REMICADE (Page 8 of 13)

14.2 Pediatric Crohn’s Disease

The safety and efficacy of REMICADE were assessed in a randomized, open-label study (Study Peds Crohn’s) in 112 pediatric patients aged 6 to 17 years old with moderately to severely active CD and an inadequate response to conventional therapies. The median age was 13 years and the median Pediatric Crohn’s Disease Activity Index (PCDAI) was 40 (on a scale of 0 to 100). All patients were required to be on a stable dose of 6-MP, AZA, or MTX; 35% were also receiving corticosteroids at baseline.

All patients received induction dosing of 5 mg/kg REMICADE at Weeks 0, 2, and 6. At Week 10, 103 patients were randomized to a maintenance regimen of 5 mg/kg REMICADE given either every 8 weeks or every 12 weeks.

At Week 10, 88% of patients were in clinical response (defined as a decrease from baseline in the PCDAI score of ≥15 points and total PCDAI score of ≤30 points), and 59% were in clinical remission (defined as PCDAI score of ≤10 points).

The proportion of pediatric patients achieving clinical response at Week 10 compared favorably with the proportion of adults achieving a clinical response in Study Crohn’s I. The study definition of clinical response in Study Peds Crohn’s was based on the PCDAI score, whereas the CDAI score was used in the adult Study Crohn’s I.

At both Week 30 and Week 54, the proportion of patients in clinical response was greater in the every 8-week treatment group than in the every 12-week treatment group (73% vs. 47% at Week 30, and 64% vs. 33% at Week 54). At both Week 30 and Week 54, the proportion of patients in clinical remission was also greater in the every 8-week treatment group than in the every 12-week treatment group (60% vs. 35% at Week 30, and 56% vs. 24% at Week 54), (Table 4).

For patients in Study Peds Crohn’s receiving corticosteroids at baseline, the proportion of patients able to discontinue corticosteroids while in remission at Week 30 was 46% for the every 8-week maintenance group and 33% for the every 12-week maintenance group. At Week 54, the proportion of patients able to discontinue corticosteroids while in remission was 46% for the every 8-week maintenance group and 17% for the every 12-week maintenance group.

Table 4: Response and Remission in Study Peds Crohn’s

	5 mg/kg REMICADE
	Every 8 Week	Every 12 Week
	Treatment Group	Treatment Group
* Defined as a decrease from baseline in the PCDAI score of ≥15 points and total score of ≤30 points. † P -value <0.01 ‡ Defined as a PCDAI score of ≤10 points. § P -value <0.05
Patients randomized	52	51
Clinical Response *
Week 30	73%†	47%
Week 54	64%†	33%
Clinical Remission ‡
Week 30	60%§	35%
Week 54	56%†	24%

14.3 Adult Ulcerative Colitis

The safety and efficacy of REMICADE were assessed in 2 randomized, double-blind, placebo-controlled clinical studies in 728 adult patients with moderately to severely active UC (Mayo score 6 to 12 [of possible range 0 to 12], Endoscopy subscore ≥2) with an inadequate response to conventional oral therapies (Studies UC I and UC II). Concomitant treatment with stable doses of aminosalicylates, corticosteroids and/or immunomodulatory agents was permitted. Corticosteroid taper was permitted after Week 8. Patients were randomized at week 0 to receive either placebo, 5 mg/kg REMICADE or 10 mg/kg REMICADE at Weeks 0, 2, 6, and every 8 weeks thereafter through Week 46 in Study UC I, and at Weeks 0, 2, 6, and every 8 weeks thereafter through Week 22 in Study UC II. In Study UC II, patients were allowed to continue blinded therapy to Week 46 at the investigator’s discretion.

Adult patients in Study UC I had failed to respond or were intolerant to oral corticosteroids, 6-MP, or AZA. Adult patients in Study UC II had failed to respond or were intolerant to the above treatments and/or aminosalicylates. Similar proportions of patients in Studies UC I and UC II were receiving corticosteroids (61% and 51%, respectively), 6-MP/AZA (49% and 43%) and aminosalicylates (70% and 75%) at baseline. More patients in Study UC II than UC I were taking solely aminosalicylates for UC (26% vs. 11%, respectively). Clinical response was defined as a decrease from baseline in the Mayo score by ≥30% and ≥3 points, accompanied by a decrease in the rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1.

