1. Peter R. McNally, DO, FACP, FACG Lone Tree, Colorado
Literature Review
Peter R. McNally, DO, FACP, FACG Lone Tree, Colorado

2. Title: 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:

3. Introduction Sandborn WJ, et al. Ann Intern Med. 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.

4. Sandborn WJ, et al. Ann Intern Med. 2007;146:829-838.
Aim
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

5. GAIN Study Design: Design:
Sandborn WJ, et al. Ann Intern Med. 2007;146:
GAIN Study Design:
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

6. GAIN Study Design: Fall > 100 points (significant improvement)
Sandborn WJ, et al. Ann Intern Med. 2007;146:
GAIN Study Design:
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

7. GAIN: Study Subjects Characteristics Placebo N=166 Adalimumab N=159
Sandborn WJ, et al. Ann Intern Med. 2007;146:
GAIN: Study Subjects
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)

8. GAIN: Baseline Disease Characteristics
Placebo
N=166
160/80 mg
N=159
Mean CDAI Score*
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%)
CDAI data: table run
IBDQ data: table run
CRP data: Table , run
And run
Baseline differences between treatment groups were not statistically significant.
Sandborn WJ, et al. Ann Intern Med. 2007;146:

9. Mean CDAI score at each visit
Sandborn WJ, et al. Ann Intern Med. 2007;146:
Mean CDAI score at each visit

10. GAIN: Efficacy Outcomes Wk 4* † *
% of Patients
12/166
34/159
56/166
82/159
41/166
61/159
*P<0.001, †P<0.01, both vs. placebo.
Sandborn WJ, et al. Ann Intern Med. 2007;146:

11. GAIN Trial Results Time CDAI Score Response Rates 4 wk
Sandborn WJ, et al. Ann Intern Med. 2007;146:
GAIN Trial Results
Time CDAI Score Response Rates 4 wk
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)

12. GAIN: Prior Response to Infliximab
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%)
691 CSR table 13; CSE table 11
Intolerant to infliximab: table run
Lost response, table run (overall N for PBO=165; loss of response PBO=52.7%; used CSR/CSE data instead [n=166 for PBO; 52.4% for loss of response in PBO)
Intolerant, lost response, both: table run
Differences in prior response to infliximab were not statistically significant.
Sandborn WJ, et al. Ann Intern Med. 2007;146:

13. GAIN: Patient Disposition
Placebo
N=166
160/80 mg
N=159
Completed, n (%)
156 (94%)
155 (98%)
Withdrawn, n (%)
10 (6%)
4 (3%)
Primary Reason (n)
Adverse event 4 2
Protocol violation 5 1
Lack of efficacy
Withdrew consent
Other
Table run
“Other”=lost to follow-up, death, administrative reasons,
other
Differences between treatment groups were not statistically significant.
Sandborn WJ, et al. Ann Intern Med. 2007;146:

14. GAIN: Efficacy Outcomes at Week 4* † *
% of Patients
Remission data: Stats table run
Delta 70: stats table run
Delta 100: stats table run
12/166
34/159
56/166
82/159
41/166
61/159
*P<0.001, †P<0.01, both vs. placebo.
Sandborn WJ, et al. Ann Intern Med. 2007;146:

15. GAIN: Remission Rates: CDAI<150
Week
% of Patients 6 4 7 * 21
Stats table run
*P<0.001 vs. placebo.
Sandborn WJ, et al. Ann Intern Med. 2007;146:

16. Response Rate 70-Point CDAI Decrease (CR-70)* †
Week 21 35 52 33 34
% of Patients
Delta 70: stats table run
*P<0.005, †P<0.001, both vs. placebo
Sandborn WJ, et al. Ann Intern Med. 2007;146:

17. Week 4 Remission by Baseline Immunosuppressant (IMM) Use
6/84
16/73
18/86
6/82
Table , run
Sandborn WJ, et al. Ann Intern Med. 2007;146:

18. Week 4 Remission by Infliximab History
% of Patients
691 CSR table 13; CSE table 11
Loss of response data, ,
Intolerance data, ,
Loss of response and intolerance, ,
7/87
15/77
5/95
21/95
0/21
3/19
Sandborn WJ, et al. Ann Intern Med. 2007;146:

19. Wk 4 Remission by Baseline HACA* to Infliximab
2/58
10/48
21/105
10/101
Table , run
*Human anti-chimeric antibodies (HACAs).
Sandborn WJ, et al. Ann Intern Med. 2007;146:

20. Conclusions
52% of Crohn’s pts 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.
Sandborn WJ, et al. Ann Intern Med. 2007;146:

21. Reviewer Comments
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 pts will go into remission.
Sandborn WJ, et al. Ann Intern Med. 2007;146: