

The lack of a difference in MIs or all thrombotic events in the
population taking low dose aspirin indicates that lumiracoxib does not
interfere with the anti-thrombotic effect of low-dose ASA.

## Relationship between hypertension and subsequent thrombotic events

The relationship between hypertension and subsequent thrombotic events
was assessed in the following hypertensive categories of patients with:

1.  hypertension at baseline

2.  aggravated hypertension (during the study),

3.  de novo hypertension (developing during the study),

4.  and a subgroup that has neither hypertension at baseline nor
    develops de novo hypertension.

As is shown in Table 5-6, the number of patients who had aggravated
hypertension or de novo hypertension and subsequently had an APTC event
was low. For patients who were hypertensive at baseline, there was no
difference in the APTC event rates for patients taking lumiracoxib
(0.81%) and patients on NSAIDs (0.82%). Patients who had no hypertension
during the study also had similar rates. The event rates did not differ
between naproxen and ibuprofen.

###### Table 5-6 TARGET: Incidence of confirmed or probable APTC events in patient categories with hypertension {#table-5-6-target-incidence-of-confirmed-or-probable-aptc-events-in-patient-categories-with-hypertension .unnumbered}

+---------------------+-------------------------+----------------------+
| **Hypertension      | **Lumiracoxib**         | **NSAIDs**           |
| category**          |                         |                      |
|                     | **n /N (%)**            | **n/N (%)**          |
+---------------------+-------------------------+----------------------+
| Baseline            | 36/4469 (0.81)          | 36 /4391 (0.82)      |
| hypertension        |                         |                      |
+---------------------+-------------------------+----------------------+
| Aggravated          | 4/323 (1.24)            | 2/384 (0.52)         |
+---------------------+-------------------------+----------------------+
| De novo             | 0/250                   | 3/330 (0.91)         |
+---------------------+-------------------------+----------------------+
| Normotensive        | 23/4648 (0.49)          | 14/4736 (0.30)       |
| throughout study    |                         |                      |
+---------------------+-------------------------+----------------------+

Post hoc table.

# NDA database of long-term studies

This section reports on the long-term safety dataset that was included
in the New Drug Application (NDA), i.e. on all studies except acute pain
studies and the TARGET study. Given that additional studies have been
completed since the NDA was submitted, the dataset has been updated
accordingly. This analysis focuses on lumiracoxib daily doses of 100 mg
and 200 mg (as opposed to 400 mg as investigated in TARGET, a dose
intended only for short term use in acute pain).

## Updated NDA long-term safety dataset: CV events

The incidence of cardiovascular adverse events was similar for patients
taking lumiracoxib and other NSAIDs (Table 6-1 below).

###### Table 6-1 Incidence of cardiovascular events {#table-6-1-incidence-of-cardiovascular-events .unnumbered}

+------------+---------+---------+--------+------------+-------------+
|            | **N     | **Ibup  | **Pla  | **Lum      | **All**     |
|            | aproxen | rofen** | cebo** | iracoxib** |             |
|            | 500 mg  |         |        |            | **NSAID**   |
|            | bid**   | **800   | **N=   | **100/200  |             |
|            |         | mg      | 3234** | mg**       | **N=1342**  |
|            | **N=    | tid**   |        |            |             |
|            | 681**   |         | **n    | **n=5064** | **n (%)**   |
|            |         | **      | (%)**  |            |             |
|            | **n     | N=476** |        | **n (%)**  |             |
|            | (%)**   |         |        |            |             |
|            |         | **n     |        |            |             |
|            |         | (%)**   |        |            |             |
+------------+---------+---------+--------+------------+-------------+
| Total      | 38      | 21      | 72     | 211 (4.2)  | 61 (4.5)    |
| pr         | (5.6)   | (4.4)   | (2.2)  |            |             |
| especified |         |         |        |            |             |
| AEs        |         |         |        |            |             |
+------------+---------+---------+--------+------------+-------------+
| \*         | 5 (0.7) | 2 (0.4) | 7      | 23 (0.5)   | 7 (0.5)     |
| Thrombotic |         |         | (0.2)  |            |             |
| events     |         |         |        |            |             |
| (Total)    |         |         |        |            |             |
+------------+---------+---------+--------+------------+-------------+
| Edema      | 19      | 13      | 32     | 89 (1.8)   | 34 (2.5)    |
| (Total)    | (2.8)   | (2.7)   | (1.0)  |            |             |
+------------+---------+---------+--------+------------+-------------+
| Hy         | 18      | 7 (1.5) | 32     | 107 (2.1)  | 25 (1.9)    |
| pertension | (2.6)   |         | (1.0)  |            |             |
| (Total)    |         |         |        |            |             |
+------------+---------+---------+--------+------------+-------------+

\* Thrombotic events includes all categories of MI, stroke, DVT and
cardiac death

Source: Updated NDA datasets.

### Serious cardiac events (SAEs) regardless of study drug relationship

The number of patients that had a cardiac SAE was low for both
lumiracoxib (100 or 200 mg daily) patients (21 events in 5064 patients
-- 0.4%) and patients taking NSAIDs (4 events in 1342 - 0.3%). Further
analysis of the individual components comprising cardiac SAEs showed
similar incidence rates.

Myocardial infarctions occurred infrequently in both groups: lumiracoxib
(100 or 200 mg daily) (10 events - 0.2%) and NSAIDs (3 events - 0.2%).
The incidence of pulmonary embolism and DVT in the lumiracoxib group
(100 or 200 mg daily) was low and comparable to placebo (0.0% and 0.1%
respectively).

### Thrombotic ADRs and relationship to dose

This section addresses the relationship to dose for the occurrence of
the following endpoints: APTC (CV death, stroke and MI pooled), MIs,
strokes, peripheral events, and MI/ stroke/ peripheral events combined.
The meta-analysis of all available events in our database for these
endpoints has been presented in section 1. The table for the APTC
endpoint is reproduced below (Table 6-2).

