REMICADE (Page 9 of 13)

14.4 Pediatric Ulcerative Colitis

The safety and effectiveness of REMICADE for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients aged 6 years and older with moderately to severely active UC who have had an inadequate response to conventional therapy are supported by evidence from adequate and well-controlled studies of REMICADE in adults. Additional safety and pharmacokinetic data were collected in an open-label pediatric UC trial in 60 pediatric patients aged 6 through 17 years (median age 14.5 years) with moderately to severely active UC (Mayo score of 6 to 12; Endoscopic subscore ≥2) and an inadequate response to conventional therapies. At baseline, the median Mayo score was 8, 53% of patients were receiving immunomodulator therapy (6-MP/AZA/MTX), and 62% of patients were receiving corticosteroids (median dose 0.5 mg/kg/day in prednisone equivalents). Discontinuation of immunomodulators and corticosteroid taper were permitted after Week 0.

All patients received induction dosing of 5 mg/kg REMICADE at Weeks 0, 2, and 6. Patients who did not respond to REMICADE at Week 8 received no further REMICADE and returned for safety follow-up. At Week 8, 45 patients were randomized to a maintenance regimen of 5 mg/kg REMICADE given either every 8 weeks through Week 46 or every 12 weeks through Week 42. Patients were allowed to change to a higher dose and/or more frequent administration schedule if they experienced loss of response.

Clinical response at Week 8 was defined as a decrease from baseline in the Mayo score by ≥30% and ≥3 points, including a decrease in the rectal bleeding subscore by ≥1 points or achievement of a rectal bleeding subscore of 0 or 1.

Clinical remission at Week 8 was measured by the Mayo score, defined as a Mayo score of ≤2 points with no individual subscore >1. Clinical remission was also assessed at Week 8 and Week 54 using the Pediatric Ulcerative Colitis Activity Index (PUCAI)1 score and was defined by a PUCAI score of <10 points.

Endoscopies were performed at baseline and at Week 8. A Mayo endoscopy subscore of 0 indicated normal or inactive disease and a subscore of 1 indicated mild disease (erythema, decreased vascular pattern, or mild friability).

Of the 60 patients treated, 44 were in clinical response at Week 8. Of 32 patients taking concomitant immunomodulators at baseline, 23 achieved clinical response at Week 8, compared to 21 of 28 of those not taking concomitant immunomodulators at baseline. At Week 8, 24 of 60 patients were in clinical remission as measured by the Mayo score and 17 of 51 patients were in remission as measured by the PUCAI score.

At Week 54, 8 of 21 patients in the every 8-week maintenance group and 4 of 22 patients in the every 12-week maintenance group achieved remission as measured by the PUCAI score.

During maintenance phase, 23 of 45 randomized patients (9 in the every 8-week group and 14 in the every 12-week group) required an increase in their dose and/or increase in frequency of REMICADE administration due to loss of response. Nine of the 23 patients who required a change in dose had achieved remission at Week 54. Seven of those patients received the 10 mg/kg every 8-week dosing.

14.5 Rheumatoid Arthritis

The safety and efficacy of REMICADE in adult patients with RA were assessed in 2 multicenter, randomized, double-blind, pivotal trials: ATTRACT (Study RA I) and ASPIRE (Study RA II). Concurrent use of stable doses of folic acid, oral corticosteroids (≤10 mg/day) and/or non-steroidal anti-inflammatory drugs (NSAIDs) was permitted.

Study RA I was a placebo-controlled study of 428 patients with active RA despite treatment with MTX. Patients enrolled had a median age of 54 years, median disease duration of 8.4 years, median swollen and tender joint count of 20 and 31 respectively, and were on a median dose of 15 mg/wk of MTX. Patients received either placebo+MTX or one of 4 doses/schedules of REMICADE+MTX: 3 mg/kg or 10 mg/kg of REMICADE by IV infusion at Weeks 0, 2 and 6 followed by additional infusions every 4 or 8 weeks in combination with MTX.

Study RA II was a placebo-controlled study of 3 active treatment arms in 1004 MTX naive patients of 3 or fewer years’ duration active RA. Patients enrolled had a median age of 51 years with a median disease duration of 0.6 years, median swollen and tender joint count of 19 and 31 , respectively, and >80% of patients had baseline joint erosions. At randomization, all patients received MTX (optimized to 20 mg/wk by Week 8) and either placebo, 3 mg/kg or 6 mg/kg REMICADE at Weeks 0, 2, and 6 and every 8 weeks thereafter.

Data on use of REMICADE without concurrent MTX are limited [see Adverse Reactions (6.1)].

Clinical Response

In Study RA I, all doses/schedules of REMICADE+MTX resulted in improvement in signs and symptoms as measured by the American College of Rheumatology response criteria (ACR 20) with a higher percentage of patients achieving an ACR 20, 50 and 70 compared to placebo+MTX (Table 7). This improvement was observed at Week 2 and maintained through Week 102. Greater effects on each component of the ACR 20 were observed in all patients treated with REMICADE+MTX compared to placebo+MTX (Table 8). More patients treated with REMICADE reached a major clinical response than placebo-treated patients (Table 7).

