1. University Colorado Denver Center for Human Simulation
Literature Review
Peter R. McNally, DO, MACG
University Colorado Denver
School of Medicine
Center for Human Simulation
Aurora, Colorado 80045

2. Introduction
Ulcerative Colitis is a lifelong, disabling disorder with 20-30% of patients requiring surgery in their lifetime.
Steroid refractory UC ranges from 25-57%, of which only 40-60% are responsive to immunomodulator Rx with AZA or 6-MP. This leaves a substantial number of UC patients with medically refractory disease and need for surgical solution or new effective medical Rx.
Langholz E, et al. Gastroenterol. 1992;103:

3. Introduction
The Active Ulcerative Colitis Trials (ACT-1 and Act-2) were the first large, randomized, placebo controlled trials that firmly established the efficacy of Infliximab (IFX, Anti-TNF-α) in the treatment of moderate to severe UC.
Development of neutralizing antibodies to IFX (ATI), primary lack of response, need for intravenous administration, has lead to the evaluation of other less antigenic Anti-TNF agents that can be administered subcutaneously.
Rutgeerts P,et al.Infliximab for induction & maintenance therapy for UC.NEJM.2005;353: Oussalah A,et al. Aliment Pharm Ther. 2008;28: Peyrin-Biroulet L, et al. World J Gastro. 2007;13:

4. Introduction
This VHJOE Literature Review will examine the results of two Clinical Drug Trails evaluating Adalimumab (ADA) for the induction and maintenance treatment of Moderate-Severe UC failing conventional therapy.
Study # 1 by Reinisch W, et al, examined the efficacy of ADA for the induction of clinical remission of moderate-severe UC (ULTRA-1).
Study # 2 by, Sandborn WJ, et al, examined the efficacy of ADA to induce and maintain clinical remission of moderate-severe UC (ULTRA-2).
Reinisch W, et al. Gut. 2011;60: Sandborn WJ, et al. Gastroenterology. 2012;42:

5. Study # 2: Ulcerative colitis long-term remission and maintenance with adalimumab (ULTRA 2)

6. WILLIAM J. SANDBORN,* GERT VAN ASSCHE,‡ WALTER REINISCH,§ JEAN–FREDERIC COLOMBEL, GEERT D’HAENS,¶,# DOUGLAS C. WOLF,** MARTINA KRON,‡‡ MARY BETH TIGHE,§§ ANDREAS LAZAR,‡‡ and ROOPAL B. THAKKAR§§
Adalimumab Induces and Maintains Clinical Remission in Patients With Moderate-to-Severe Ulcerative Colitis GASTROENTEROLOGY 2012;142:257–265
*University of California San Diego, La Jolla, California; ‡University Hospital of Gasthuisberg, Leuven, Belgium; §Medical University Vienna, Vienna, Austria; Centre Hospitalier Universitaire de Lille, Lille, France; ¶Academic Medical Center, Amsterdam, The Netherlands; #Imelda GI Clinical Research Center, Bonheiden, Belgium; **Atlanta Gastroenterology Associates, Atlanta, Georgia; ‡‡Abbott GmbH & Co. KG, Ludwigshafen, Germany; §§Abbott, Abbott Park, Illinois.

7. Abbreviations Used ADA Adalimumab
5-ASA 5-aminosalicylic acid or Mesalamine
Anti-TNF α Anti-TNF Antibody
ATI Antibody to Infliximab
AZA Azathioprine
IFX Infliximab
6MP 6 mercaptopurine
PBO Placebo
TNF Tumor necrosis factor
ULTRA Ulcerative colitis long-term remission and maintenance with adalimumab

8. Sandborn WJ, et al. Gastro. 2012;42:257-265
Methods
Study Design: Phase 3, multicenter randomized, double-blind, placebo-controlled trial conducted at 103 centers North America, Europe, New Zealand, and Israel.
All UC patients were adults with moderate to severe UC ( > 3 mo. duration), defined by Mayo Score > 6 and endoscopy sub score > 2 despite concurrent corticosteroids or immunosuppressant drugs.
Patients were randomly assigned to 2 groups:
Group 1: ADA (160/80/40 mg) Rx T0, T2wk, T4wk, T6wk,…EOW...T52wk
Group 2: PBO (PBO/PBO/PBO) Rx T0, T2wk, T4wk, T6wk,....EOW…T52wk
Patients received study medication through week 52 with final study evaluations at week 52.
After 12 wks non-responders were allowed into Open label ADA 40 mg EOW, non-responders at that dose were allowed to escalate to ADA 40 mg EW.

