Adalimumab Induction Therapy for Crohn’s Disease Previously Treated with Infliximab.
Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, et al.
Annals of Internal Medicine. 2007;146:829-838. |
• Tumor Necrosis factor (TNF) is an important pro inflammatory cytokine seen in Crohn’s disease. Infliximab is a chimeric, anti-TNF monocolonal antibody that is effective in inducing and maintaining clinical remission in Crohn’s patients. Loss of efficacy, need for dose escalation, or infusion reactions with infliximab have been reported in upto 40% of cases (Hanauer SB, et al. Lancet. 2002;359:1541-9).
• Adalimumab is a new phage derived purely human TNF antagonist that has been shown to be effective in Crohn’s patients that are naive to and some patients that have lost response to or are intolerant to Infliximab.
• Sandborn WJ, et al conducted a prospective randomized placebo controlled trial of adalimumab for Crohn patients intolerant to or unresponsive to Infliximab.
• Determine if Adalimumab is more effective than placebo in inducing remission among patients that are intolerant or resistant to Infliximab therapy.
• Study Eponym: GAIN
Gauging
Adalimumab Efficacy in Infliximab
Non-Responders
• Design:
4-week, randomized, double-blind, placebo-controlled trial.
• Subjects:
325 adults with Moderate to severe Crohn’s disease (CDAI 220–450).
All intolerant to or loss of response to Infliximab
Stopped infliximab at least 8 weeks prior to the study
Stable dose concurrent treatment allowed
• Treatment arms:
Adalimumab: 160 mg at Week 0 and 80 mg at Week 2
Placebo at Weeks 0 and 2
• Measurements:
CDAI
Fall ≥ 70 points (moderate improvement)
Fall ≥ 100 points (significant improvement)
Remission = CDAI < 150 points
• Evaluation Time Points
T-2 weeks, T0, T1, T2, & T4 weeks
Characteristics |
Placebo
N=166 |
Adalimumab
N=159 |
Men n (%) |
65(39) |
50(31) |
Mean age (SD), y |
37(12) |
39(12) |
Loss resp to Infliximab n (%) |
87(52) |
77(48) |
Acute Reaction Infliximab |
63(38) |
68(43) |
Delay Reaction Infliximab |
52(31) |
43(27) |
HACA |
60(38) |
50(33) |
|
Placebo
N=166 |
160/80 mg
N=159 |
Mean CDAI Score* |
313 |
313 |
Mean IBDQ Score† |
124 |
120 |
Median CRP <1 mg/dl |
59% |
52% |
Steroids |
73 (44%) |
55(35%) |
Immunosuppressants |
85 (51%) |
73(46%) |
5-ASAs |
60 (36%) |
45(28%) |
Baseline differences between treatment groups were not
statistically significant. |
| Time CDAI Score Response Rates 4 Week |
| CDAI |
Placebo |
Adalimumab |
p-value |
| ≥ 70 ↓ |
34% |
52% |
|
| ≥ 100 ↓ |
25% |
38% |
|
| <150 (remission) |
7% |
21% |
< 0.001 |
Remission in Adalimumab group 21% or a
Δ 14.2%
(95% CI, 6.7 to 21.6 percentage points) |
| |
Placebo
N=166 |
160/80 mg
N=159 |
| Prior AE to infliximab |
95 (57%) |
95 (60%) |
| Acute (≤24 hr) |
63 (38%) |
68 (43%) |
| Delayed |
52 (31%) |
43 (27%) |
| Both |
20 (12%) |
15 (9%) |
| Lost response, % |
87 (53%) |
77 (48%) |
| Prior AE & lost response, % |
21 (13%) |
19 (12%) |
| Differences in prior response to infliximab were not statistically significant. |
| |
Placebo
N=166 |
160/80 mg
N=159 |
| Completed, n(%) |
156 (94%) |
155 (98%) |
| Withdrawn, n(%) |
10 (6%) |
4 (3%) |
| Primary Reason |
|
|
| Adverse Event |
4 |
2 |
| Protocol violation |
5 |
1 |
| Lack of efficacy |
0 |
0 |
| Withdrew consent |
1 |
1 |
| Other |
0 |
0 |
| Differences between treatment groups were not statistically significant. |
- 52% of Crohn’s patients no longer responsive to Infliximab at 5mg/kg clinically improved (↓ CDAI > 70 points) on Adalimumab 160/80mg and 21% of pts went into remission by 4wks.
Response to Adalimumab was not influenced by presence of HACA (+) or co-therapy with IMM.
- This study does NOT show that Infliximab “non- responders” will have long term response to Adalimumab.
- This trial did NOT directly compare efficacy of Infliximab & Adalimumab.
• Infliximab “non responders” are seen in up to 40% of Crohn’s patients within a year of treatment. This study provides important information that Adalimumab is a valuable alternative for these patients.
• Expect 52% of Crohn’s pts that are Infliximab “non-responders” to experience improvement in CDAI > 70 pts after 4 wk of Adalimumab 160/80 mg and 21% of patients will go into remission.
|
