Efficacy and Safety of Adalimumab in Subjects With Moderately to Severely Active Ulcerative Colitis

• Sponsor: Abbott (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00408629
• Collaborator: (none)
• Enrollment: 518
• Locations: 108
• Arms: 2
• Duration (Months): 40
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This was a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of the human anti-tumor necrosis factor (TNF) monoclonal antibody adalimumab (ADA) in patients with moderately to severely active ulcerative colitis (UC).

Condition or Disease	Intervention/Treatment	Phase
Ulcerative Colitis	Biological: adalimumab; Biological: placebo	Phase 3

Detailed Description

This was a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of adalimumab (ADA) in patients with moderately to severely active ulcerative colitis (UC).

The duration of the study was up to 65 weeks, including a Screening Period of up to 3 weeks, a double-blind (DB) placebo-controlled treatment period of up to 52 weeks, and a 70 day follow-up phone call for participants who prematurely discontinued or who did not enroll in the extension study NCT# 00573794 (M10-223).

Adult participants with moderate to severe UC (Mayo score of 6 to 12 points with endoscopy subscore of 2 to 3 points), confirmed by colonoscopy with biopsy or flexible sigmoidoscopy with biopsy, were to be enrolled at approximately 120 sites worldwide. Planned enrollment was 500 participants.

Participants were to be stratified by prior exposure to infliximab and/or other anti-TNF agents, and randomized in a 1:1 ratio to receive ADA or placebo by subcutaneous injection. Participants assigned to the ADA treatment arm were to receive an induction dose of 160 mg at Week 0 and 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4. Participants assigned to the placebo treatment arm were to receive matching placebo during the same period of time. At or after Week 10, participants who met the criteria for inadequate response could be switched to open-label (OL) ADA 40 mg eow beginning at Week 12. Inadequate response was defined as:

• Partial Mayo score greater than or equal to Baseline score on 2 consecutive visits at least 14 days apart (for participants with a partial Mayo score of 4 to 7 at Baseline).

• Partial Mayo score greater than or equal to 7 on 2 consecutive visits at least 14 days apart (for participants with a partial Mayo score of 8 or 9 at Baseline).

Participants who demonstrated inadequate response at 2 consecutive visits at least 14 days apart while on OL administration ADA 40 mg eow were permitted to dose escalate to ADA 40 mg weekly (ew). Participants with persistent inadequate response while on ADA 40 mg ew may have been discontinued from the study at the Investigator's discretion. Upon completion of the study, participants had the option to enroll into the OL extension Study M10-223 in which they could receive ADA treatment.

Efficacy and safety measurements were performed throughout the study. A follow-up phone call was made 70 days after the last dose of study drug to obtain information on any ongoing or new adverse events (AEs) for all participants who terminated early or who did not enroll in the OL extension study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 518 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Human Anti-TNF Monoclonal Antibody Adalimumab for the Induction and Maintenance of Clinical Remission in Subjects With Moderately to Severely Active Ulcerative Colitis
• Study Start Date: Nov 1, 2006
• Actual Primary Completion Date: Mar 1, 2010
• Actual Study Completion Date: Mar 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: adalimumab group	Biological: adalimumab; Prefilled syringe, 40 mg, 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week between Weeks 4 and 50.; Other Names: ABT-D2E7 Humira
Experimental: placebo group	Biological: placebo; Matching Placebo for prefilled syringe, 40 mg,

Outcome Measures

Primary Outcome Measures

1. Proportion of Participants Who Achieved Clinical Remission Per Mayo Score at Week 8 [Week 8]

   Clinical remission per Mayo score is defined as a total Mayo score of at least 2 and no individual subscore greater than 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: Stool Frequency Subscore (SFS), Rectal Bleeding Subscore (RBS), Endoscopy Subscore, and Physician's Global Assessment Subscore (PGA), each of which ranges from 0 (normal) to 3 (severe disease).

2. Proportion of Participants Who Achieved Clinical Remission Per Mayo Score at Week 52 [Week 52]

   Clinical remission per Mayo score is defined as a total Mayo score of at least 2 and no individual subscore greater than 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).

Secondary Outcome Measures

1. Proportion of Participants Who Achieved Sustained Clinical Remission Per Mayo Score at Both Week 8 and Week 52 [Week 8, Week 52]

   Clinical remission per Mayo score is defined as a total Mayo score of at least 2 and no individual subscore greater than 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).

2. Proportion of Participants Who Achieved Clinical Response Per Mayo Score at Week 8 [Week 8]

   Clinical response per Mayo score is defined as a decrease in Mayo score of at least 3 points and at least 30% from Baseline, plus either a decrease in rectal bleeding subscore (RBS) of at least 1 point from Baseline or an absolute RBS of 0 or 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).

3. Proportion of Participants Who Achieved Clinical Response Per Mayo Score at Week 52 [Week 52]

   Clinical response per Mayo score is defined as a decrease in Mayo score of at least 3 points and at least 30% from Baseline, plus either a decrease in RBS of at least 1 point from Baseline or an absolute RBS of 0 or 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).

4. Proportion of Participants Who Achieved Sustained Clinical Response Per Mayo Score at Both Week 8 and Week 52 [Week 8, Week 52]

   Clinical response per Mayo score is defined as a decrease in Mayo score of at least 3 points and at least 30% from Baseline, plus either a decrease in RBS of at least 1 point from Baseline or an absolute RBS of 0 or 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).

5. Proportion of Participants Who Achieved Mucosal Healing at Week 8 [Week 8]

   Mucosal healing is defined as an Endoscopy Subscore of 0 or 1 as assessed by flexible sigmoidoscopy. Possible scores range from 0-3 as follows: 0 = Normal or inactive disease, 1 = Mild disease (erythema, decreased vascular pattern, mild friability), 2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions), 3 = Severe disease(spontaneous bleeding, ulceration).

6. Proportion of Participants Who Achieved Mucosal Healing at Week 52 [Week 52]

   Mucosal healing is defined as an Endoscopy Subscore of 0 or 1 as assessed by flexible sigmoidoscopy. Possible scores range from 0-3 as follows: 0 = Normal or inactive disease, 1 = Mild disease (erythema, decreased vascular pattern, mild friability), 2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions), 3 = Severe disease(spontaneous bleeding, ulceration).

7. Proportion of Participants Who Achieved Sustained Mucosal Healing at Both Week 8 and Week 52 [Week 8, Week 52]

   Mucosal healing is defined as an Endoscopy Subscore of 0 or 1 as assessed by flexible sigmoidoscopy. Possible scores range from 0-3 as follows: 0 = Normal or inactive disease, 1 = Mild disease (erythema, decreased vascular pattern, mild friability), 2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions), 3 = Severe disease(spontaneous bleeding, ulceration).

8. Proportion of Participants Who Discontinued Corticosteroid Use Before Week 52 and Achieved Clinical Remission Per Mayo Score at Week 52 [Baseline to Week 52]

   Clinical remission per Mayo score is defined as a total Mayo score of at least 2 and no individual subscore greater than 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).

9. Proportion of Participants With Physician's Global Assessment Subscore Indicative of Mild Disease (a Score of 0 or 1) at Week 8 [Week 8]

   The PGA includes the 3 other subscores (SFS, RBS, and Endoscopy), the participant's daily record of abdominal discomfort and functional assessment, and other observations such as physical findings and the participant's performance status. Possible scores range from 0-3 as follows: 0 = Normal (other subscores are 0), 1 = Mild disease (other subscores are mostly 1), 2 = Moderate disease (other subscores are 1 to 2), 3 = Severe disease (other subscores are 2 to 3).

