Appendix to

Lumiracoxib (COX189) Background Document for Novartis Presentation to FDA Advisory Committee

(February 16-18, 2005)

 

Errata: Comparison of document released on January 13, 2005 with the updated version released on February 3, 2005

Document status:

Final

Release date:

February 10, 2005

Number of pages:

15

Property of Novartis Pharmaceuticals Corporation

All Rights Reserved

 

        AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION


 

Page 8

Change: 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.

To: 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 randomized controlled trials of lumiracoxib ≥ 1 week duration completed by December 31, 2004.

Change: (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)

To: (44 patient – years compared with 9797 patient-years for patients taking lumiracoxib for treatment of the signs and symptoms of either osteoarthritis or rheumatoid arthritis

Page 12

Change: 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. … 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).

To: A total of 33,933 patients were included in the safety population from these trials used for the analyses; of these, 17339 patients (9797 patient-years exposure) were randomized to lumiracoxib and 16594 patients were allocated to controls (8824.6 patient-years exposure). Prospective adjudication for the components of Antiplatelet Trialist’s Collaboration (APTC) endpoint occurred for 15,679.3 of the total 18,621.6 patient-years exposure. … Four trials continued for one year (TARGET, and trials 112, 2335, and 2361 with their extensions) totaling 22,781 safety patients (16,526.7 patient-years exposure).


Page 13

Change: Table 1-2     Relative risk of APTC endpoint with lumiracoxib and comparators  from a stratified meta-analysis

Comparisons

Contrasts

Risk
ratio

95% CI for
risk ratio

Interaction
p-value

All comparators

all Lumiracoxib - all control

1.14

( 0.83,1.57)

 

 

Type of control

Lumiracoxib - placebo

0.88

( 0.34,2.25)

0.6172

 

Lumiracoxib - Non Naproxen NSAID

0.83

( 0.46,1.51)

 

 

Lumiracoxib - Naproxen

1.49

( 0.94,2.36)

 

 

Duration

>3 months:  Lumiracoxib - control

1.18

( 0.84,1.67)

0.6121

 

<=3 months: Lumiracoxib - control

0.93

( 0.38,2.29)

 

 

External Adjudication

external:    Lumiracoxib - control

1.08

( 0.75,1.54)

0.5562

 

no external: Lumiracoxib - control

1.36

( 0.66,2.80)

 

 

Dose*

Lumiracoxib high dose -control

1.17

( 0.84,1.65)

0.5379

 

Lumiracoxib low dose -control

0.99

( 0.57,1.71)

 

To:

Comparisons

Contrasts

Risk
ratio

95% CI for
risk ratio

Interaction
p-value

All comparators

all Lumiracoxib -all control

1.12

( 0.82,1.55)

 

_____________________________________________________________________________

Type of control

Lumiracoxib - placebo

1.08

( 0.41,2.86)

0.9102

 

Lumiracoxib - non-naproxen NSAID

0.83

( 0.46,1.51)

 

 

Lumiracoxib - Naproxen

1.49

( 0.94,2.36)

 

_____________________________________________________________________________

Indication

RA: Lumiracoxib - control

1.59

( 0.61,4.13)

0.4360

 

OA: Lumiracoxib - control

1.08

( 0.77,1.51)

 

_____________________________________________________________________________

Duration

>3 months:  Lumiracoxib - control

1.15

( 0.82,1.61)

0.8162

 

<=3 months: Lumiracoxib - control

1.02

( 0.41,2.57)

 

_____________________________________________________________________________

External Adjudication

external:    Lumiracoxib - control

1.06

( 0.74,1.51)

0.5274

 

no external: Lumiracoxib - control

1.36

( 0.66,2.80)

 

_____________________________________________________________________________

Dose

Lumiracoxib high dose -control

1.15

( 0.82,1.61)

0.5506

 

Lumiracoxib low dose -control

0.98

( 0.57,1.69)

 

Page 14

Change: Table 1-3     Relative risk of MI with lumiracoxib and comparators from a stratified meta-analysis