9. Methods: Concurrent Therapy
Sandborn WJ, et al. Gastro. 2012;42:
Methods: Concurrent Therapy
Concurrent Therapy
Corticosteroid stable dose oral prednisone (> 20 mg / day for at least 2 wk or < 20 mg/day for at least 40 days) before baseline.
Pts on immunomodulators were to receive at least a 3-mo consecutive course of azathioprine (AZA, at least 1.5 mg/kg/day, or highest dose tolerated) or 6-mercaptopurine (6-MP, at least 1 mg/kg/day). Both drugs had to be given at a stable dose for at least 4 weeks.
Concurrent therapy was not required for those patients intolerant to Rx
Prior Anti-TNF other than ADA was allowed, if the pt. was intolerant to or had loss of response to the agent for > 8 wks.

10. Methods Study Subjects (inclusion criteria)
Sandborn WJ, et al. Gastro. 2012;42:
Methods
Study Subjects (inclusion criteria)
All adults, giving informed written consent.
UC confirmed by colonoscopy or sigmoidoscopy with biopsy performed within 21 days of study initiation.
Moderate Severe UC despite stable treatment with corticosteroids &/or immunomodulators (concurrent Rx not required for those intolerant to these Rx).
UC Disease Severity defined by “Full” Mayo Score.
maximum score = 12
Total score = (Moderate to Severe)
Endoscopy sub score = 2-3
Schroeder KW, et al. NEJM. 1987;317:1625-9

11. Methods Study Subjects (inclusion criteria)
Sandborn WJ, et al. Gastro. 2012;42:
Methods
Study Subjects (inclusion criteria)
Definition of Stable Treatments
Prednisone > 20 mg for > 14 days or < 20 mg/day for > 40 days
And/or
Immunomodulator for > 90 days and stable dose for > 28 days. (AZA dose > 1.5 mg/kg/day or 6-MP dose > 1 mg/kg/day) .
Female patients were post menopausal or using accepted birth control methods.

12. Methods Study Subjects (exclusion criteria)
Sandborn WJ, et al. Gastro. 2012;42:
Methods
Study Subjects (exclusion criteria)
Patients with JUST Ulcerative Proctitis.
IV corticosteroids <14 days from screening
Any Cyclosporine, Tacrolimus, or Mycophenolate mofetil within 30 days.
Enema therapy within 2 wk of study entry.
Pregnancy, TPN, C difficile infection (< 30 days of baseline), ATBX (IV < 1 mo. or oral < 2 wk), Antivirals.
History of Listeria, Histoplasmosis, Chronic HBV, HIV, Immunodeficiency, CNS demyelination, Untreated TB, Malignancy or dysplasia, drug or ETOH abuse last year

13. Demographics Characteristic Placebo N=246 ADA N=248 Total N=494
Gender ♂ (%)
152 (62%)
142 (57%)
294 (59%)
Age, years (mean)
41 yr
40 yr
Weight, kg (mean)
77 kg
75 kg
76 kg
Disease Location (%)
Pan-colitis
49%
48%
Left-sided
39%
Other 9% 8%
Sandborn WJ, et al. Gastro. 2012;42:

14. Demographics Characteristic Placebo N=246 ADA N=248 Total N=494
Disease Duration, yrs (mean)
8.5 yr
8.1 yr
8.3 yr
Mayo Score, mean
8.9
Endoscopy sub score
2.5
Rectal bleeding, sub score
1.7
PGA sub score
2.2
Stool Frequency, sub score
2.6
CRP, mg/l: median
4.2
4.1
Sandborn WJ, et al. Gastro. 2012;42:

15. Demographics Characteristic Placebo N=246 ADA N=248 Total N=494
Concomitant Rx, (%)
Corticosteroid (without IMM)
57%
61%
59%
IMM (without corticosteroid)
33%
38%
35%
Corticosteroid + IMM
18%
20%
19%
Prior Anti-TNF Therapy
Sandborn WJ, et al. Gastro. 2012;42:

16. Study Design pts randomized (1 : 1) N = 494 248 pts ADA 246 pts
Sandborn WJ, et al. Gastro. 2012;42:
Study Design
pts randomized
(1 : 1)
N = 494
248 pts
ADA
246 pts
Placebo
Completed – n=154
Discontinued – n= 94
Withdrew n=8
Lost f/u n=1
Protocol violation n=1
Other n=9
Completed – n=131
Discontinued – n=115
Adverse Event – 4
Withdrew
Protocol violation n=5
Other - n=11

17. Study Design: Induction Phase ADA 160/80 Randomization 1:1
Study Evaluations
Time wks
Endoscopy
Score
Mayo Score
Time 0
Up to -21 days Endoscopy
Randomization
1:1
Time 52 wk
Primary End Point
(Remission)
Treatment Interval (Time in Weeks) ,…
ADA mg
Placebo PBO PBO PBO PBO PBO PBO
Sandborn WJ, et al. Gastro. 2012;42:

18. Sandborn WJ, et al. Gastro. 2012;42:257-265
Study Design: ADA Maintenance for Responders & Open Label ADA for Non-Responders at 12 wk
Study Evaluations: 0,2,4,8,12,16,20,26,32, 38, 44, 52 wk
Full Mayo : 0, , , wk
Partial Mayo : 0, 4,8, , , wk
IBD Questionnaire:0, 4,8, , 32, wk
After 12 wk able to switch to open label ADA 40 mg EOW
Time 52 wk
Primary End Point
(Remission)
Time in Weeks
… wk
Maintenance ADA mg EOW,…
Open label ADA mg EOW,…
Definition: Inadequate or Non-Responder
Mayo Score > baseline on 2 consecutive visits
Partial Mayo Score > 7 on 2 consecutive visits
While on Open label ADA 40 mg EOW, non-remitters permitted to escalate to ADA 40 mg weekly

19. Definitions: Remission & Response to ADA
Primary Efficacy Endpoint: Clinical Remission
Definition Clinical Remission
Total “Full” Mayo Score < 2 and
No individual sub score > 1
Definition of Clinical Response
A ↓ in “Full” Mayo Score by > 3 points (or > 30% drop) from baseline with a rectal bleeding score ↓ by > 1 or absolute rectal bleeding score of 0-1.
Sandborn WJ, et al. Gastro. 2012;42:

20. Study Design Intra-Study Management of Concomitant Rx Open Label ADA
Sandborn WJ, et al. Gastro. 2012;42:
Study Design
Intra-Study Management of Concomitant Rx
Immunomodulator Rx remained at constant dosage
5-ASA Rx remained at constant dosage
Prednisone could be tapered after 8 weeks at the discretion of the investigator, that pt. had a satisfactory clinical response.
Taper 5 mg/wk until a dosage of 10 mg reached, thereafter taper at 2.5 mg/wk until “0”
Open Label ADA
Allowed to escalate dosage to 40 mg every week, if demonstrated inadequate response at two consecutive visits.

21. Study Evaluations Evaluations performed at: Mayo Score at:
Weeks: 0,2,4,8,12,16,20,26,32,38,44,52/early termination
Mayo Score at:
Weeks: 0,8,32,52/early termination
Partial Mayo Score
determined at all visits
IBD Questionnaire:
Weeks: 0,4,8,20,32,52/early termination
Sandborn WJ, et al. Gastro. 2012;42:

22. Study Definitions Definition Clinical Remission
Mayo Score < 2, no individual score > 1
Definition Clinical Response
Mayo Score ↓ > 3 pts and at least 30% with ↓ bleeding sub score of at least 1 pt. or absolute rectal bleeding sub score of 0 or 1.
Sandborn WJ, et al. Gastro. 2012;42:

23. “Full” Mayo Score Scores range from 0 to 3 pts for each variable
Bowel movement (BM) frequency
Normal (0 pts); 1-2 BM > nl (1 pts); 3-4 BM > nl (2 pts); > 5 BM > nl (3 pts).
Rectal bleeding
None (0 pts); Streaks on stool < 50% BM’s (1 pts); Obvious blood with most BM’s (2 pts); Blood alone (3 pts).
Endoscopy
Normal (0 pts); Mild: erythema, ↓ vascularity,Mild friability (1 pts); Moderate: marked erythema, lack vascular pattern, friability (2 pts); Severe: spontaneous bleeding, ulceration (3 pts).
Physician Global Assessment (PGA)
Normal (0 pts); Mild (1 pts); Moderate (2 pts); Severe (3 pts)

24. Mayo Endoscopic Criteria Severe Video Clip
Click on image to activate

25. “Partial” Mayo Score Scores range from 0 to 3 pts for each variable
Bowel movement (BM) frequency
Normal (0 pts); 1-2 BM > nl (1 pts); 3-4 BM > nl (2 pts); > 5 BM > nl (3 pts)
Rectal bleeding
None (0 pts); Streaks on stool < 50% BM’s (1 pts); Obvious blood with most BM’s (2 pts); Blood alone (3 pts)
No Endoscopy
Physician Global Assessment (PGA)
Normal (0 pts); Mild (1 pts); Moderate (2 pts); Severe (3 pts)

26. Evaluated Efficacy End Points
Placebo
N=246
ADA
N=248
P value
Sustained Remission per Mayo 8 & 52 wk
4.1
8.5
.047
Sustained Response per Mayo 8 & 52 wk
12.2
23.8
<.001
Sustained mucosal healing per Mayo 8 & 52 wk
10.6
18.5
.013
PGA < 1 at 8 wk
37.4 46
.058
SFS < 1 at 8 wk
28.5
37.9
.028
RBS < 1 at 8 wk
58.1
70.2
.006
Sandborn WJ, et al. Gastro. 2012;42:

27. Evaluated Efficacy End Points
Placebo
N=246
ADA
N=248
P value
Discontinued corticosteroid before 52 wk and 52wk remission
5.7
13.3
.035
Discontinued corticosteroid and achieved sustained remission at 32 wk and 52wk remission
1.4 10
.002
IBDQ responder at 52 wk
16.3
26.2
.007
IBDQ responder at 8 wk
45.5
58.1
.006
Sandborn WJ, et al. Gastro. 2012;42:

28. Results: Remission Rates (%)* *
* P < 0.05
Sandborn WJ, et al. Gastro. 2012;42:

29. Results: Response Rates (%)* *
* P < 0.05
Sandborn WJ, et al. Gastro. 2012;42:

30. Results: Mucosal Healing (%)* *
* P < 0.05
Sandborn WJ, et al. Gastro. 2012;42:

31. Results: Patients with Remission per Partial Mayo Score (%)*
* P < 0.05
Sandborn WJ, et al. Gastro. 2012;42:

32. Results: Patients Who Discontinued Steroids (%)*
* P < 0.05
Sandborn WJ, et al. Gastro. 2012;42:

33. Median Trough ADA Concentrations Over Time by Remission Status @ 52 wk
Mean + SD (Nnmiss)
Treatment Group
Week 8
Week 32
Week 52
40 mg EOW pts who were remitters (n=42)
(41)
(39)
(39)
40 mg EOW pts who were non-remitters
N=153
(110)
(70)
(62)
Sandborn WJ, et al. Gastro. 2012;42:

34. Summary of Treatment-Emergent Adverse Events
Only one AE to reached statistical significance:
“Any injection site related AE”
Placebo 10 (3.8%) vs. ADA 31 (12.1%), p < 0.001
Malignancy was seen only in the ADA group
Squamous cell carcinoma (1) and Gastric cancer (1)
Sandborn WJ, et al. Gastro. 2012;42:

35. Development of ADA-Antibodies
2.9% (7 of 245 pts) developed antibodies to ADA.
All patients developing ADA-AB were on ADA-mono therapy
Sandborn WJ, et al. Gastro. 2012;42:

36. Sandborn WJ, et al. Gastro. 2012;42:257-265
Study Conclusions
ADA is effective and safe for induction and maintenance of remission of moderate to severe UC failing conventional therapy.
ADA appears to be less effective in patients that have already failed Anti-TNF therapy.
ADA trough levels of > 10 appear to be predictive of remission.
Development of ADA – Ab is more common among patients on ADA-mono therapy.