The meta-analysis shows that for all endpoints the interaction with dose
categorized as low (up to 200 mg daily, i.e. maximum OA dose) or high
(from 400 mg daily, i.e. acute pain dose) was not statistically
significant. The crude incidence data displayed below show a non
significant numerical increase of the incidence from 100 mg od to 400 mg
od. However the incidence for the 400 mg od group is lower than that
observed with the naproxen 500 mg bid group.

A similar picture is observed for all individual components of the APTC
endpoint.

###### Table 6-2 Crude incidence of APTC endpoint by dose {#table-6-2-crude-incidence-of-aptc-endpoint-by-dose .unnumbered}

+--------------------------+---------------+----------+--------------+
|                          | Patients with |          | Total        |
|                          | APTC event    |          |              |
+==========================+===============+==========+==============+
| Frequency Raw Pct        | No            | Yes      |              |
|                          |               |          |              |
|                          | N             | N        |              |
|                          |               |          |              |
|                          | \%            | \%       |              |
+--------------------------+---------------+----------+--------------+
| Lumiracoxib 100 mg od    | 2746\         | 8\       | 2754         |
|                          | 99.71         | 0.29     |              |
+--------------------------+---------------+----------+--------------+
| Lumiracoxib 200 mg od    | 3689\         | 13\      | 3702         |
|                          | 99.65         | 0.35     |              |
+--------------------------+---------------+----------+--------------+
| Lumiracoxib 400 mg od    | 12613\        | 70\      | 12683        |
|                          | 99.45         | 0.55     |              |
+--------------------------+---------------+----------+--------------+
| Naproxen 500 mg bid      | 5607\         | 32\      | 5639         |
|                          | 99.43         | 0.57     |              |
+--------------------------+---------------+----------+--------------+
| Ibuprofen 800 mg tid     | 4849\         | 24\      | 4873         |
|                          | 99.51         | 0.49     |              |
+--------------------------+---------------+----------+--------------+
| Placebo                  | 4357\         | 9\       | 4366         |
|                          | 99.79         | 0.21     |              |
+--------------------------+---------------+----------+--------------+

Only groups with a meaningful number of patients are included in the
in-text table.

Source: The FREQ Procedure post-text table in Appendix 9.1

### Thrombotic ADRs and relationship to duration of treatment

This section addresses the relationship to duration of treatment for the
occurrence of the following endpoints: APTC (CV death, stroke and MI
pooled), MIs, strokes, peripheral events, and MI/ stroke/ peripheral
events combined. The meta-analysis of all available events in our
database for these endpoints has been presented in section 1. The table
for the APTC endpoint is reproduced below (Table 6-3).

The meta-analysis (described in section 1) shows that for all endpoints
the interaction with duration categorized as short (up to 3 months) or
long (more than 3 months) was not statistically significant. The crude
incidence table below confirms that the relative difference of
incidences between active treatments is similar for up to 3 months data
compared to more than 3 months.

###### Table 6-3 Crude incidence of APTC endpoint by duration {#table-6-3-crude-incidence-of-aptc-endpoint-by-duration .unnumbered}

+----------------------+---+--------------+---+--------------+---+--------------+
| Duration of          |   |              |   |              |   |              |
| treatment up to      |   |              |   |              |   |              |
| 13 weeks             |   |              |   |              |   |              |
+======================+===+==============+===+==============+===+==============+
| treatment            | P |              |   |              |   | Total        |
|                      | a |              |   |              |   |              |
|                      | t |              |   |              |   |              |
|                      | i |              |   |              |   |              |
|                      | e |              |   |              |   |              |
|                      | n |              |   |              |   |              |
|                      | t |              |   |              |   |              |
|                      | s |              |   |              |   |              |
|                      | w |              |   |              |   |              |
|                      | i |              |   |              |   |              |
|                      | t |              |   |              |   |              |
|                      | h |              |   |              |   |              |
|                      | A |              |   |              |   |              |
|                      | P |              |   |              |   |              |
|                      | T |              |   |              |   |              |
|                      | C |              |   |              |   |              |
|                      | e |              |   |              |   |              |
|                      | v |              |   |              |   |              |
|                      | e |              |   |              |   |              |
|                      | n |              |   |              |   |              |
|                      | t |              |   |              |   |              |
+----------------------+---+--------------+---+--------------+---+--------------+
| Frequency Raw Pct    | N |              |   | Yes          |   |              |
|                      | o |              |   |              |   |              |
|                      |   |              |   | N            |   |              |
|                      | N |              |   |              |   |              |
|                      |   |              |   | \%           |   |              |
|                      | \ |              |   |              |   |              |
|                      | % |              |   |              |   |              |
+----------------------+---+--------------+---+--------------+---+--------------+
| Lumiracoxib 100 mg   |   | 1735\        | 3 |              | 1 |              |
| od                   |   | 99.83        | \ |              | 7 |              |
|                      |   |              | 0 |              | 3 |              |
|                      |   |              | . |              | 8 |              |
|                      |   |              | 1 |              |   |              |
|                      |   |              | 7 |              |   |              |
+----------------------+---+--------------+---+--------------+---+--------------+
| Lumiracoxib 200 mg   |   | 2293\        | 3 |              | 2 |              |
| od                   |   | 99.87        | \ |              | 2 |              |
|                      |   |              | 0 |              | 9 |              |
|                      |   |              | . |              | 6 |              |
|                      |   |              | 1 |              |   |              |
|                      |   |              | 3 |              |   |              |
+----------------------+---+--------------+---+--------------+---+--------------+
| Lumiracoxib 400 mg   |   | 2731\        | 4 |              | 2 |              |
| od                   |   | 99.85        | \ |              | 7 |              |
|                      |   |              | 0 |              | 3 |              |
|                      |   |              | . |              | 5 |              |
|                      |   |              | 1 |              |   |              |
|                      |   |              | 5 |              |   |              |
+----------------------+---+--------------+---+--------------+---+--------------+
| Naproxen 500 mg bid  |   | 268\         | 1 |              | 2 |              |
|                      |   | 99.63        | \ |              | 6 |              |
|                      |   |              | 0 |              | 9 |              |
|                      |   |              | . |              |   |              |
|                      |   |              | 3 |              |   |              |
|                      |   |              | 7 |              |   |              |
+----------------------+---+--------------+---+--------------+---+--------------+
| Ibuprofen 800 mg tid |   | 475\         | 1 |              | 4 |              |
|                      |   | 99.79        | \ |              | 7 |              |
|                      |   |              | 0 |              | 6 |              |
|                      |   |              | . |              |   |              |
|                      |   |              | 2 |              |   |              |
|                      |   |              | 1 |              |   |              |
+----------------------+---+--------------+---+--------------+---+--------------+
| Placebo              |   | 4074\        | 8 |              | 4 |              |
|                      |   | 99.80        | \ |              | 0 |              |
|                      |   |              | 0 |              | 8 |              |
|                      |   |              | . |              | 2 |              |
|                      |   |              | 2 |              |   |              |
|                      |   |              | 0 |              |   |              |
+----------------------+---+--------------+---+--------------+---+--------------+