10. Proportion of Participants With Stool Frequency Subscore Indicative of Mild Disease (a Score of 0 or 1) at Week 8 [Week 8]

    SFS ranges from 0-3 as follows: 0 = Normal number of stools for this participant, 1 = 1-2 stools more than normal, 2 = 3-4 stools more than normal, 3 = 5 or more stools more than normal. The participant served as his/her own control.

11. Proportion of Participants With Rectal Bleeding Subscore Indicative of Mild Disease (a Score of 0 or 1) at Week 8 [Week 8]

    RBS ranges from 0-3 as follows: 0 = no blood seen, 1 = streaks of blood with stool less than half the time, 2 = obvious blood with stool most of the time, 3 = blood alone passed

12. Proportion of Participants Who Discontinued Corticosteroid Use for At Least 90 Days and Achieved Clinical Remission Per Mayo Score at Week 52 [Baseline to Week 52]

    Clinical remission per Mayo score is defined as a total Mayo score of at least 2 and no individual subscore greater than 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).

13. Proportion of Participants Who Discontinued Corticosteroid Use and Achieved Clinical Remission Per Mayo Score (Sustained) at Both Weeks 32 and 52 [Week 32, Week 52]

    Clinical remission per Mayo score is defined as a total Mayo score of at least 2 and no individual subscore greater than 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).

14. Proportion of Inflammatory Bowel Disease Questionnaire Responders at Week 52 [Week 52]

    Response per the Inflammatory Bowel Disease Questionnaire (IBDQ) was defined as at least a 16-point increase from Baseline in total IBDQ score. The IBDQ is a 32-item questionnaire consisting of 4 dimensions: bowel-related symptoms, systemic function, social function, and emotional status. The responses to questions within each domain range from 1 (significant impairment) to 7 (no impairment), with total score ranging from 32 (very poor) to 224 (perfect health-related quality of life).

15. Proportion of Inflammatory Bowel Disease Questionnaire Responders at Week 8 [Week 8]

    Response per the Inflammatory Bowel Disease Questionnaire (IBDQ) was defined as at least a 16-point increase from Baseline in total IBDQ score. The IBDQ is a 32-item questionnaire consisting of 4 dimensions: bowel-related symptoms, systemic function, social function, and emotional status. The responses to questions within each domain range from 1 (significant impairment) to 7 (no impairment), with total score ranging from 32 (very poor) to 224 (perfect health-related quality of life).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Participants >=18 years of age and in good health (Investigator discretion) with a recent stable medical history

2. Diagnosis of UC for greater than 90 days prior to Baseline

3. Diagnosis of active UC confirmed by colonoscopy with biopsy or flexible sigmoidoscopy with biopsy during the Screening Period, with exclusion of infection

4. Active UC with a Mayo score of 6 to 12 points and endoscopy subscore of 2 to 3 points, despite concurrent treatment with at least 1 of the following (oral corticosteroids or immunosuppressants or both as defined below):

• Stable oral corticosteroid dose (prednisone >= 20 mg/day or equivalent) for at least 14 days prior to Baseline or maintenance, corticosteroid dose (prednisone < 20 mg/day or equivalent) for at least 40 days prior to Baseline

and/or

• At least a 90 day course of azathioprine (AZA) or 6-mercaptopurine (6-MP) prior to Baseline, with a dose of AZA >= 1.5 mg/kg/day or 6-MP >= 1 mg/kg/day (rounded to the nearest available tablet formulation), or a dose that is the highest tolerated by the participant (e.g., due to leukopenia, elevated liver enzymes, nausea) during that time. Participant must be on a stable dose for at least 28 days prior to Baseline.

Concurrent therapy was not required for participants who were previously treated with corticosteroids or immunosuppressants (AZA or 6-MP) during the past 5 years and in the judgment of the Investigator have failed to respond to, or could not tolerate, their treatment.

1. Participants may have been included if they had previously used an anti-tumor necrosis factor (TNF) agent (except ADA) and discontinued its use due to a loss of response or intolerance to the agent.

2. Had to be able to self-administer or had caregiver who could reliably administer subcutaneous (SC) injections.

3. Had to be able and willing to give written informed consent and to comply with the requirements of the study protocol.

4. Female had to be either not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), or of childbearing potential and practicing an approved method of birth control throughout the study and for 150 days after the last dose of study drug. Examples of approved methods of birth control included the following:

• Condoms, sponge, foams, jellies, diaphragm, or intrauterine device

• Oral, parenteral, intravaginal contraceptives for 90 days prior to study drug administration

• A vasectomized partner The results of the serum pregnancy test performed at the Screening Visit and urine pregnancy test performed at the Baseline Visit must have been negative.

1. Judged to be in generally good health as determined by the Investigator

Exclusion Criteria:

1. History of subtotal colectomy with ileorectostomy or colectomy with ileoanal pouch, Koch pouch, or ileostomy for UC, or planned bowel surgery.

2. Received previous treatment with ADA or previous participation in an ADA clinical study.

3. Received cyclosporine, tacrolimus, or mycophenolate mofetil within 30 days of Baseline.

4. Received intravenous (IV) corticosteroids within 14 days of Screening or during the Screening Period.

5. Received therapeutic enema or suppository, other than required for endoscopy, within 14 days of the Screening endoscopy and during the remainder of the Screening Period.

6. Current diagnosis of fulminant colitis and/or toxic megacolon.

7. Disease limited to the rectum (ulcerative proctitis).

8. Current diagnosis of indeterminate colitis.

9. Current diagnosis and/or history of Crohns disease (CD).

10. Currently receiving total parenteral nutrition.

11. Used aminosalicylates for < 90 days before Baseline or not on a stable dose for at least 28 days before Baseline or discontinued use within 28 days of Baseline.

12. Positive Clostridium difficile stool assay.

13. Previously used infliximab or any anti-TNF agent within 56 days of Baseline.

14. Previously used infliximab or any anti-TNF agent without clinical response at any time ("primary non-responder") unless subject experienced a treatment-limiting reaction.

15. Infections requiring treatment with IV antibiotics, antivirals, or antifungals within 30 days of Baseline or oral antibiotics, antivirals, or antifungals within 14 days of Baseline.

16. History of malignancy other than a successfully treated non-metastatic cutaneous squamous cell or basal cell carcinoma and/or localized carcinoma in situ of the cervix. If the Screening colonoscopy/flexible sigmoidoscopy showed evidence of dysplasia or a malignancy, subject was not to be enrolled in the study.

17. History of listeria, histoplasmosis, chronic or active hepatitis B infection, human immunodeficiency virus (HIV), immunodeficiency syndrome, central nervous system demyelinating disease, or untreated tuberculosis (TB).

18. Female subject who was pregnant or breast-feeding or considering becoming pregnant during the study (there should be at least 150 days between the last dose of study drug and either conception or initiation of breast-feeding in women of childbearing potential).

19. Poorly controlled medical condition(s), such as uncontrolled diabetes, unstable ischemic heart disease, moderate to severe congestive heart failure (CHF), recent cerebrovascular accident, and any other condition, which in the opinion of the investigator, put the subject at risk by participation in the protocol.

20. Received any investigational agent within 30 days or 5 half lives prior to Baseline (whichever was longer).

21. History of clinically significant drug or alcohol abuse during the past year.

22. Known hypersensitivity to the excipients of ADA as stated in the label.

23. Any prior exposure to Tysabri® (natalizumab), or Orencia® (abatacept) or any other biological therapy [other than Kineret® (anakinra) and anti-TNF agents].

