Remicade - Clinical Pharmacology

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In the single-dose trial8 of 108 patients, 16% (4/25) of placebo patients achieved a clinical response (decrease in CDAI =70 points) at week 4 vs. 81% (22/27) of patients receiving 5 mg/kg REMICADE (p<0.001, two-sided, Fisher’s Exact test). Additionally, 4% (1/25) of placebo patients and 48% (13/27) of patients receiving 5 mg/kg REMICADE achieved clinical remission (CDAI<150) at week 4. In a multidose trial (ACCENT I [Study Crohn’s I])9, 545 patients received 5 mg/kg at week 0 and were then randomized to one of three treatment groups: the placebo maintenance group received placebo at weeks 2 and 6, and then every 8 weeks; the 5 mg/kg maintenance group received 5 mg/kg at weeks 2 and 6, and then every 8 weeks; and the 10 mg/kg maintenance group received 5 mg/kg at weeks 2 and 6, and then 10 mg/kg every 8 weeks.

Patients in response at week 2 were randomized and analyzed separately from those not in response at week 2. Corticosteroid taper was permitted after week 6. At week 2, 57% (311/545) of patients were in clinical response. At week 30, a significantly greater proportion of these patients in the 5 mg/kg and 10 mg/kg maintenance groups achieved clinical remission compared to patients in the placebo maintenance group (Table 4). Additionally, a significantly greater proportion of patients in the 5 mg/kg and 10 mg/kg infliximab maintenance groups were in clinical remission and were able to discontinue corticosteroid use compared to patients in the placebo maintenance group at week 54 (Table 4).

Radiographic response

Structural damage in both hands and feet was assessed radiographically at week 54 by the change from baseline in the van der Heijde-modified Sharp (vdH-S) score, a composite score of structural damage that measures the number and size of joint erosions and the degree of joint space narrowing in hands/wrists and feet. In Study RA I, approximately 80% of patients had paired x-ray data at 54 weeks and approximately 70% at 102 weeks. The inhibition of progression of structural damage was observed at 54 weeks (Table 3) and maintained through 102 weeks.

In Study RA II, >90% of patients had at least two evaluable x-rays. Inhibition of progression of structural damage was observed at weeks 30 and 54 (Table 3) in the REMICADE + MTX groups compared to MTX alone. In an exploratory analysis of Study RA II, patients treated with REMICADE + MTX demonstrated less progression of structural damage compared to MTX alone, whether baseline acute phase reactants (ESR and CRP) were normal or elevated: patients with elevated baseline acute phase reactants treated with MTX alone demonstrated a mean progression in vdH-S score of 4.2 units compared to patients treated with REMICADE + MTX who demonstrated 0.5 units of progression; patients with normal baseline acute phase reactants treated with MTX alone demonstrated a mean progression in vdH-S score of 1.8 units compared to REMICADE + MTX who demonstrated 0.2 units of progression. Of patients receiving REMICADE + MTX, 59% had no progression (vdH-S score = 0 unit) of structural damage compared to 45% patients receiving MTX alone.

In a subset of patients who began the study without erosions, REMICADE + MTX maintained an erosion free state at 1 year in a greater proportion of patients than MTX alone, 79% (77/98) vs. 58% (23/40), respectively (p<0.01). Fewer patients in the REMICADE + MTX groups (47%) developed erosions in uninvolved joints compared to MTX alone (59%).

Table 3

RADIOGRAPHIC CHANGE

FROM BASELINE TO WEEK 54

Study RA I Study RA II

REMICADE + MTX REMICADE + MTX

3 mg/kg 10 mg/kg 3 mg/kg 6 mg/kg

Placebo

+ MTX

q 8

wks

q 8

wks

Placebo

+ MTX

q 8

wks

q 8

wks

(n=64) (n=71) (n=77) (n=282) (n=359) (n=363)

Total Score Baseline Mean Median

79

55

78

57

65

56

11.3

5.1

11.6

5.2

11.2

5.3

Change from baseline Mean Median

6.9

4.0

1.3 a

0.5

0.2 a

0.5

3.7

0.4

0.4 a

0.0

0.5 a

0.0

Erosion Score Baseline Mean Median

44

25

44

29

33

22

8.3

3.0

8.8

3.8

8.3

3.8

Change from baseline Mean Median

4.1

2.0

0.2 a

0.0

0.2 a

0.5

3.0

0.3

0.3 a

0.0

0.1 a

0.0

JSN Score Baseline Mean Median

36

26

34

29

31

24

3.0

1.0

2.9

1.0

2.9

1.0

Change from baseline Mean Median

2.9

1.5

1.1 a

0.0

0.0 a

0.0

0.6

0.0

0.1 a

0.0

0.2

0.0

a

p<0.001 for each outcome aga inst placebo.

Table 4

CLINICAL REMISSION AND STEROID WITHDRAWAL

Single 5 mg/kg Dosea

Placebo Maintenance

25/102

25%

6/54

11%

Week 30

Clinical remission

p-valuec

Week 54

Patients in remission able to

discontinue corticosteroid used

p-valuec

a REMICADE at week 0

b REMICADE 5 mg/kg administered at weeks 0, 2, and 6

c p-values represent pairwise comparisons to placebo

d Of those receiving corticosteroids at baseline

Three-Dose Inductionb

Infliximab Maintenance q 8 wks

41/104

39%

0.022

14/56

25%

0.059

48/105

46%

0.001

18/53

34%

0.005

5 mg/kg 10 mg/kg

Patients who achieved a fistula response and subsequently lost response were eligible to receive REMICADE maintenance therapy at a dose that was 5 mg/kg higher than the dose to which they were randomized. Of the placebo maintenance patients, 66% (25/38) responded to 5 mg/kg REMICADE, and 57% (12/21) of REMICADE maintenance patients responded to 10 mg/kg. Patients who had not achieved a response by week 14 were unlikely to respond to additional doses of REMICADE. Similar proportions of patients in either group developed new fistulas (17% overall) and similar numbers developed abscesses (15% overall).