+----------------------+---------------+---+--------------+---+--------------+
| Duration of          |               |   |              |   |              |
| treatment longer     |               |   |              |   |              |
| than 13 weeks        |               |   |              |   |              |
+======================+===============+===+==============+===+==============+
| treatment            | Patients with |   |              |   | Total        |
|                      | APTC event    |   |              |   |              |
+----------------------+---------------+---+--------------+---+--------------+
| Frequency Raw Pct    | No            | Y |              |   |              |
|                      |               | e |              |   |              |
|                      | N             | s |              |   |              |
|                      |               |   |              |   |              |
|                      | \%            | N |              |   |              |
|                      |               |   |              |   |              |
|                      |               | \ |              |   |              |
|                      |               | % |              |   |              |
+----------------------+---------------+---+--------------+---+--------------+
| Lumiracoxib 100 mg   | 1011\         |   | 5\           | 1 |              |
| od                   | 99.51         |   | 0.49         | 0 |              |
|                      |               |   |              | 1 |              |
|                      |               |   |              | 6 |              |
+----------------------+---------------+---+--------------+---+--------------+
| Lumiracoxib 200 mg   | 1396\         |   | 10\          | 1 |              |
| od                   | 99.29         |   | 0.71         | 4 |              |
|                      |               |   |              | 0 |              |
|                      |               |   |              | 6 |              |
+----------------------+---------------+---+--------------+---+--------------+
| Lumiracoxib 400 mg   | 9882\         |   | 66\          | 9 |              |
| od                   | 99.34         |   | 0.66         | 9 |              |
|                      |               |   |              | 4 |              |
|                      |               |   |              | 8 |              |
+----------------------+---------------+---+--------------+---+--------------+
| Naproxen 500 mg bid  | 5339\         |   | 31\          | 5 |              |
|                      | 99.42         |   | 0.58         | 3 |              |
|                      |               |   |              | 7 |              |
|                      |               |   |              | 0 |              |
+----------------------+---------------+---+--------------+---+--------------+
| Ibuprofen 800 mg tid | 4374\         |   | 23\          | 4 |              |
|                      | 99.48         |   | 0.52         | 3 |              |
|                      |               |   |              | 9 |              |
|                      |               |   |              | 7 |              |
+----------------------+---------------+---+--------------+---+--------------+
| Placebo              | 283\          |   | 1\           | 2 |              |
|                      | 99.65         |   | 0.35         | 8 |              |
|                      |               |   |              | 4 |              |
+----------------------+---------------+---+--------------+---+--------------+

Source: Updated NDA datasets

## Updated NDA long-term safety dataset -- hypertension adverse events

Patients taking lumiracoxib (100/200 mg) had a numerically lower
incidence of hypertension adverse events (2.1%) compared to patients on
naproxen (2.6%) (Table 6-5 below). Hypertensive rates by category did
not differ.

###### Table 6-5 Hypertension adverse events by category and preferred term (safety patients- all non acute pain studies) {#table-6-5-hypertension-adverse-events-by-category-and-preferred-term-safety-patients--all-non-acute-pain-studies .unnumbered}

Naproxen Ibuprofen COX189 All

500mg bid 800mg tid Placebo 100/200mg NSAID

Primary System Organ Class N=681 N=476 N=3234 N=5064 N=1342

n (%) n (%) n (%) n (%) n (%)

Hypertension (E)

    -Total 18(2.6) 7(1.5) 32(1.0) 107(2.1) 25(1.9)

    Blood pressure diastolic 0(0.0) 0(0.0) 0(0.0) 3(0.1) 0(0.0)

     increased

    Blood pressure 0(0.0) 0(0.0) 1(0.0) 0(0.0) 0(0.0)

     fluctuation

    Blood pressure increased 2(0.3) 6(1.3) 8(0.2) 29(0.6) 8(0.6)

    Blood pressure systolic 0(0.0) 0(0.0) 0(0.0) 1(0.0) 0(0.0)

     increased

    Hypertension 15(2.2) 0(0.0) 22(0.7) 72(1.4) 15(1.1)

Hypertensive crisis 1(0.1) 1(0.2) 1(0.0) 0(0.0) 2(0.1)

    Labile hypertension 0(0.0) 0(0.0) 0(0.0) 1(0.0) 0(0.0)

    Systolic hypertension 0(0.0) 0(0.0) 1(0.0) 1(0.0) 0(0.0)

Source: Updated NDA datasets

## Updated NDA long-term safety dataset -- edema adverse events

Patients taking NSAIDs (2.5%) had a numerically higher incidence of
edema than patients on lumiracoxib (1.8%). The incidence was similar for
naproxen (2.8%) and ibuprofen (2.7%). The most common presentation was
peripheral edema (Table 6-6).