24. Currently taking both budesonide and prednisone (or equivalent) simultaneously.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Site Ref # / Investigator 5394	Anaheim	California	United States	92801
2	Site Ref # / Investigator 3753	Wheat Ridge	Colorado	United States	80033
3	Site Ref # / Investigator 3754	Hamden	Connecticut	United States	06518
4	Site Ref # / Investigator 12903	Gainesville	Florida	United States	32607
5	Site Ref # / Investigator 3747	Hollywood	Florida	United States	33021
6	Site Ref # / Investigator 5106	Jacksonville	Florida	United States	32256
7	Site Ref # / Investigator 11601	Naples	Florida	United States	34102
8	Site Ref # / Investigator 6846	Sarasota	Florida	United States	34239
9	Site Ref # / Investigator 3742	Winter Park	Florida	United States	32789
10	Site Ref # / Investigator 3760	Zephyrhills	Florida	United States	33542
11	Site Ref # / Investigator 3739	Atlanta	Georgia	United States	30342
12	Site Ref # / Investigator 7658	Macon	Georgia	United States	31201
13	Site Ref # / Investigator 5397	Moline	Illinois	United States	61265
14	Site Ref # / Investigator 7453	Topeka	Kansas	United States	66606
15	Site Ref # / Investigator 3759	Annapolis	Maryland	United States	21401
16	Site Ref # / Investigator 3762	Annapolis	Maryland	United States	21401
17	Site Ref # / Investigator 3738	Lutherville	Maryland	United States	21093
18	Site Ref # / Investigator 7472	Troy	Michigan	United States	48098
19	Site Ref # / Investigator 3744	Rochester	Minnesota	United States	55905
20	Site Ref # / Investigator 6088	St. Louis	Missouri	United States	63128
21	Site Ref # / Investigator 3756	Great Neck	New York	United States	11021
22	Site Ref # / Investigator 3752	Charlotte	North Carolina	United States	28207
23	Site Ref # / Investigator 3758	Jacksonville	North Carolina	United States	28546
24	Site Ref # / Investigator 3745	Cincinnati	Ohio	United States	45219
25	Site Ref # / Investigator 7709	Oklahoma City	Oklahoma	United States	73104
26	Site Ref # / Investigator 3740	Tulsa	Oklahoma	United States	74104
27	Site Ref # / Investigator 3765	Sayre	Pennsylvania	United States	18840
28	Site Ref # / Investigator 3741	Columbia	South Carolina	United States	29204
29	Site Ref # / Investigator 3737	Germantown	Tennessee	United States	38138
30	Site Ref # / Investigator 6077	Nashville	Tennessee	United States	37203
31	Site Ref # / Investigator 5107	Nashville	Tennessee	United States	37205
32	Site Ref # / Investigator 3743	Nashville	Tennessee	United States	37212-1610
33	Site Ref # / Investigator 5398	Ogden	Utah	United States	84405
34	Site Ref # / Investigator 8064	Spokane	Washington	United States	99202
35	Site Ref # / Investigator 3750	Spokane	Washington	United States	99204
36	Site Ref # / Investigator 3761	West Bend	Wisconsin	United States	53095
37	Site Ref # / Investigator 6853	Buenos Aires		Argentina	C1181ACH
38	Site Ref # / Investigator 13722	Garran	Australian Capital Territory	Australia	2605
39	Site Ref # / Investigator 16141	Bankstown	New South Wales	Australia	NSW 2200
40	Site Ref # / Investigator 13723	Herston	Queensland	Australia	4029
41	Site Ref # / Investigator 10706	Bedford Park	South Australia	Australia	SA 5042
42	Site Ref # / Investigator 14882	Box Hill	Victoria	Australia	3128
43	Site Ref # / Investigator 9002	Malvern	Victoria	Australia	3144
44	Site Ref # / Investigator 10704	Fremantle	Western Australia	Australia	6160
45	Site Ref # / Investigator 9802	Vienna		Austria	1090
46	Site Ref # / Investigator 5256	Bonheiden		Belgium	2820
47	Site Ref # / Investigator 5253	Brussels		Belgium	1070
48	Site Ref # / Investigator 6225	Brussels		Belgium	1200
49	Site Ref # / Investigator 6079	Ghent		Belgium	9000
50	Site Ref # / Investigator 6078	Leuven		Belgium	3000
51	Site Ref # / Investigator 10423	Kelowna	British Columbia	Canada	B1Y 1Z9
52	Site Ref # / Investigator 3766	Victoria	British Columbia	Canada	V8T 5G4
53	Site Ref # / Investigator 3769	Hamilton	Ontario	Canada	L8N 3Z5
54	Site Ref # / Investigator 13556	Sudbury	Ontario	Canada	P3E 2N8
55	Site Ref # / Investigator 3736	Toronto	Ontario	Canada	M5G 1X5
56	Site Ref # / Investigator 3771	Montreal	Quebec	Canada	H3A 1A1
57	Site Ref # / Investigator 3764	Montreal	Quebec	Canada	H3G 1A4
58	Site Ref # / Investigator 3768	Montreal	Quebec	Canada	H3T 1E2
59	Site Ref # / Investigator 3770	Quebec City	Quebec	Canada	G1S 4L8
60	Site Ref # / Investigator 7021	Ceske Budejovice		Czech Republic	370 87
61	Site Ref # / Investigator 6307	Hradec Kravlove 12		Czech Republic	500 12
62	Site Ref # / Investigator 6606	Olomouc		Czech Republic	775 20
63	Site Ref # / Investigator 7481	Prague 4		Czech Republic	140 21
64	Site Ref # / Investigator 7479	Prague 5		Czech Republic	15006
65	Site Ref # / Investigator 6483	Hvidovre		Denmark	DK-2650
66	Site Ref # / Investigator 7477	Odense C		Denmark	5000
67	Site Ref # / Investigator 6231	Clichy		France	92110
68	Site Ref # / Investigator 7476	Lille Cedex		France	59037
69	Site Ref # / Investigator 7475	Pessac Cedex		France	33600
70	Site Ref # / Investigator 7474	Toulouse		France	31059
71	Site Ref # / Investigator 15321	Hamburg		Germany	20148
72	Site Ref # / Investigator 9069	Hamburg		Germany	22559
73	Site Ref # / Investigator 14642	Magdeburg		Germany	39120
74	Site Ref # / Investigator 9067	Minden		Germany	32423
75	Site Ref # / Investigator 14761	Muenster		Germany	48159
76	Site Ref # / Investigator 14661	Munich		Germany	80639
77	Site Ref # / Investigator 9801	Munich		Germany	81377
78	Site Ref # / Investigator 5247	Regensburg		Germany	93053
79	Site Ref # / Investigator 7485	Budapest		Hungary	H-1076
80	Site Ref # / Investigator 5025	Budapest		Hungary	H-1135
81	Site Ref # / Investigator 10625	Debrecen		Hungary	4032
82	Site Ref # / Investigator 14104	Gyula		Hungary	5700
83	Site Ref # / Investigator 4987	Miskoic		Hungary	H-3051
84	Site Ref # / Investigator 5036	Miskolc		Hungary	H-3526
85	Site Ref # / Investigator 12744	Kfar Saba		Israel	44281
86	Site Ref # / Investigator 10623	Petah Tikva		Israel	49100
87	Site Ref # / Investigator 15361	Tel Aviv		Israel	64239
88	Site Ref # / Investigator 13301	Auckland		New Zealand	0620
89	Site Ref # / Investigator 13181	Auckland		New Zealand	1148
90	Site Ref # / Investigator 13148	Christchurch		New Zealand	8011
91	Site Ref # / Investigator 13482	Hamilton		New Zealand
92	Site Ref # / Investigator 9561	Gjovik		Norway	2819
93	Site Ref # / Investigator 5197	Oslo		Norway	0027
94	Site Ref # / Investigator 6297	Oslo		Norway	0514
95	Site Ref # / Investigator 5194	Tromso		Norway	9038
96	Site Ref # / Investigator 5193	Trondheim		Norway	7006
97	Site Ref # / Investigator 5242	Lodz		Poland	90-153
98	Site Ref # / Investigator 5266	Warsaw		Poland	02 781
99	Site Ref # / Investigator 5265	Warsaw		Poland	02-507
100	Site Ref # / Investigator 15263	Wroclaw		Poland	54-144
101	Site Ref # / Investigator 5264	Faro		Portugal	8000-386
102	Site Ref # / Investigator 7473	Lisbon		Portugal	1150-314
103	Site Ref # / Investigator 5263	Lisbon		Portugal	1769-001
104	Site Ref # / Investigator 5211	Barcelona		Spain	08036
105	Site Ref # / Investigator 5212	Madrid		Spain	28040
106	Site Ref # / Investigator 10221	Basel		Switzerland	4031
107	Site Ref # / Investigator 10222	Bern		Switzerland	3010
108	Site Ref # / Investigator 9162	Zurich		Switzerland	8091