Clinical Response, Clinical Remission, and Mucosal Healing

In both Study UC I and Study UC II, greater percentages of patients in both REMICADE groups achieved clinical response, clinical remission and mucosal healing than in the placebo group. Each of these effects was maintained through the end of each trial (Week 54 in Study UC I, and Week 30 in Study UC II). In addition, a greater proportion of patients in REMICADE groups demonstrated sustained response and sustained remission than in the placebo groups (Table 5).

Of patients on corticosteroids at baseline, greater proportions of adult patients in the REMICADE treatment groups were in clinical remission and able to discontinue corticosteroids at Week 30 compared with the patients in the placebo treatment groups (22% in REMICADE treatment groups vs. 10% in placebo group in Study UC I; 23% in REMICADE treatment groups vs. 3% in placebo group in Study UC II). In Study UC I, this effect was maintained through Week 54 (21% in REMICADE treatment groups vs. 9% in placebo group). The REMICADE-associated response was generally similar in the 5 mg/kg and 10 mg/kg dose groups.

Table 5: Response, Remission and Mucosal Healing in Adult UC Studies (Studies UC I and UC II)

	Study UC I			Study UC II
	Placebo	5 mg/kg REMICADE	10 mg/kg REMICADE	Placebo	5 mg/kg REMICADE	10 mg/kg REMICADE
* Defined as a decrease from baseline in the Mayo score by ≥30% and ≥3 points, accompanied by a decrease in the rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1. (The Mayo score consists of the sum of four subscores: stool frequency, rectal bleeding, physician’s global assessment and endoscopy findings). † Patients who had a prohibited change in medication, had an ostomy or colectomy, or discontinued study infusions due to lack of efficacy are considered to not be in clinical response, clinical remission or mucosal healing from the time of the event onward. ‡ P <0.001, § P <0.01 ¶ Defined as a Mayo score ≤2 points, no individual subscore >1. # Defined as a 0 or 1 on the endoscopy subscore of the Mayo score.
Patients randomized	121	121	122	123	121	120
Clinical Response * , †
Week 8	37%	69%‡	62%‡	29%	65%‡	69%‡
Week 30	30%	52%‡	51%§	26%	47%‡	60%‡
Week 54	20%	45%‡	44%‡	NA	NA	NA
Sustained Response †
(Clinical response at both Weeks 8 and 30)	23%	49%‡	46%‡	15%	41%‡	53%‡
(Clinical response at Weeks 8, 30, and 54)	14%	39%‡	37%‡	NA	NA	NA
Clinical Remission ¶ , †
Week 8	15%	39%‡	32%§	6%	34%‡	28%‡
Week 30	16%	34%§	37%‡	11%	26%§	36%‡
Week 54	17%	35%§	34%§	NA	NA	NA
Sustained Remission †
(Clinical remission at both Weeks 8 and 30)	8%	23%§	26%‡	2%	15%‡	23%‡
(Clinical remission at Weeks 8, 30 and 54)	7%	20%§	20%§	NA	NA	NA
Mucosal Healing # , †
Week 8	34%	62%‡	59%‡	31%	60%‡	62%‡
Week 30	25%	50%‡	49%‡	30%	46%§	57%‡
Week 54	18%	45%‡	47%‡	NA	NA	NA

The improvement with REMICADE was consistent across all Mayo subscores through Week 54 (Study UC I shown in Table 6; Study UC II through Week 30 was similar).

Table 6: Proportion of Adult UC Patients in Study UC I with Mayo Subscores Indicating Inactive or Mild Disease Through Week 54

	Study UC I
		REMICADE
	Placebo	5 mg/kg	10 mg/kg
	(n=121)	(n=121)	(n=122)
Stool frequency
Baseline	17%	17%	10%
Week 8	35%	60%	58%
Week 30	35%	51%	53%
Week 54	31%	52%	51%
Rectal bleeding
Baseline	54%	40%	48%
Week 8	74%	86%	80%
Week 30	65%	74%	71%
Week 54	62%	69%	67%
Physician’s Global Assessment
Baseline	4%	6%	3%
Week 8	44%	74%	64%
Week 30	36%	57%	55%
Week 54	26%	53%	53%
Endoscopy findings
Baseline	0%	0%	0%
Week 8	34%	62%	59%
Week 30	26%	51%	52%
Week 54	21%	50%	51%