###### Table 6-6 Edema adverse events by category and preferred term (safety patients -- all non acute pain studies) {#table-6-6-edema-adverse-events-by-category-and-preferred-term-safety-patients-all-non-acute-pain-studies .unnumbered}

**Naproxen Ibuprofen COX189 All**

**500mg bid 800mg tid Placebo 100/200mg NSAID**

**Primary System Organ Class N=681 N=476 N=3234 N=5064 N=1342**

**n (%) n (%) n (%) n (%) n (%)**

**Edema (C)**

**    -Total 19(2.8) 13(2.7) 32(1.0) 89(1.8) 34(2.5)**

**    Face oedema 0(0.0) 1(0.2) 1(0.0) 1(0.0) 2(0.1)**

**    Fluid retention 1(0.1) 1(0.2) 2(0.1) 5(0.1) 2(0.1)**

**    Gravitational oedema 0(0.0) 0(0.0) 2(0.1) 0(0.0) 0(0.0)**

**    Oedema 1(0.1) 0(0.0) 2(0.1) 4(0.1) 1(0.1)**

**    Oedema peripheral 15(2.2) 8(1.7) 25(0.8) 67(1.3) 23(1.7)**

**    Periorbital oedema 0(0.0) 0(0.0) 1(0.0) 2(0.0) 1(0.1)**

**    Pitting oedema 0(0.0) 0(0.0) 0(0.0) 5(0.1) 0(0.0)**

**    Swelling 0(0.0) 0(0.0) 0(0.0) 0(0.0) 0(0.0)**

**    Swelling face 2(0.3) 3(0.6) 0(0.0) 5(0.1) 5(0.4)**

Source: Updated NDA datasets

# How do lumiracoxib CV data compare with rofecoxib?

This section tentatively compares the available data for lumiracoxib and
rofecoxib in non-head-to-head studies with respect to CV safety,
especially since the withdrawal of rofecoxib has raised concern about a
possible 'class effect'. Because there is no long term head to head
study comparing rofecoxib to lumiracoxib, we have made the following
assumptions and justifications in comparing VIGOR and TARGET:

1.  Since VIGOR did not allow low dose aspirin and compared rofecoxib to
    naproxen only, we will use the data from the lumiracoxib vs naproxen
    substudy in TARGET in the ***non aspirin population only***.

2.  VIGOR compared RA patients while TARGET studied OA patients only.
    This is likely to have implications for the cardiovascular adverse
    event rates seen in VIGOR,, as RA is associated with a higher CV
    risk than OA, but the relative difference in CV adverse events
    between naproxen and rofecoxib (VIGOR) and between naproxen and
    lumiracoxib (TARGET, non ASA population only) is perhaps the best
    available comparison across studies. Further, as it will be shown
    below, the incidence of CV adverse events in absolute terms for the
    naproxen arms in both TARGET and VIGOR are nearly identical,
    supporting a similar baseline risk in the two populations and the
    appropriateness of the cross-study comparison.

3.  Both studies compared doses that were two or four times the proposed
    chronic doses.

4.  Finally, it is important to note that there was much less patient
    exposure in VIGOR because of the difference in patient numbers
    (VIGOR n=8,076 vs. TARGET n=18,325) and duration (VIGOR -- median of
    9 months, TARGET -- fixed duration of 12 months). As such TARGET
    provides more robust cardiovascular safety data and the results
    should more closely approximate the real CV risk compared to NSAIDs.

## VIGOR vs TARGET (naproxen substudy and non ASA population)

### APTC endpoint

The Table below (Table 7-1) compares the APTC endpoint equivalents
between VIGOR and TARGET (non aspirin population). While there was a
significant difference between the COX-2 inhibitor and NSAID in the APTC
endpoint in VIGOR (OR 1.94, p = 0.0233), the difference was not
significant in TARGET (OR 1.57, p = 0.1883) even though TARGET was of
longer duration and with greater exposure. Further, in VIGOR the APTC
event rate per 100 patient--years for naproxen (0.67) closely
approximates that in TARGET (0.53), supporting the comparison across
studies, although the assumptions and caveats outlined above should be
taken into consideration.

###### Table 7-8 APTC events: VIGOR vs TARGET (non aspirin population -- naproxen vs lumiracoxib) {#table-7-8-aptc-events-vigor-vs-target-non-aspirin-population-naproxen-vs-lumiracoxib .unnumbered}

  ------------ --------------- ------------ --------------- ------------ -------------
  **Study**    **Treatment**   **Rate per   **Odds          **95% CI**   **P-value**
                               100 patient  ratio\*\*\***                
                               years**                                   

  VIGOR\*      Rofecoxib       1.30         1.94            1.10 --3.44  0.0223

               Naproxen        0.67                                      

                                                                         

  TARGET\*\*   Lumiracoxib     0.80         1.57            0.80 -- 3.07 0.1883

               Naproxen        0.53                                      

                                                                         

               Lumiracoxib     0.51         0.94            0.44 -- 2.04 0.8842

               Ibuprofen       0.54                                      
  ------------ --------------- ------------ --------------- ------------ -------------

\* VIGOR: CV death, Cardiac event (non-fatal)-MI and CVA (non-fatal)\
\*\* TARGET: CV death, clinical and silent MI, hemorrhagic and ischemic
stroke -- non aspirin population\
\*\*\* from logistic regression model\
Source: VIGOR NDA 21-042/s 007 VIOXX p 13, TARGET Farkouh M et al. 2004