Sponsors and Collaborators

• Abbott

Investigators

• Study Director: Roopal B Thakkar, M.D., Abbott

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00408629
• Other Study ID Numbers: M06-827; 2006-002782-40
• First Posted: Dec 7, 2006
• Last Update Posted: May 3, 2011
• Last Verified: Apr 1, 2011

• Keywords provided by , ,: Ulcerative Colitis; Adalimumab; TNF Antagonist; Mayo Score
• Additional relevant MeSH terms: Colitis; Colitis, Ulcerative; Ulcer; Adalimumab

Study Results

Participant Flow

Arm/Group Title	Adalimumab 160/80/40	Placebo
Arm/Group Description	During the Double-Blind (DB) period, the Adalimumab (ADA) treatment group received a dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4 (160/80/40 mg).	The placebo treatment group received placebo throughout the Double-Blind (DB) period.
Period Title: Overall Study
STARTED	258	260
COMPLETED	161	135
NOT COMPLETED	97	125

Baseline Characteristics

Arm/Group Title	Adalimumab 160/80/40	Placebo	Total
Arm/Group Description	During the Double-Blind (DB) period, the Adalimumab (ADA) treatment group received a dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4 (160/80/40 mg).	The placebo treatment group received placebo throughout the Double-Blind (DB) period.	Total of all reporting groups
Overall Participants	248	246	494
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	39.6 (12.47)	41.3 (13.22)	40.4 (12.86)
Age, Customized (Number) [Number]
< 40 years	136 54.8%	118 48%	254 51.4%
40 to 64 years	105 42.3%	116 47.2%	221 44.7%
>=65 years	7 2.8%	12 4.9%	19 3.8%
Sex: Female, Male (Count of Participants)
Female	106 42.7%	94 38.2%	200 40.5%
Male	142 57.3%	152 61.8%	294 59.5%
Region of Enrollment (Number) [Number]
Portugal	2 0.8%	1 0.4%	3 0.6%
United States	78 31.5%	82 33.3%	160 32.4%
Spain	4 1.6%	7 2.8%	11 2.2%
Austria	0 0%	4 1.6%	4 0.8%
Israel	5 2%	0 0%	5 1%
France	18 7.3%	14 5.7%	32 6.5%
Czech Republic	18 7.3%	25 10.2%	43 8.7%
Hungary	13 5.2%	13 5.3%	26 5.3%
Canada	18 7.3%	19 7.7%	37 7.5%
Poland	14 5.6%	15 6.1%	29 5.9%
Belgium	26 10.5%	18 7.3%	44 8.9%
Australia	11 4.4%	9 3.7%	20 4%
Denmark	2 0.8%	3 1.2%	5 1%
Norway	5 2%	1 0.4%	6 1.2%
Germany	19 7.7%	22 8.9%	41 8.3%
New Zealand	4 1.6%	4 1.6%	8 1.6%
Switzerland	11 4.4%	9 3.7%	20 4%

Outcome Measures

1. Primary Outcome

Title	Proportion of Participants Who Achieved Clinical Remission Per Mayo Score at Week 8
Description	Clinical remission per Mayo score is defined as a total Mayo score of at least 2 and no individual subscore greater than 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: Stool Frequency Subscore (SFS), Rectal Bleeding Subscore (RBS), Endoscopy Subscore, and Physician's Global Assessment Subscore (PGA), each of which ranges from 0 (normal) to 3 (severe disease).
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) analysis set using the non-responder imputation (NRI) method in which all missing remission values and values after switch to open-label (OL) treatment were considered to be non-remission.

Arm/Group Title	Adalimumab 160/80/40	Placebo
Arm/Group Description	During the Double-Blind (DB) period, the Adalimumab (ADA) treatment group received a dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4 (160/80/40 mg).	The placebo treatment group received placebo throughout the Double-Blind (DB) period.
Measure Participants	248	246
Number [Percentage of Participants]	16.5 6.7%	9.3 3.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adalimumab 160/80/40, Placebo
	Comments	Assuming that 5% of the subjects in the placebo group achieve clinical remission at Week 52 or Week 8, a sample size of 250 in each treatment group will be adequate to detect a difference of at least 7 percentage points from the adalimumab group using Chi squared test with 80% power at a 0.05 two-sided significance level.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.019
	Comments	Testing for ranked co-primary endpoints occurred in hierarchical order to control for multiple testing. Week 8 remission rate was tested first. If a significant difference in group rates was found at alpha=0.05, Week 52 rate was tested at alpha=0.05.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratification levels for Cochran-Mantel-Haenszel = prior anti-TNF versus anti-TNF-naive.

2. Primary Outcome

Title	Proportion of Participants Who Achieved Clinical Remission Per Mayo Score at Week 52
Description	Clinical remission per Mayo score is defined as a total Mayo score of at least 2 and no individual subscore greater than 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set using the non-responder imputation (NRI) method in which all missing remission values and values after switch to OL treatment were considered to be non-remission.

Arm/Group Title	Adalimumab 160/80/40	Placebo
Arm/Group Description	During the Double-Blind (DB) period, the Adalimumab (ADA) treatment group received a dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4 (160/80/40 mg).	The placebo treatment group received placebo throughout the Double-Blind (DB) period.
Measure Participants	248	246
Number [Percentage of Participants]	17.3 7%	8.5 3.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adalimumab 160/80/40, Placebo
	Comments	Assuming that 5% of the subjects in the placebo group achieve clinical remission at Week 52 or Week 8, a sample size of 250 in each treatment group will be adequate to detect a difference of at least 7 percentage points from the adalimumab group using Chi squared test with 80% power at a 0.05 two-sided significance level.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	Testing for ranked co-primary endpoints occurred in hierarchical order to control for multiple testing. Week 8 remission rate was tested first. If a significant difference in group rates was found at alpha=0.05, Week 52 rate was tested at alpha=0.05.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratification levels for Cochran-Mantel-Haenszel = prior anti-TNF versus anti-TNF-naive.

3. Secondary Outcome

Title	Proportion of Participants Who Achieved Sustained Clinical Remission Per Mayo Score at Both Week 8 and Week 52
Description	Clinical remission per Mayo score is defined as a total Mayo score of at least 2 and no individual subscore greater than 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).
Time Frame	Week 8, Week 52

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set using the non-responder imputation (NRI) method in which all missing remission values and values after switch to open-label treatment were considered to be non-remission.

Arm/Group Title	Adalimumab 160/80/40	Placebo
Arm/Group Description	During the Double-Blind (DB) period, the Adalimumab (ADA) treatment group received a dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4 (160/80/40 mg).	The placebo treatment group received placebo throughout the Double-Blind (DB) period.
Measure Participants	248	246
Number [Percentage of Participants]	8.5 3.4%	4.1 1.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adalimumab 160/80/40, Placebo
	Comments	The Cochran-Mantel-Haenszel test was used to test the null hypothesis of no difference between adalimumab and placebo. Treatment differences were deemed statistically significant at a significance level of 0.05.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.047
	Comments	Testing of ranked secondary measures was only started if significant group differences existed for both co-primary measures. Significant results for higher-ranked measure was needed to test next lower-ranked measure to control for multiple testing.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratification levels for Cochran-Mantel-Haenszel = prior anti-TNF versus anti-TNF-naive.

4. Secondary Outcome

Title	Proportion of Participants Who Achieved Clinical Response Per Mayo Score at Week 8
Description	Clinical response per Mayo score is defined as a decrease in Mayo score of at least 3 points and at least 30% from Baseline, plus either a decrease in rectal bleeding subscore (RBS) of at least 1 point from Baseline or an absolute RBS of 0 or 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set using the non-responder imputation (NRI) method in which all missing remission values and values after switch to open-label treatment were considered to be non-remission.

Arm/Group Title	Adalimumab 160/80/40	Placebo
Arm/Group Description	During the Double-Blind (DB) period, the Adalimumab (ADA) treatment group received a dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4 (160/80/40 mg).	The placebo treatment group received placebo throughout the Double-Blind (DB) period.
Measure Participants	248	246
Number [Percentage of Participants]	50.4 20.3%	34.6 14.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adalimumab 160/80/40, Placebo
	Comments	The Cochran-Mantel-Haenszel test was used to test the null hypothesis of no difference between adalimumab and placebo. Treatment differences were deemed statistically significant at a significance level of 0.05.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Testing of ranked secondary measures was only started if significant group differences existed for both co-primary measures. Significant results for higher-ranked measure was needed to test next lower-ranked measure to control for multiple testing.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratification levels for Cochran-Mantel-Haenszel = prior anti-TNF versus anti-TNF-naive.

5. Secondary Outcome

Title	Proportion of Participants Who Achieved Clinical Response Per Mayo Score at Week 52
Description	Clinical response per Mayo score is defined as a decrease in Mayo score of at least 3 points and at least 30% from Baseline, plus either a decrease in RBS of at least 1 point from Baseline or an absolute RBS of 0 or 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set using the non-responder imputation (NRI) method in which all missing remission values and values after switch to open-label treatment were considered to be non-remission.

Arm/Group Title	Adalimumab 160/80/40	Placebo
Arm/Group Description	During the Double-Blind (DB) period, the Adalimumab (ADA) treatment group received a dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4 (160/80/40 mg).	The placebo treatment group received placebo throughout the Double-Blind (DB) period.
Measure Participants	248	246
Number [Percentage of Participants]	30.2 12.2%	18.3 7.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adalimumab 160/80/40, Placebo
	Comments	The Cochran-Mantel-Haenszel test was used to test the null hypothesis of no difference between adalimumab and placebo. Treatment differences were deemed statistically significant at a significance level of 0.05.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	Testing of ranked secondary measures was only started if significant group differences existed for both co-primary measures. Significant results for higher-ranked measure was needed to test next lower-ranked measure to control for multiple testing.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratification levels for Cochran-Mantel-Haenszel = prior anti-TNF versus anti-TNF-naive.

6. Secondary Outcome

Title	Proportion of Participants Who Achieved Sustained Clinical Response Per Mayo Score at Both Week 8 and Week 52
Description	Clinical response per Mayo score is defined as a decrease in Mayo score of at least 3 points and at least 30% from Baseline, plus either a decrease in RBS of at least 1 point from Baseline or an absolute RBS of 0 or 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).
Time Frame	Week 8, Week 52

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set using the non-responder imputation (NRI) method in which all missing remission values and values after switch to open-label treatment were considered to be non-remission.

Arm/Group Title	Adalimumab 160/80/40	Placebo
Arm/Group Description	During the Double-Blind (DB) period, the Adalimumab (ADA) treatment group received a dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4 (160/80/40 mg).	The placebo treatment group received placebo throughout the Double-Blind (DB) period.
Measure Participants	248	246
Number [Percentage of Participants]	23.8 9.6%	12.2 5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adalimumab 160/80/40, Placebo
	Comments	The Cochran-Mantel-Haenszel test was used to test the null hypothesis of no difference between adalimumab and placebo. Treatment differences were deemed statistically significant at a significance level of 0.05.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Testing of ranked secondary measures was only started if significant group differences existed for both co-primary measures. Significant results for higher-ranked measure was needed to test next lower-ranked measure to control for multiple testing.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratification levels for Cochran-Mantel-Haenszel = prior anti-TNF versus anti-TNF-naive.

7. Secondary Outcome

Title	Proportion of Participants Who Achieved Mucosal Healing at Week 8
Description	Mucosal healing is defined as an Endoscopy Subscore of 0 or 1 as assessed by flexible sigmoidoscopy. Possible scores range from 0-3 as follows: 0 = Normal or inactive disease, 1 = Mild disease (erythema, decreased vascular pattern, mild friability), 2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions), 3 = Severe disease(spontaneous bleeding, ulceration).
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set using the non-responder imputation (NRI) method in which all missing remission values and values after switch to open-label treatment were considered to be non-remission.

Arm/Group Title	Adalimumab 160/80/40	Placebo
Arm/Group Description	During the Double-Blind (DB) period, the Adalimumab (ADA) treatment group received a dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4 (160/80/40 mg).	The placebo treatment group received placebo throughout the Double-Blind (DB) period.
Measure Participants	248	246
Number [Percentage of Participants]	41.1 16.6%	31.7 12.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adalimumab 160/80/40, Placebo
	Comments	The Cochran-Mantel-Haenszel test was used to test the null hypothesis of no difference between adalimumab and placebo. Treatment differences were deemed statistically significant at a significance level of 0.05.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.032
	Comments	Testing of ranked secondary measures was only started if significant group differences existed for both co-primary measures. Significant results for higher-ranked measure were needed to test next lower-ranked measure to control for multiple testing.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratification levels for Cochran-Mantel-Haenszel = prior anti-TNF versus anti-TNF-naive.

8. Secondary Outcome

Title	Proportion of Participants Who Achieved Mucosal Healing at Week 52
Description	Mucosal healing is defined as an Endoscopy Subscore of 0 or 1 as assessed by flexible sigmoidoscopy. Possible scores range from 0-3 as follows: 0 = Normal or inactive disease, 1 = Mild disease (erythema, decreased vascular pattern, mild friability), 2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions), 3 = Severe disease(spontaneous bleeding, ulceration).
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set using the non-responder imputation (NRI) method in which all missing remission values and values after switch to open-label treatment were considered to be non-remission.

Arm/Group Title	Adalimumab 160/80/40	Placebo
Arm/Group Description	During the Double-Blind (DB) period, the Adalimumab (ADA) treatment group received a dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4 (160/80/40 mg).	The placebo treatment group received placebo throughout the Double-Blind (DB) period.
Measure Participants	248	246
Number [Percentage of Participants]	25.0 10.1%	15.4 6.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adalimumab 160/80/40, Placebo
	Comments	The Cochran-Mantel-Haenszel test was used to test the null hypothesis of no difference between adalimumab and placebo. Treatment differences were deemed statistically significant at a significance level of 0.05.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments	Testing of ranked secondary measures was only started if significant group differences existed for both co-primary measures. Significant results for higher-ranked measure was needed to test next lower-ranked measure to control for multiple testing.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratification levels for Cochran-Mantel-Haenszel = prior anti-TNF versus anti-TNF-naive.

9. Secondary Outcome

Title	Proportion of Participants Who Achieved Sustained Mucosal Healing at Both Week 8 and Week 52
Description	Mucosal healing is defined as an Endoscopy Subscore of 0 or 1 as assessed by flexible sigmoidoscopy. Possible scores range from 0-3 as follows: 0 = Normal or inactive disease, 1 = Mild disease (erythema, decreased vascular pattern, mild friability), 2 = Moderate disease (marked erythema, absent vascular pattern, friability, erosions), 3 = Severe disease(spontaneous bleeding, ulceration).
Time Frame	Week 8, Week 52

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set using the non-responder imputation (NRI) method in which all missing remission values and values after switch to open-label treatment were considered to be non-remission.

Arm/Group Title	Adalimumab 160/80/40	Placebo
Arm/Group Description	During the Double-Blind (DB) period, the Adalimumab (ADA) treatment group received a dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4 (160/80/40 mg).	The placebo treatment group received placebo throughout the Double-Blind (DB) period.
Measure Participants	248	246
Number [Percentage of Participants]	18.5 7.5%	10.6 4.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adalimumab 160/80/40, Placebo
	Comments	The Cochran-Mantel-Haenszel test was used to test the null hypothesis of no difference between adalimumab and placebo. Treatment differences were deemed statistically significant at a significance level of 0.05.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments	Testing of ranked secondary measures was only started if significant group differences existed for both co-primary measures. Significant results for higher-ranked measure was needed to test next lower-ranked measure to control for multiple testing.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratification levels for Cochran-Mantel-Haenszel = prior anti-TNF versus anti-TNF-naive.

10. Secondary Outcome

Title	Proportion of Participants Who Discontinued Corticosteroid Use Before Week 52 and Achieved Clinical Remission Per Mayo Score at Week 52
Description	Clinical remission per Mayo score is defined as a total Mayo score of at least 2 and no individual subscore greater than 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).
Time Frame	Baseline to Week 52

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set using the non-responder imputation (NRI) method in which all missing remission values and values after switch to open-label treatment were considered to be non-remission.

Arm/Group Title	Adalimumab 160/80/40	Placebo
Arm/Group Description	During the Double-Blind (DB) period, the Adalimumab (ADA) treatment group received a dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4 (160/80/40 mg).	The placebo treatment group received placebo throughout the Double-Blind (DB) period.
Measure Participants	150	140
Number [Percentage of Participants]	13.3 5.4%	5.7 2.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adalimumab 160/80/40, Placebo
	Comments	The Cochran-Mantel-Haenszel test was used to test the null hypothesis of no difference between adalimumab and placebo. Treatment differences were deemed statistically significant at a significance level of 0.05.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.035
	Comments	Testing of ranked secondary measures was only started if significant group differences existed for both co-primary measures. Significant results for higher-ranked measure was needed to test next lower-ranked measure to control for multiple testing.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratification levels for Cochran-Mantel-Haenszel = prior anti-TNF versus anti-TNF-naive.

11. Secondary Outcome

Title	Proportion of Participants With Physician's Global Assessment Subscore Indicative of Mild Disease (a Score of 0 or 1) at Week 8
Description	The PGA includes the 3 other subscores (SFS, RBS, and Endoscopy), the participant's daily record of abdominal discomfort and functional assessment, and other observations such as physical findings and the participant's performance status. Possible scores range from 0-3 as follows: 0 = Normal (other subscores are 0), 1 = Mild disease (other subscores are mostly 1), 2 = Moderate disease (other subscores are 1 to 2), 3 = Severe disease (other subscores are 2 to 3).
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set using the non-responder imputation (NRI) method in which all missing remission values and values after switch to open-label treatment were considered to be non-remission.

Arm/Group Title	Adalimumab 160/80/40	Placebo
Arm/Group Description	During the Double-Blind (DB) period, the Adalimumab (ADA) treatment group received a dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4 (160/80/40 mg).	The placebo treatment group received placebo throughout the Double-Blind (DB) period.
Measure Participants	248	246
Number [Percentage of Participants]	46.0 18.5%	37.4 15.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adalimumab 160/80/40, Placebo
	Comments	The Cochran-Mantel-Haenszel test was used to test the null hypothesis of no difference between adalimumab and placebo. Treatment differences were deemed statistically significant at a significance level of 0.05.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.058
	Comments	Testing of ranked secondary measures was only started if significant group differences existed for both co-primary measures. Significant results for higher-ranked measure was needed to test next lower-ranked measure to control for multiple testing.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratification levels for Cochran-Mantel-Haenszel = prior anti-TNF versus anti-TNF-naive.

12. Secondary Outcome

Title	Proportion of Participants With Stool Frequency Subscore Indicative of Mild Disease (a Score of 0 or 1) at Week 8
Description	SFS ranges from 0-3 as follows: 0 = Normal number of stools for this participant, 1 = 1-2 stools more than normal, 2 = 3-4 stools more than normal, 3 = 5 or more stools more than normal. The participant served as his/her own control.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set using the non-responder imputation (NRI) method in which all missing remission values and values after switch to open-label treatment were considered to be non-remission.

Arm/Group Title	Adalimumab 160/80/40	Placebo
Arm/Group Description	During the Double-Blind (DB) period, the Adalimumab (ADA) treatment group received a dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4 (160/80/40 mg).	The placebo treatment group received placebo throughout the Double-Blind (DB) period.
Measure Participants	248	246
Number [Percentage of Participants]	37.9 15.3%	28.5 11.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adalimumab 160/80/40, Placebo
	Comments	The Cochran-Mantel-Haenszel test was used to test the null hypothesis of no difference between adalimumab and placebo. Treatment differences were deemed statistically significant at a significance level of 0.05.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.028
	Comments	Testing of ranked secondary measures was only started if significant group differences existed for both co-primary measures. Significant results for higher-ranked measure was needed to test next lower-ranked measure to control for multiple testing.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratification levels for Cochran-Mantel-Haenszel = prior anti-TNF versus anti-TNF-naive.

13. Secondary Outcome

Title	Proportion of Participants With Rectal Bleeding Subscore Indicative of Mild Disease (a Score of 0 or 1) at Week 8
Description	RBS ranges from 0-3 as follows: 0 = no blood seen, 1 = streaks of blood with stool less than half the time, 2 = obvious blood with stool most of the time, 3 = blood alone passed
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set using the non-responder imputation (NRI) method in which all missing remission values and values after switch to open-label treatment were considered to be non-remission.

Arm/Group Title	Adalimumab 160/80/40	Placebo
Arm/Group Description	During the Double-Blind (DB) period, the Adalimumab (ADA) treatment group received a dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4 (160/80/40 mg).	The placebo treatment group received placebo throughout the Double-Blind (DB) period.
Measure Participants	248	246
Number [Percentage of Participants]	70.2 28.3%	58.1 23.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adalimumab 160/80/40, Placebo
	Comments	The Cochran-Mantel-Haenszel test was used to test the null hypothesis of no difference between adalimumab and placebo. Treatment differences were deemed statistically significant at a significance level of 0.05.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	Testing of ranked secondary measures was only started if significant group differences existed for both co-primary measures. Significant results for higher-ranked measure was needed to test next lower-ranked measure to control for multiple testing.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratification levels for Cochran-Mantel-Haenszel = prior anti-TNF versus anti-TNF-naive.