Comparisons

Contrasts

Risk
ratio

95% CI for
risk ratio

Interaction
p-value

All comparators

all Lumiracoxib -all control

1.28

( 0.78, 2.12)

 

 

Type of control

Lumiracoxib - placebo

1.06

( 0.20, 6.69)

0.7484

 

Lumiracoxib - Non Naproxen NSAID

0.80

( 0.28, 2.25)

 

 

Lumiracoxib - Naproxen

1.69

( 0.82, 3.48)

 

 

Duration

>3 months:  Lumiracoxib - control

1.30

( 0.75, 2.27)

0.9191

 

<=3 months: Lumiracoxib - control

1.39

( 0.41, 4.72)

 

 

External Adjudication

external:    Lumiracoxib - control

1.20

( 0.67, 2.16)

0.7152

 

no external: Lumiracoxib - control

1.48

( 0.54, 4.05)

 

 

Dose

Lumiracoxib high dose -control

1.34

( 0.79, 2.29)

0.5799

 

Lumiracoxib low dose -control

1.07

( 0.46, 2.49)

 

To:

Comparisons

Contrasts

Risk
ratio

95% CI for
risk ratio

Interaction
p-value

All comparators

all Lumiracoxib -all control

1.28

( 0.78,2.12)

 

___________________________________________________________________________

Type of control

Lumiracoxib - placebo

1.27

( 0.25,6.56)

0.9010

 

Lumiracoxib - non-naproxen NSAID

0.80

( 0.28,2.25)

 

 

Lumiracoxib - Naproxen

1.69

( 0.82,3.48)

 

___________________________________________________________________________

Indication

RA: Lumiracoxib - control

2.32

( 0.43,12.4)

0.4407

 

OA: Lumiracoxib - control

1.20

( 0.71,2.05)

 

___________________________________________________________________________

Duration

>3 months:  Lumiracoxib - control

1.30

( 0.75,2.27)

0.9189

 

<=3 months: Lumiracoxib - control

1.39

( 0.41,4.72)

 

__________________________________________________________________________

External Adjudication

external:    Lumiracoxib - control

1.20

( 0.67,2.16)

0.7151

 

no external: Lumiracoxib - control

1.48

( 0.54,4.05)

 

___________________________________________________________________________

Dose

Lumiracoxib high dose -control

1.34

( 0.79,2.29)

0.5859

 

Lumiracoxib low dose -control

1.07

( 0.46,2.50)

 

 


Page 14

Change: The cumulative meta-analysis analyzed more than 34 000 patients with a total of 161 APTC events including 66 myocardial infarctions.

 

To: The cumulative meta-analysis analyzed more than 34 000 patients with a total of 162 APTC events including 66 myocardial infarctions.


Page 15

Change: Figure 1-1    Cumulative stratified meta-analysis of APTC events in randomized trials comparing lumiracoxib with controls

To:


Page 15

Change: Figure 1-2    Cumulative stratified meta-analysis of MI in randomized trials comparing lumiracoxib with controls

To:


Page 16

Change: 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)

To: When the analysis was done excluding naproxen a stratified meta-analysis was performed comparing lumiracoxib to non-naproxen comparators, the risk decreased to 1.01 (95 % CI 0.50 – 2.02) which supports our assertion that naproxen at the high dose of 500 mg bid may have an antithrombotic effect (Figure 1-3 below)


Page 16

Change: Figure 1-3    Cumulative meta-analysis of MI in randomized trials comparing lumiracoxib with non-naproxen NSAIDs

To: Figure 1-3    Cumulative meta-analysis of MI in randomized trials comparing lumiracoxib versus all non-naproxen comparators


Page 17

Change: Table 1-4     Relative risk of stroke with lumiracoxib and comparators from a stratified meta-analysis

Comparisons

Contrasts

Risk
ratio

95% CI for
risk ratio

Interaction
p-value

All comparators

all Lumiracoxib - all control

1.20

( 0.70, 2.07)

 

 