### Myocardial Infarcts

###### Table 7-9 MI events: VIGOR vs TARGET (non aspirin population -- naproxen vs lumiracoxib) {#table-7-9-mi-events-vigor-vs-target-non-aspirin-population-naproxen-vs-lumiracoxib .unnumbered}

  ----------- --------------- ------------ --------- ------------ -------------
  **Study**   **Treatment**   **Rate per   **Odds\   **95% CI**   **P-value**
                              100 patient  ratio                  
                              years**      \*\***                 

  VIGOR       Rofecoxib       0.74         5.00      1.71 -- 14.6 0.0033

              Naproxen        0.15                                

                                                                  

  TARGET\*    Lumiracoxib     0.36         2.50      0.78 -- 7.97 0.1224

              Naproxen        0.15                                

                                                                  

              Lumiracoxib     0.16         0.75      0.20 -- 2.79 0.6669

              Ibuprofen       0.21                                
  ----------- --------------- ------------ --------- ------------ -------------

\*Adjudicated clinical and silent MIs\
\*\* from logistic regression model\
Source: VIGOR NDA 21-042/s 007 VIOXX, TARGET Farkouh M et al. 2004

While there is a significant difference in MIs in VIGOR (OR 5.00, p =
0.0033), the difference was not significant in TARGET (OR 2.50, p =
0.1224) (Table 7-2). Since CV events were not prospectively adjudicated
in VIGOR and since Novartis lacks information on the post-hoc
adjudication process in VIGOR, Novartis cannot comment on whether silent
MIs were included or not in that study. However, it is noteworthy that
the rate of MI events per 100 patient years for naproxen is the same in
the 2 studies (0.15). With the caveats stated above, this would give
weight to the comparison of MI events per 100 patients years for
lumiracoxib (0.36) vs rofecoxib (0.74) even though the populations
studied are different (RA vs OA).

### Venous thrombosis (deep vein thrombosis and pulmonary embolism)

Although the number of events is low, when TARGET (naproxen vs
lumiracoxib, non-ASA population) is compared to VIGOR, more patients
taking rofecoxib had a serious venous thrombosis compared to patients
allocated to naproxen. This trend was not evident in the TARGET naproxen
substudy (Table 7.3 below).

###### Table 7-10 Serious venous thrombotic events: VIGOR vs TARGET (non aspirin population -- naproxen vs lumiracoxib) {#table-7-10-serious-venous-thrombotic-events-vigor-vs-target-non-aspirin-population-naproxen-vs-lumiracoxib .unnumbered}

  -------------- --------------- -------------- -------------- --------------
  **Study**      **Treatment**   **n**          **N**          **%**

  VIGOR          Rofecoxib       6              4047           0.15

                 Naproxen        1              4029           0.02

                                                               

  TARGET\*       Lumiracoxib     3              3549           0.08

                 Naproxen        4              3537           0.11
  -------------- --------------- -------------- -------------- --------------

\* Adjudicated confirmed/probable DVTs and Pulmonary Embolism\
Source: VIGOR NDA 21-042/s 007 VIOXX, TARGET study report

### Hypertension, edema and congestive heart failure (CHF)

The most obvious differences in the CV profiles of rofecoxib and
lumiracoxib are in their effects on BP, edema and CHF.

In VIGOR rofecoxib was worse than naproxen for edema related AEs,
discontinuations due to hypertension AEs, and more patients taking
rofecoxib had CHF as an AE (Table 7-4, 7-5, 7-6 and 7-7 below).

###### Table 7-11 VIGOR: Results of pre-specified safety analyses {#table-7-11-vigor-results-of-pre-specified-safety-analyses .unnumbered}

  -----------------------------------------------------------------------------------------------------------------
                                                                          **Relative                  
                                                                          Risk**                      
  ---------------------- --------------- ------- ------------ ----------- -------------- ------------ -------------
  **Type of AE**         **Treatment**   **N**   **Events**   **Rates**   **Estimate**   **95%CI**    **P-value**

  Discontinuations due   Rofecoxib\      4047\   25\          0.93\       1.92           0.98- 3.75   0.057
  to edema-related AEs   \               \       \            \                                       
                         Naproxen        4029    13           0.48                                    

  Discontinuations due   Rofecoxib\      4047\   28\          1.04\       4.67           1.93-11.28   \<0.001
  to                     \               \       \            \                                       
  hypertension-related   Naproxen        4029    6            0.22                                    
  AEs                                                                                                 

  CHF AEs                Rofecoxib\      4047\   19\          0.70\       2.11           0.96-4.67    0.065
                         \               \       \            \                                       
                         Naproxen        4029    9            0.33                                    
  -----------------------------------------------------------------------------------------------------------------

Source: NDA 21-042/s 007 VIOXX Table 16 page 41

The corresponding data for TARGET are provided below (Tables 7.5 and
7.6) \[statistical test performed on the combined row\].

###### Table 7-12 Edema discontinuations data in TARGET {#table-7-12-edema-discontinuations-data-in-target .unnumbered}

  ------------- --------- --------- --------- --------- --------- ---------
                Lumi      NSAIDs    Lumi      Napro     Lumi      Ibu

  Anasarca      0         1         0         1         0         0

  Edema         9         11        3         2         6         9

  Edema         27        33        14        11        13        22
  Peripheral                                                      

  Pitting edema 1         2         1         0         0         2

  Swelling      2         0         1         0         1         0

  Face edema    0         1         0         0         0         1

  Swelling face 2         3         1         1         1         2

  Periorbital   1         0         0         0         1         0
  edema                                                           

  Fluid         1         5         0         3         1         2
  retention                                                       

  total         43        55        20        18        23        37
  ------------- --------- --------- --------- --------- --------- ---------

Total lumiracoxib vs NSAIDs: p = 0.2651, lumiracoxib vs naproxen: p =
0.8712, lumiracoxib vs ibuprofen: p = 0.0914

###### Table 7-13 Hypertension discontinuations data in TARGET {#table-7-13-hypertension-discontinuations-data-in-target .unnumbered}