14. Secondary Outcome

Title	Proportion of Participants Who Discontinued Corticosteroid Use for At Least 90 Days and Achieved Clinical Remission Per Mayo Score at Week 52
Description	Clinical remission per Mayo score is defined as a total Mayo score of at least 2 and no individual subscore greater than 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).
Time Frame	Baseline to Week 52

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set using the non-responder imputation (NRI) method in which all missing remission values and values after switch to open-label treatment were considered to be non-remission.

Arm/Group Title	Adalimumab 160/80/40	Placebo
Arm/Group Description	During the Double-Blind (DB) period, the Adalimumab (ADA) treatment group received a dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4 (160/80/40 mg).	The placebo treatment group received placebo throughout the Double-Blind (DB) period.
Measure Participants	150	140
Number [Percentage of Participants]	13.3 5.4%	5.7 2.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adalimumab 160/80/40, Placebo
	Comments	The Cochran-Mantel-Haenszel test was used to test the null hypothesis of no difference between adalimumab and placebo. Treatment differences were deemed statistically significant at a significance level of 0.05.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.035
	Comments	Testing of ranked secondary measures was only started if significant group differences existed for both co-primary measures. Significant results for higher-ranked measure was needed to test next lower-ranked measure to control for multiple testing.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratification levels for Cochran-Mantel-Haenszel = prior anti-TNF versus anti-TNF-naive.

15. Secondary Outcome

Title	Proportion of Participants Who Discontinued Corticosteroid Use and Achieved Clinical Remission Per Mayo Score (Sustained) at Both Weeks 32 and 52
Description	Clinical remission per Mayo score is defined as a total Mayo score of at least 2 and no individual subscore greater than 1. The Mayo Score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 12 (severe disease) and is a composite of 4 subscores: SFS, RBS, Endoscopy Subscore, and PGA, each of which ranges from 0 (normal) to 3 (severe disease).
Time Frame	Week 32, Week 52

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set using the non-responder imputation (NRI) method in which all missing remission values and values after switch to open-label treatment were considered to be non-remission.

Arm/Group Title	Adalimumab 160/80/40	Placebo
Arm/Group Description	During the Double-Blind (DB) period, the Adalimumab (ADA) treatment group received a dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4 (160/80/40 mg).	The placebo treatment group received placebo throughout the Double-Blind (DB) period.
Measure Participants	150	140
Number [Percentage of Participants]	10.0 4%	1.4 0.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adalimumab 160/80/40, Placebo
	Comments	The Cochran-Mantel-Haenszel test was used to test the null hypothesis of no difference between adalimumab and placebo. Treatment differences were deemed statistically significant at a significance level of 0.05.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	Testing of ranked secondary measures was only started if significant group differences existed for both co-primary measures. Significant results for higher-ranked measure was needed to test next lower-ranked measure to control for multiple testing.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratification levels for Cochran-Mantel-Haenszel = prior anti-TNF versus anti-TNF-naive.

16. Secondary Outcome

Title	Proportion of Inflammatory Bowel Disease Questionnaire Responders at Week 52
Description	Response per the Inflammatory Bowel Disease Questionnaire (IBDQ) was defined as at least a 16-point increase from Baseline in total IBDQ score. The IBDQ is a 32-item questionnaire consisting of 4 dimensions: bowel-related symptoms, systemic function, social function, and emotional status. The responses to questions within each domain range from 1 (significant impairment) to 7 (no impairment), with total score ranging from 32 (very poor) to 224 (perfect health-related quality of life).
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set using the non-responder imputation (NRI) method in which all missing remission values and values after switch to open-label treatment were considered to be non-remission.

Arm/Group Title	Adalimumab 160/80/40	Placebo
Arm/Group Description	During the Double-Blind (DB) period, the Adalimumab (ADA) treatment group received a dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4 (160/80/40 mg).	The placebo treatment group received placebo throughout the Double-Blind (DB) period.
Measure Participants	248	246
Number [Percentage of Participants]	26.2 10.6%	16.3 6.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adalimumab 160/80/40, Placebo
	Comments	The Cochran-Mantel-Haenszel test was used to test the null hypothesis of no difference between adalimumab and placebo. Treatment differences were deemed statistically significant at a significance level of 0.05.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	Testing of ranked secondary measures was only started if significant group differences existed for both co-primary measures. Significant results for higher-ranked measure was needed to test next lower-ranked measure to control for multiple testing.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratification levels for Cochran-Mantel-Haenszel = prior anti-TNF versus anti-TNF-naive.

17. Secondary Outcome

Title	Proportion of Inflammatory Bowel Disease Questionnaire Responders at Week 8
Description	Response per the Inflammatory Bowel Disease Questionnaire (IBDQ) was defined as at least a 16-point increase from Baseline in total IBDQ score. The IBDQ is a 32-item questionnaire consisting of 4 dimensions: bowel-related symptoms, systemic function, social function, and emotional status. The responses to questions within each domain range from 1 (significant impairment) to 7 (no impairment), with total score ranging from 32 (very poor) to 224 (perfect health-related quality of life).
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set using the non-responder imputation (NRI) method in which all missing remission values and values after switch to open-label treatment were considered to be non-remission.

Arm/Group Title	Adalimumab 160/80/40	Placebo
Arm/Group Description	During the Double-Blind (DB) period, the Adalimumab (ADA) treatment group received a dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4 (160/80/40 mg).	The placebo treatment group received placebo throughout the Double-Blind (DB) period.
Measure Participants	248	246
Number [Percentage of Participants]	58.1 23.4%	45.5 18.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Adalimumab 160/80/40, Placebo
	Comments	The Cochran-Mantel-Haenszel test was used to test the null hypothesis of no difference between adalimumab and placebo. Treatment differences were deemed statistically significant at a significance level of 0.05.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	Testing of ranked secondary measures was only started if significant group differences existed for both co-primary measures. Significant results for higher-ranked measure was needed to test next lower-ranked measure to control for multiple testing.
	Method	Cochran-Mantel-Haenszel
	Comments	Stratification levels for Cochran-Mantel-Haenszel = prior anti-TNF versus anti-TNF-naive.