Type of control

Lumiracoxib - placebo

0.89

( 0.15, 5.08)

0.3174

 

Lumiracoxib - Non Naproxen NSAID

0.91

( 0.35, 2.35)

 

 

Lumiracoxib - Naproxen

1.46

( 0.70, 3.07)

 

 

Duration

>3 months:  Lumiracoxib - control

1.18

( 0.68, 2.06)

 

 

<=3 months: Lumiracoxib - control

 

not estimable

 

 

External Adjudication

external:    Lumiracoxib - control

1.06

( 0.59, 1.88)

0.1424

 

no external: Lumiracoxib - control

4.44

( 0.51, 38.9)

 

 

Dose

Lumiracoxib high dose - control

1.19

( 0.67, 2.11)

0.8955

 

Lumiracoxib low dose - control

1.12

( 0.43, 2.92)

 

To:

Comparisons

Contrasts

Risk
ratio

95% CI for
risk ratio

Interaction
p-value

All comparators

all Lumiracoxib -all control

1.02

( 0.61,1.71)

 

___________________________________________________________________________

Type of control

Lumiracoxib - placebo

0.59

( 0.13,2.74)

0.8603

 

Lumiracoxib - non-naproxen NSAID

0.91

( 0.35,2.35)

 

 

Lumiracoxib - Naproxen

1.42

( 0.70,2.91)

 

___________________________________________________________________________

Indication

RA: Lumiracoxib - control

2.32

( 0.43,12.4)

0.2793

 

OA: Lumiracoxib - control

0.93

( 0.54,1.60)

 

___________________________________________________________________________

Duration

>3 months:  Lumiracoxib - control

1.08

( 0.64,1.84)

0.3445

 

<=3 months: Lumiracoxib - control

0.38

( 0.04,3.84)

 

___________________________________________________________________________

External Adjudication

external:    Lumiracoxib - control

0.97

( 0.56,1.68)

0.5705

 

no external: Lumiracoxib - control

1.48

( 0.36,6.13)

 

___________________________________________________________________________

Dose

Lumiracoxib high dose -control

1.01

( 0.59,1.75)

0.9928

 

Lumiracoxib low dose -control

1.02

( 0.42,2.45)

 

 


Page 17

Change: Figure 1-4    Cumulative stratified meta-analysis of stroke in randomized trials comparing lumiracoxib with controls

To:


Page 18

Change: Table 1-5     Relative risk of peripheral vascular event with lumiracoxib and comparators from a stratified meta-analysis

Comparisons

Contrasts

Risk
ratio

95% CI for
risk ratio

Interaction
p-value

All comparators

all Lumiracoxib -all control

1.10

( 0.56, 2.16)

 

 

Type of control

Lumiracoxib - placebo

0.99

( 0.25, 3.97)

0.1631

 

Lumiracoxib - Non Naproxen NSAID

1.82

( 0.44, 7.53)

 

 

Lumiracoxib - Naproxen

0.79

( 0.26, 2.42)

 

 

Duration

>3 months:  Lumiracoxib - control

1.36

( 0.62, 2.95)

0.3967

 

<=3 months: Lumiracoxib - control

0.68

( 0.16, 2.95)

 

 

External Adjudication

external:    Lumiracoxib - control

1.01

( 0.45, 2.26)

0.7378

 

no external: Lumiracoxib - control

1.30

( 0.37, 4.57)

 

 

Dose

Lumiracoxib high dose - control

0.98

( 0.46, 2.09)

0.3570

 

Lumiracoxib low dose - control

1.55

( 0.61, 3.95)

 

To:

Comparisons

Contrasts

Risk
ratio

95% CI for
risk ratio

Interaction
p-value

All comparators

all Lumiracoxib -all control

0.98

( 0.51,1.89)

 

___________________________________________________________________________

Type of control

Lumiracoxib - placebo

0.74

( 0.21,2.61)

0.1086

 

Lumiracoxib - non-naproxen NSAID

1.82

( 0.44,7.53)

 

 