  -------------- --------- --------- --------- --------- --------- ---------
                 Lumi      NSAIDs    Lumi      Napro     Lumi      Ibu

  Blood pressure 5         7         2         0         3         7
  increased                                                        

  Hypertension   25        44        9         15        16        29

  Hypertensive   5         0         4         0         1         0
  crisis                                                           

  Labile blood   2         0         0         0         2         0
  pressure                                                         

  Systolic       0         1         0         0         0         1
  hypertension                                                     

  total          37        52        15        15        22        37
  -------------- --------- --------- --------- --------- --------- ---------

Total lumiracoxib vs NSAIDs: p = 0.1364, lumiracoxib vs naproxen: p
=1.000, lumiracoxib vs ibuprofen: p = 0.066

In VIGOR there was a significant increase in blood pressure with
rofecoxib compared with naproxen (systolic mean: 4.6 mmHg increase from
baseline with rofecoxib compared with 1.0 mmHg with naproxen; diastolic
mean: 1.7 mmHg increase with rofecoxib compared with 0.1 mmHg with
naproxen). In TARGET systolic and diastolic mean blood pressure changes
were significantly lower with lumiracoxib than with NSAIDs (diastolic
least squares mean change from baseline was -0.1 mmHg for lumiracoxib
compared with +0.5 mmHg with NSAIDs; systolic +0.4 mmHg with lumiracoxib
vs +2.1 mmHg with NSAIDs, both P ≤ 0.0001).

Findings from a large population based, observational cohort study
showed that patients taking rofecoxib had a higher risk of congestive
heart failure (CHF) than patients taking NSAIDs. Further, patients on
rofecoxib were significantly more likely to be treated and or admitted
for CHF (Mamdani M et al. 2004). Both COX-1 and COX-2 are expressed in
the kidney and non-selective NSAIDs/COX-2 inhibitors use may affect
water and salt retention in some patients which may lead to weight gain
and CHF. In TARGET, patients taking lumiracoxib had numerically fewer
cases of an increase in weight from baseline \>5% and CHF (Table 7-7).

###### Table 7-14 TARGET -- lumiracoxib vs naproxen: Incidence of edema, CHF as an AE and weight increase (no aspirin population) {#table-7-14-target-lumiracoxib-vs-naproxen-incidence-of-edema-chf-as-an-ae-and-weight-increase-no-aspirin-population .unnumbered}

  --------------------- ----------------- ----------------- --------------
                        **Lumiracoxib     **Naproxen        **P-value#**
                        (N=3549)**        (N=3537)**        

                        **n (%)**         **n (%)**         

  CHF (post hoc         4 (0.11)          9 (0.25)          0.1785
  analysis)                                                 

                        **Lumiracoxib     **Naproxen        
                        (N=3355)**        (N=3318)**        

  Increase in weight    283 (8.4)         307 (9.3)         0.2445
  from baseline \> 5%                                       
  --------------------- ----------------- ----------------- --------------

Source: TARGET study report; \# Fisher's exact test

## Summary: VIGOR vs TARGET (naproxen substudy and non ASA population)

When VIGOR is compared to TARGET (naproxen substudy and non ASA
population) the following differences in the CV adverse event profile
between rofecoxib and lumiracoxib are observed:

1.  **Rofecoxib** is associated with a significant increase compared to
    naproxen in:

```{=html}
<!-- -->
```
1.  The APTC endpoint (OR 1.94, p \< 0.05)

2.  MIs (OR 5.00, p = 0.0033)

3.  Discontinuations due to hypertension related AEs (RR 4.67, p \<
    0.001). Systolic BP increase of 3.6 mmHg for patients taking
    rofecoxib.

4.  Discontinuations due to edema related AEs (RR 1.92, p =0.057)

5.  A numerical increase in CHF adverse events (rofecoxib 19 events vs
    naproxen 9 events; RR 2.11, p = 0.065) and

6.  A numerical difference in serious venous thrombosis (rofecoxib 6
    events vs naproxen 1 event)

```{=html}
<!-- -->
```
2.  In contrast, when compared to naproxen (non-ASA population),
    **lumiracoxib** was not associated with a significant difference in:

-   The APTC endpoint (OR 1.57, p = 0.1883)

-   Clinical and silent MIs ( OR 2.50, p = 0.1224)

-   Serious venous thrombosis (lumiracoxib 3 event and naproxen 4
    events); and lumiracoxib patients had

-   Less CHF adverse events (lumiracoxib 4 events vs naproxen 9 events);
    and

-   Significantly less mean increase in systolic (p \< 0.0001) and
    diastolic BP (p\< 0.0002) increases.

# Celecoxib in the CLASS study compared to lumiracoxib in TARGET

## CLASS vs TARGET: differences that could impact CV results

Comparison across studies is potentially affected by methodological
flaws. However, the current review on COX 2 and CV safety warrants
comparisons across studies as there are no long term head-to-head
studies comparing COX 2s. The CLASS and TARGET studies differ in several
respects that could impact on cardiovascular safety. These include the
fact that;

1.  TARGET (\>18 000 patients) was more than twice the size of CLASS
    (\>8 000 patients)

2.  TARGET had a drop out rate of about 40% at the end of 1 year
    compared to CLASS in which more than 90% dropped out by 12 months.

3.  the overall patient-year exposure for lumiracoxib in TARGET was over
    6800 pt-yrs and only 2320 pt-yrs for patients taking celecoxib in
    CLASS

4.  patients in TARGET were stratified to low dose aspirin (24% of
    population) while there was no stratification in CLASS (\~ 21% on
    aspirin)

5.  TARGET included OA patients while CLASS included OA (72%) and RA
    (28%) patients. RA patients are thought to have a higher CV baseline
    risk.

6.  TARGET prospectively defined and adjudicated all serious CV adverse
    events (MI, stroke, CV death, DVT and PE), while this was done
    retrospectively in CLASS.

## TARGET and CLASS: CV data summary

There was no significant difference in the APTC endpoint or MIs for
patients taking celecoxib compared to ibuprofen and diclofenac in the
CLASS study. However acknowledging the pitfalls of cross-study
comparisons, patients taking lumiracoxib had fewer MIs per 100 patients
years in TARGET (0.33) compared to celecoxib patients in CLASS (0.8).
Also, the cumulative APTC incidence at 1 year was lower for lumiracoxib
patients (0.68%) than for patients in CLASS on celecoxib (1.4%) (Table
8-1 below) using a post hoc analysis of serious thromboembolic adverse
cardiac events.

###### Table 8-15 TARGET vs CLASS comparison for MI and APTC event rates {#table-8-15-target-vs-class-comparison-for-mi-and-aptc-event-rates .unnumbered}

+------------------------+-------------+-------------------------------+
| Study                  | MI rate per | \* APTC (cumulative incidence |
|                        | 100 patient | at one year)                  |
|                        | years       |                               |
|                        |             | (non ASA population)          |
+------------------------+-------------+-------------------------------+
| [TARGET:]{.underline}  | 0.3         | 0.7%                          |
| Lumiracoxib 400 mg od  |             |                               |
+------------------------+-------------+-------------------------------+
| [CLASS:]{.underline}   | 0.8         | 1.4%                          |
| Celecoxib 400 mg bid   |             |                               |
+------------------------+-------------+-------------------------------+

\* TARGET used prespecified APTC endpoint; CLASS analysis uses post hoc
thromboembolic cardiovascular adverse events

The APTC cumulative rates for lumiracoxib in TARGET and the post hoc
thromboembolic cardiovascular adverse event rate for celecoxib in CLASS
are further illustrated in the Figures below (Figure 8-1 and Figure
8-2). In TARGET the event rate for patients taking lumiracoxib was lower
than for patients taking ibuprofen. In CLASS this was the reverse, with
patients taking ibuprofen experiencing lower rates than patients taking
celecoxib. Importantly, in both studies the differences compared to
NSAIDs were not statistically significant.

####### Figure 8-2 APTC events in TARGET- Lumiracoxib vs ibuprofen in the no low-dose ASA population {#figure-8-2-aptc-events-in-target--lumiracoxib-vs-ibuprofen-in-the-no-low-dose-asa-population .unnumbered}

![](media/image18.wmf){width="6.308333333333334in"
height="4.246527777777778in"}

####### Figure 8-3 Posthoc depiction of thromboembolic cardiovascular events in non-aspirin users in the CLASS study (Ref: FitzGerald G) {#figure-8-3-posthoc-depiction-of-thromboembolic-cardiovascular-events-in-non-aspirin-users-in-the-class-study-ref-fitzgerald-g .unnumbered}

![](media/image19.wmf){width="6.003472222222222in"
height="4.696527777777778in"}

The above data suggests that the degree of COX 2 selectivity probably
impacts more on the extent of gastrointestinal protection than the
incidence of CV adverse events. Supporting this is the fact that
valdecoxib (Bextra^®^) has been shown in two duplicate CABG studies to
significantly increase CV adverse events compared to controls.
Furthermore, rofecoxib has a lower COX 2/COX 1 selectivity ratio than
lumiracoxib, but it has been associated with a significant increase in
MIs, APTC events, and hypertension and numerically more cases of
congestive heart failure.

Finally, TARGET achieved its primary objective. Patients taking
lumiracoxib had a 79% reduction in ulcer complications (non ASA
population) compared to patients on NSAIDS. There was no significant
difference in the primary endpoint of ulcer complications when celecoxib
was compared to NSAIDs in CLASS.

# Possible explanations for the specific rofecoxib CV profile

Several hypotheses have been put forward to explain the thrombotic
safety issues seen with rofecoxib.

The first argument was put forth by the sponsor to explain the
difference in MI events between rofecoxib and naproxen. This hypothesis
was that naproxen had antithrombotic activity. While retrospective
population cohort studies have questioned naproxen anti-thrombotic
activity (Ray et al, 2002), several well-controlled studies have
demonstrated that naproxen (500 mg bid) is capable of reducing platelet
thromboxane production to an extent similar to low dose aspirin and,
thus, prevent platelet aggregation (Capone et al, 2004). In a
meta-analysis of randomized trials aspirin afforded a 32% reduction in
first MI (Eidelman et al. 2003). In a recent meta-analysis of all
naproxen observational studies, naproxen was associated with a
significant 14% decrease in MIs (OR 0.86, 95% CI 0.75 -- 0.99, Ref: Juni
et al.). Assuming that naproxen could achieve the same level of
reduction in MI as low dose aspirin (32 -- 44%), this reduction may be a
contributing factor but by itself appears to be inadequate to explain
the 4-fold difference seen between naproxen and rofecoxib in the VIGOR
trial. Yet, this reduction by naproxen would largely account for the
smaller difference observed between naproxen and lumiracoxib in TARGET
in the non-aspirin treated population (Section 4).

A second, not mutually exclusive possibility is that rofecoxib is
prothrombotic. FitzGerald et al. (2004) have argued that inhibition of
the COX-2-dependent activity in the face of unopposed platelet COX-1
activity might favor a prothrombotic state. Thus, the inclusion of low
dose aspirin (COX-1 selective effect) should neutralize the risk.