37. Sandborn WJ, et al. Gastro. 2012;42:257-265
Study Conclusions
ADA was more effective than Placebo in both 8 and 52 wk mucosal healing.
Placebo vs.. ADA
Mucosal healing
8 week: 31.7% vs. 41.1% p < 0.05
52 week: % vs. 25.0% p < 0.05

38. Study Conclusions
ADA 160/80/40 EOW appears to be safe in the treatment of moderate-severe UC.
No significant difference between ADA vs.. Placebo for any AE: malignancy, injection reaction, opportunistic infection, CHF, demyelination or Lupus-like reactions.
Sandborn WJ, et al. Gastro. 2012;42:

39. Reviewer Comments
Sandborn, et al, have conducted a much needed prospective placebo controlled study on the efficacy of ADA 160/80 induction followed by 40 mg EOW for the induction and maintenance treatment of patients with moderate-severe UC (non-proctitis) failing conventional corticosteroid &/or immunomodulator Rx.
The investigators’ research shows that ADA 160/80 induction followed by 40 mg EOW is clearly more effective than and Placebo for induction and maintenance of remission for 52 wk.
P R McNally, DO, MACG

40. Reviewer Comments
Sandborn, et al, ULTRA-2 study has several important differences from previous Anti-TNF (IFX ACT 1 and ACT 2) treatment of patients with moderate to severe UC failing conventional therapy:
The ULTRA-2 ADA-UC Trial was conducted 8-10 yrs after the ACT 1 & ACT 2 IFX-UC Trials. None of the pts in the ACT trial had received prior biologic Rx, while 40% of the pts in the ULTRA-2 ADA-UC trial had intolerance or failure of prior Anti-TNF.
P R McNally, DO, MACG

41. Reviewer Comments
ACT 1 & ACT 2 IFX trials did not permit pts with inadequate response to leave the blinded trial and receive open label drug.
The ULTRA-2 ADA-UC Trial used different methodology to calculate the Mayo Score: worst score from the last 3 days, versus the average score for the last 3 days for the ACT 1 & ACT IFX-UC Trials.
P R McNally, DO, MACG

42. P R McNally, DO, MACG
Reviewer Conclusions
The ULTRA-2 ADA-UC Trial clearly demonstrates that ADA 160/80 then 40 mg EOW is effective acute and maintenance treatment for UC patients failing conventional treatment with corticosteroids and/or AZA/6-MP.
There appears to be a definable ADA trough of 10 for remitters, suggesting that dose adjustment to ADA trough drug levels may improve remission rates. This needs to be evaluated prospectively!

43. P R McNally, DO, MACG
Reviewer Conclusions
There is much is to be further learned by the ULTRA-2 Sub analysis. The opportunity for both ADA and PBO patients to switch into open label ADA 40mg EOW and then escalate into ADA 40 mg EW will further our understanding of ADA dose response in UC.
ADA group had 116 switch to open label (ADA 40 mg EOW) at 12 wk and 68 of these pts later dose escalated (ADA 40 mg EW).
PBO group had 135 switch to open label (ADA 40 mg EOW) at 12 wk and 84 pts later dose escalated (40 mg EW).

44. P R McNally, DO, MACG
Reviewer Conclusions
The future of biologic therapy for UC is NOT one size/one dose fits all. Anti-TNF dose adjustment by weight, disease severity/inflammation (CRP > 10) and ADA trough > 10.
The key primary end point for future IBD treatment trials will be complete mucosal healing. Achievement of that end point will lead to complete disease free remission.
Mucosal healing