Adverse Events

Time Frame	Double-Blind (DB) period: From 1st study drug dose in DB period to 70 days after last DB study drug dose or until switch to Open-Label. Any Adalimumab: From 1st adalimumab dose up 70 days after last adalimumab dose or until switch to extension study.
Adverse Event Reporting Description	**518 participants were randomized into the study; 1 subject did not receive study drug and was excluded from the safety analyses. The number of participants in the Safety population (at least 1 dose of study drug) was higher (517) than that in the ITT population (494), as the latter excluded participants from 3 non-compliant clinical sites.**
Arm/Group Title	Adalimumab Group - Double-Blind Period		Placebo Group - Double-Blind Period		Any Adalimumab
Arm/Group Description	During the Double-Blind period, the Adalimumab treatment group received a dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4 (160/80/40 mg).		The placebo treatment group received placebo throughout the Double-Blind period.		During the Double-Blind period, only the Adalimumab treatment group received active study drug (dose of 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (eow) starting at Week 4 [160/80/40 mg]). After the switch to open-label treatment, participants in both treatment groups received adalimumab 40 mg eow, unless they dose-escalated, in which case they received adalimumab 40 mg every week (ew). Consequently, this analysis set combined adalimumab exposure from both the Double-Blind and Open-Label periods.
All Cause Mortality
	Adalimumab Group - Double-Blind Period		Placebo Group - Double-Blind Period		Any Adalimumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Adalimumab Group - Double-Blind Period		Placebo Group - Double-Blind Period		Any Adalimumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/257 (12.1%)		32/260 (12.3%)		61/398 (15.3%)
Blood and lymphatic system disorders
Anaemia	2/257 (0.8%)		1/260 (0.4%)		3/398 (0.8%)
Leukopenia	1/257 (0.4%)		0/260 (0%)		1/398 (0.3%)
Gastrointestinal disorders
Abdominal pain	1/257 (0.4%)		0/260 (0%)		2/398 (0.5%)
Abdominal pain lower	1/257 (0.4%)		0/260 (0%)		1/398 (0.3%)
Anal fistula	0/257 (0%)		1/260 (0.4%)		0/398 (0%)
Colitis	1/257 (0.4%)		0/260 (0%)		1/398 (0.3%)
Colitis ulcerative	16/257 (6.2%)		18/260 (6.9%)		35/398 (8.8%)
Constipation	1/257 (0.4%)		0/260 (0%)		1/398 (0.3%)
Gastrointestinal dysplasia	1/257 (0.4%)		0/260 (0%)		1/398 (0.3%)
Crohn's disease	0/257 (0%)		0/260 (0%)		1/398 (0.3%)
Inguinal hernia	0/257 (0%)		0/260 (0%)		2/398 (0.5%)
Irritable bowel syndrome	1/257 (0.4%)		0/260 (0%)		1/398 (0.3%)
Localized intraabdominal fluid collection	1/257 (0.4%)		0/260 (0%)		1/398 (0.3%)
Obstruction gastric	1/257 (0.4%)		0/260 (0%)		1/398 (0.3%)
Pancreatitis acute	0/257 (0%)		1/260 (0.4%)		0/398 (0%)
Rectal haemorrhage	1/257 (0.4%)		0/260 (0%)		1/398 (0.3%)
Rectal perforation	0/257 (0%)		1/260 (0.4%)		0/398 (0%)
Upper gastrointestinal haemorrhage	0/257 (0%)		1/260 (0.4%)		0/398 (0%)
General disorders
Non-cardiac chest pain	0/257 (0%)		0/260 (0%)		1/398 (0.3%)
Hepatobiliary disorders
Cholelithiasis	1/257 (0.4%)		0/260 (0%)		1/398 (0.3%)
Infections and infestations
Anal abscess	1/257 (0.4%)		1/260 (0.4%)		1/398 (0.3%)
Appendicitis	1/257 (0.4%)		0/260 (0%)		2/398 (0.5%)
Catheter sepsis	1/257 (0.4%)		0/260 (0%)		1/398 (0.3%)
Cytomegalovirus colitis	0/257 (0%)		1/260 (0.4%)		1/398 (0.3%)
Erysipelas	0/257 (0%)		0/260 (0%)		1/398 (0.3%)
Herpes simplex	0/257 (0%)		0/260 (0%)		1/398 (0.3%)
Liver abscess	0/257 (0%)		1/260 (0.4%)		0/398 (0%)
Perineal abscess	0/257 (0%)		1/260 (0.4%)		0/398 (0%)
Pneumonia	0/257 (0%)		1/260 (0.4%)		0/398 (0%)
Pneumonia necrotizing	0/257 (0%)		1/260 (0.4%)		0/398 (0%)
Respiratory tract infection	0/257 (0%)		0/260 (0%)		1/398 (0.3%)
Salmonellosis	1/257 (0.4%)		0/260 (0%)		1/398 (0.3%)
Scrotal abscess	0/257 (0%)		1/260 (0.4%)		0/398 (0%)
Injury, poisoning and procedural complications
Radius fracture	1/257 (0.4%)		0/260 (0%)		1/398 (0.3%)
Wound	1/257 (0.4%)		0/260 (0%)		1/398 (0.3%)
Metabolism and nutrition disorders
Failure to thrive	0/257 (0%)		0/260 (0%)		1/398 (0.3%)
Hypovolaemia	0/257 (0%)		0/260 (0%)		1/398 (0.3%)
Musculoskeletal and connective tissue disorders
Flank pain	0/257 (0%)		0/260 (0%)		1/398 (0.3%)
Ligament calcification	0/257 (0%)		1/260 (0.4%)		0/398 (0%)
Spinal osteoarthritis	0/257 (0%)		0/260 (0%)		1/398 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gastric cancer	1/257 (0.4%)		0/260 (0%)		1/398 (0.3%)
Gastrointestinal tract adenoma	1/257 (0.4%)		0/260 (0%)		1/398 (0.3%)
Pregnancy, puerperium and perinatal conditions
Abortion	0/257 (0%)		0/260 (0%)		1/398 (0.3%)
Renal and urinary disorders
Calculus ureteric	1/257 (0.4%)		1/260 (0.4%)		1/398 (0.3%)
Nephrolithiasis	1/257 (0.4%)		0/260 (0%)		1/398 (0.3%)
Renal failure acute	0/257 (0%)		0/260 (0%)		1/398 (0.3%)
Reproductive system and breast disorders
Cystocele	0/257 (0%)		1/260 (0.4%)		0/398 (0%)
Vaginal haemorrhage	0/257 (0%)		0/260 (0%)		1/398 (0.3%)
Respiratory, thoracic and mediastinal disorders
Organizing pneumonia	0/257 (0%)		1/260 (0.4%)		0/398 (0%)
Pulmonary embolism	0/257 (0%)		1/260 (0.4%)		1/398 (0.3%)
Skin and subcutaneous tissue disorders
Dermatitis bullous	1/257 (0.4%)		0/260 (0%)		1/398 (0.3%)
Psoriasis	1/257 (0.4%)		1/260 (0.4%)		1/398 (0.3%)
Pyoderma gangrenosum	0/257 (0%)		4/260 (1.5%)		0/398 (0%)
Vascular disorders
Deep vein thrombosis	2/257 (0.8%)		1/260 (0.4%)		2/398 (0.5%)
Orthostatic hypotension	0/257 (0%)		1/260 (0.4%)		0/398 (0%)
Thrombophlebitis superficial	0/257 (0%)		1/260 (0.4%)		0/398 (0%)
Other (Not Including Serious) Adverse Events
	Adalimumab Group - Double-Blind Period		Placebo Group - Double-Blind Period		Any Adalimumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	139/257 (54.1%)		142/260 (54.6%)		204/398 (51.3%)
Blood and lymphatic system disorders
Anaemia	8/257 (3.1%)		14/260 (5.4%)		21/398 (5.3%)
Gastrointestinal disorders
Abdominal pain	19/257 (7.4%)		16/260 (6.2%)		27/398 (6.8%)
Colitis ulcerative	42/257 (16.3%)		58/260 (22.3%)		71/398 (17.8%)
Nausea	15/257 (5.8%)		22/260 (8.5%)		23/398 (5.8%)
General disorders
Fatigue	16/257 (6.2%)		15/260 (5.8%)		25/398 (6.3%)
Pyrexia	11/257 (4.3%)		14/260 (5.4%)		23/398 (5.8%)
Infections and infestations
Nasopharyngitis	45/257 (17.5%)		27/260 (10.4%)		68/398 (17.1%)
Upper respiratory tract infection	11/257 (4.3%)		14/260 (5.4%)		0/398 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	20/257 (7.8%)		16/260 (6.2%)		30/398 (7.5%)
Nervous system disorders
Headache	22/257 (8.6%)		37/260 (14.2%)		31/398 (7.8%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	15/257 (5.8%)		7/260 (2.7%)		23/398 (5.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Abbott requests that any investigator or institution that plans on presenting/publishing results disclosure, provide written notification of their request 60 days prior to their presentation/publication. Abbott requests that no presentation/publication will be instituted until 12 months after a study is completed, or after the first presentation/publication whichever occurs first. A delay may be proposed of a presentation/publication if Abbott needs to secure patent or proprietary protection.