There may therefore be another mechanism by which rofecoxib is exerting
a prothrombotic effect. The third possibility relates to rofecoxib's
unique metabolic pathway, a pathway distinct from the one utilized by
lumiracoxib. Metabolism of rofecoxib is through cytosolic reduction
catalyzed by aldo-ketoreductase. In the vasculature this enzyme is
responsible for detoxification of oxidized phospholipids (Srivastava et
al., 2004). Reduction of oxidized lipids is a critical defense
mechanism, as oxidized phospholipids are associated with atherosclerosis
(Gaut and Heinecke, 2001), heart failure (Maack et al, 2003) and
ischemic-reperfusion injury (Kloner and Jennings, 2001). Additionally,
aldo-ketoreductase in the liver is involved in the synthesis of
vasoactive hormones, including aldosterone (Krum et al, 2004). Given its
long half life and micromolar blood levels, rofecoxib could act as a
competitive inhibitor, preventing access of other substrates to this
enzyme. The effect of rofecoxib on aldosterone levels is of interest
since this hormone plays a role in fluid and sodium retention.

In contrast, lumiracoxib is metabolized by cytochrome P450 2C9, an
enzyme not involved with the production of vasoactive hormones or
metabolism of oxidized phospholipids.

Recently, Reddy and Corey (2004) suggested that oxidation of the
conjugate base of rofecoxib to a maleic anhydride derivative may be a
factor in the long-term toxicity of rofecoxib. This reactivity has not
been previously been described, and does not occur in any other COX-2
inhibitor developed to date. The authors suggest that some of the
anhydride may survive long enough *in vivo* to react with tissues. They
wrote: "The consequences of this may be a low-level chronic toxicity
that is cumulative and possibly dangerous over periods of many months."

## Structure

COX-2 selective inhibitors can be categorized into three chemical types.
Celecoxib and valdecoxib have sulphonamide groups, rofecoxib and
etoricoxib have a methylsulphone group, but lumiracoxib lacks a
sulphur-containing group, possessing instead a carboxylic acid group
which confers weakly acidic properties (Brune and Hinz, 2004).

A recent publication found that sulphone COX-2 inhibitors (rofecoxib and
etoricoxib) increased the susceptibility of human LDL and plasma to
oxidative modification compared to non-sulphone COX2 inhibitors and
NSAIDs. They suggested that this may provide a mechanistic insight into
the reported differences in cardiovascular risk for COX2 inhibitors
(Walter MF at al Arthrosclerosis 2004).

## Half--life

Lumiracoxib has the shortest plasma elimination half-life amongst all
the current COX-2 inhibitors (3-6 hours), compared to rofecoxib (15-18
hours), celecoxib (6-12 hours), valdecoxib (6-10 hours) and etoricoxib
(20-26 hours). A long half-life has been offered as one of the
hypotheses for CV adverse events causing a sustained inhibition of COX
2-dependent prostacyclin production over a 24 hour time period. Indeed,
lumiracoxib is associated with less inhibition of urinary PGI2
metabolites over 24 hours than other NSAIDs in non-head-to-head studies
(Lumiracoxib Study 2349, Catella-Lawson 1999).

## PK/PD (Distribution kinetics)

Lumiracoxib has been shown in RA patients (Lumiracoxib Study 0122) to
have a longer mean residence time in the synovial fluid compartment
compared to the vascular compartment. Less time spent in the vascular
compartment may translate to less vascular prostacyclin inhibition over
a 24 hour period and therefore fewer CV adverse events.

## Inhibition of the vasoprotective prostaglandin PGI~2~

PGI2 is a vasoactive prostaglandin responsible for suppressing platelet
aggregation and acting as a vasodilator. Catella-Lawson et al (1999)
have shown that rofecoxib (50 mg) reduced the production of PGI2 by 73%
as measured as PGI2 metabolites in urine that was collected 0 -- 6 hours
following administration. This high level of PGI2 inhibition contrasts
with that caused by lumiracoxib, which reduced urinary PGI2 metabolites
by a maximum of 30% between 6 -- 12 hours post dose and by \~15% over of
the course of a day (Lumiracoxib Study 2349). In Study 2349 low dose
aspirin suppressed PGI2 by \~10% - a similar reduction was noted by
Capone et al (2004).

# Summary

In conclusion, the data show that:

When all the available clinical trial evidence for lumiracoxib is
reviewed, there is no evidence of an increased risk of cardiovascular
events compared with placebo, naproxen, non-naproxen NSAIDs, or all
comparators.

In addition TARGET provides data that;

1.  suggests that lumiracoxib has a neutral CV profile when compared to
    ibuprofen and has a significantly lower mean increase in systolic
    and diastolic BP.

2.  strengthens the hypothesis that naproxen is antithrombotic at the
    dose and dosing interval studied, and differs from ibuprofen in its
    CV profile. Of significance is the observation in TARGET of the
    absence of a relevant difference compared to naproxen in MIs when
    low dose ASA is coadministered (COX-1 activity).

3.  in high CV risk patients (n=2,207) and patients with a previous MI
    (n=288), no difference in the APTC endpoint nor in MIs (clinical or
    silent) between lumiracoxib and NSAIDs was observed.

4.  may indicate that naproxen may be different from ibuprofen in its CV
    profile, adding support to the belief that not all NSAIDs are the
    same in their end organ effects.

When lumiracoxib (TARGET non aspirin population) is compared to
rofecoxib in non-head-to-head studies, the two COX-2 inhibitors differ
notably in their CV profile. This analysis adds support to our
conclusion that not all COX-2 inhibitors are the same in their
physiological effects and safety profiles.

Subsequent to the rofecoxib withdrawal, lumiracoxib is the only COX-2
inhibitor to have shown in a long-term outcomes study a significant GI
benefit compared to NSAIDs. This benefit is expected to be maintained at
the 100 mg od dose (OA dose) as this benefit is a function of the COX-2
selectivity (or rather the COX-1 sparing effect) in the gastrointestinal
tract, while the CV and overall favorable safety profile is expected to
be further enhanced at the lower dose. Therefore, lumiracoxib at the
recommended chronic dose of 100 mg od is expected to have an even
greater positive benefit to risk safety profile in OA, compared to the
400 mg od dose studied in TARGET.

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