In Study RA II, after 54 weeks of treatment, both doses of REMICADE+MTX resulted in statistically significantly greater response in signs and symptoms compared to MTX alone as measured by the proportion of patients achieving ACR 20, 50 and 70 responses (Table 7). More patients treated with REMICADE reached a major clinical response than placebo-treated patients (Table 7).

Table 7: ACR Response (percent of patients) in Adult RA Patients (Studies RA I and RA II)
Study RA I Study RA II
REMICADE+MTX REMICADE+MTX
3 mg/kg 10 mg/kg 3 mg/kg 6 mg/kg
Response Placebo+MTX q8 wks q4 wks q8 wks q4 wks Placebo+MTX q8 wks q8 wks
(n=88) (n=86) (n=86) (n=87) (n=81) (n=274) (n=351) (n=355)
*
P ≤0.001
P <0.05
P <0.01
§
A major clinical response was defined as a 70% ACR response for 6 consecutive months (consecutive visits spanning at least 26 weeks) through Week 102 for Study RA I and Week 54 for Study RA II.
ACR 20
Week 30 20% 50%* 50%* 52%* 58%* N/A N/A N/A
Week 54 17% 42%* 48%* 59%* 59%* 54% 62% 66%*
ACR 50
Week 30 5% 27%* 29%* 31%* 26%* N/A N/A N/A
Week 54 9% 21% 34%* 40%* 38%* 32% 46%* 50%*
ACR 70
Week 30 0% 8% 11% 18%* 11%* N/A N/A N/A
Week 54 2% 11% 18%* 26%* 19%* 21% 33% 37%*
Major clinical response § 0% 7% 8% 15%* 6% 8% 12% 17%*
Table 8: Components of ACR 20 at Baseline and 54 Weeks (Study RA I)
Placebo+MTX REMICADE+MTX *
Parameter (medians) (n=88) (n=340)
Baseline Week 54 Baseline Week 54
*
All doses/schedules of REMICADE+MTX
Visual Analog Scale (0=best, 10=worst)
Health Assessment Questionnaire, measurement of 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities (0=best, 3=worst)
No. of Tender Joints 24 16 32 8
No. of Swollen Joints 19 13 20 7
Pain 6.7 6.1 6.8 3.3
Physician’s Global Assessment 6.5 5.2 6.2 2.1
Patient’s Global Assessment 6.2 6.2 6.3 3.2
Disability Index (HAQ-DI) 1.8 1.5 1.8 1.3
CRP (mg/dL) 3.0 2.3 2.4 0.6

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 9) and maintained through 102 weeks.

In Study RA II, >90% of patients had at least 2 evaluable X-rays. Inhibition of progression of structural damage was observed at Weeks 30 and 54 (Table 9) in the REMICADE+MTX groups compared to MTX alone. 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% of 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 9: Radiographic Change from Baseline to Week 54 in Adult RA Patients (Studies RA I and RA II)
Study RA I Study RA II
REMICADE+MTX REMICADE+MTX
3 mg/kg 10 mg/kg 3 mg/kg 6 mg/kg
Placebo+MTX q8 wks q8 wks Placebo+MTX q8 wks q8 wks
(n=64) (n=71) (n=77) (n=282) (n=359) (n=363)
*
P<0.001 for each outcome against placebo.
Total Score
Baseline
Mean 79 78 65 11.3 11.6 11.2
Median 55 57 56 5.1 5.2 5.3
Change from baseline
Mean 6.9 1.3* 0.2* 3.7 0.4* 0.5*
Median 4.0 0.5 0.5 0.4 0.0 0.0
Erosion Score
Baseline
Mean 44 44 33 8.3 8.8 8.3
Median 25 29 22 3.0 3.8 3.8
Change from baseline
Mean 4.1 0.2* 0.2* 3.0 0.3* 0.1*
Median 2.0 0.0 0.5 0.3 0.0 0.0
JSN Score
Baseline
Mean 36 34 31 3.0 2.9 2.9
Median 26 29 24 1.0 1.0 1.0
Change from baseline
Mean 2.9 1.1* 0.0* 0.6 0.1* 0.2
Median 1.5 0.0 0.0 0.0 0.0 0.0

Physical Function Response

Physical function and disability were assessed using the Health Assessment Questionnaire (HAQ-DI) and the general health-related quality of life questionnaire SF-36.

In Study RA I, all doses/schedules of REMICADE+MTX showed significantly greater improvement from baseline in HAQ-DI and SF-36 physical component summary score averaged over time through Week 54 compared to placebo+MTX, and no worsening in the SF-36 mental component summary score. The median (interquartile range) improvement from baseline to Week 54 in HAQ-DI was 0.1 (-0.1, 0.5) for the placebo+MTX group and 0.4 (0.1, 0.9) for REMICADE+MTX (p<0.001). Both HAQ-DI and SF-36 effects were maintained through Week 102. Approximately 80% of patients in all doses/schedules of REMICADE+MTX remained in the trial through 102 weeks.

In Study RA II, both REMICADE treatment groups showed greater improvement in HAQ-DI from baseline averaged over time through Week 54 compared to MTX alone; 0.7 for REMICADE+MTX vs. 0.6 for MTX alone (P ≤0.001). No worsening in the SF-36 mental component summary score was observed.

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2023. All Rights Reserved.