Lumiracoxib - Naproxen

0.69

( 0.23,2.05)

 

___________________________________________________________________________

Indication

RA: Lumiracoxib - control

0.93

( 0.22,3.84)

0.8982

 

OA: Lumiracoxib - control

1.03

( 0.49,2.14)

 

___________________________________________________________________________

Duration

>3 months:  Lumiracoxib - control

1.15

( 0.55,2.41)

0.5175

 

<=3 months: Lumiracoxib - control

0.68

( 0.16,2.95)

 

___________________________________________________________________________

External Adjudication

external:    Lumiracoxib - control

0.87

( 0.40,1.88)

0.5815

 

no external: Lumiracoxib - control

1.30

( 0.37,4.57)

 

___________________________________________________________________________

Dose

Lumiracoxib high dose -control

0.89

( 0.43,1.86)

0.3986

 

Lumiracoxib low dose -control

1.35

( 0.54,3.38)

 

 


Page 18

Change: Figure 1-5    Cumulative stratified meta-analysis of peripheral vascular events in randomized trials comparing lumiracoxib with controls

To:


Page 19

Change: Table 1-8     Relative risk for MI / all strokes / peripheral vascular events – combined, with lumiracoxib and comparators from a stratified meta-analysis

Comparisons

Contrasts

Risk
ratio

95% CI for
risk ratio

Interaction
p-value

All comparators

all Lumiracoxib -all control

1.24

( 0.89, 1.71)

 

 

Type of control

Lumiracoxib - placebo

0.97

( 0.39, 2.41)

0.5519

 

Lumiracoxib - Non Naproxen NSAID

1.05

( 0.56, 1.98)

 

 

Lumiracoxib - Naproxen

1.40

( 0.88, 2.23)

 

 

Duration

>3 months:  Lumiracoxib - control

1.29

( 0.9, 1.83)

0.6445

 

<=3 months: Lumiracoxib - control

1.04

( 0.43,2.50)

 

 

External Adjudication

external:    Lumiracoxib - control

1.12

( 0.78, 1.62)

0.3034

 

no external: Lumiracoxib - control

1.69

( 0.82, 3.50)

 

 

Dose

Lumiracoxib high dose -control

1.22

( 0.86, 1.73)

0.9485

 

Lumiracoxib low dose -control

1.24

( 0.73, 2.11)

 

To: Table 1-6 Relative risk for MI / all strokes / peripheral vascular events – combined, with lumiracoxib and comparators from a stratified meta-analysis

Comparisons

Contrasts

Risk
ratio

95% CI for
risk ratio

Interaction
p-value

All comparators

all Lumiracoxib -all control

1.13

( 0.82,1.54)

 

___________________________________________________________________________

Type of control

Lumiracoxib - placebo

0.80

( 0.35,1.84)

0.4585

 

Lumiracoxib - non-naproxen NSAID

1.05

( 0.56,1.98)

 

 

Lumiracoxib - Naproxen

1.34

( 0.85,2.12)

 

___________________________________________________________________________

Indication

RA: Lumiracoxib - control

1.62

( 0.67,3.95)

0.3769

 

OA: Lumiracoxib - control

1.07

( 0.77,1.50)

 

___________________________________________________________________________

Duration

>3 months:  Lumiracoxib - control

1.19

( 0.84,1.67)

0.5184

 

<=3 months: Lumiracoxib - control

0.89

( 0.38,2.07)

 

___________________________________________________________________________

External Adjudication

external:    Lumiracoxib - control

1.04

( 0.73,1.49)

0.4004

 

no external: Lumiracoxib - control

1.44

( 0.72,2.86)

 

___________________________________________________________________________

Dose

Lumiracoxib high dose -control

1.12

( 0.80,1.58)

0.9647

 

Lumiracoxib low dose -control

1.14

( 0.68,1.90)

 

 


Page 20

Change: Figure 1-6    Cumulative stratified meta-analysis for MI / all strokes / peripheral vascular events – combined, in randomized trials comparing lumiracoxib with controls

To: