Clinical trial NCT00408629: Efficacy and Safety of Adalimumab in Subjects With Moderately to Severely Active Ulcerative Colitis
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Ulcerative Colitis
Keywords: Ulcerative Colitis
Adalimumab
TNF Antagonist
Mayo Score
Lead sponsor: Abbott
Sponsor class: INDUSTRY
First posted: 2006-12-07
Enrollment: 518
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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.

Eligibility criteria: 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.
5. 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.
6. Had to be able to self-administer or had caregiver who could reliably administer subcutaneous (SC) injections.
7. Had to be able and willing to give written informed consent and to comply with the requirements of the study protocol.
8. 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.
9. 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.

Primary outcomes:
measure: Proportion of Participants Who Achieved Clinical Remission Per Mayo Score at Week 8
timeFrame: Week 8
measure: Proportion of Participants Who Achieved Clinical Remission Per Mayo Score at Week 52
timeFrame: Week 52
Secondary outcomes:
measure: Proportion of Participants Who Achieved Sustained Clinical Remission Per Mayo Score at Both Week 8 and Week 52
timeFrame: Week 8, Week 52
measure: Proportion of Participants Who Achieved Clinical Response Per Mayo Score at Week 8
timeFrame: Week 8
measure: Proportion of Participants Who Achieved Clinical Response Per Mayo Score at Week 52
timeFrame: Week 52
measure: Proportion of Participants Who Achieved Sustained Clinical Response Per Mayo Score at Both Week 8 and Week 52
timeFrame: Week 8, Week 52
measure: Proportion of Participants Who Achieved Mucosal Healing at Week 8
timeFrame: Week 8
measure: Proportion of Participants Who Achieved Mucosal Healing at Week 52
timeFrame: Week 52
measure: Proportion of Participants Who Achieved Sustained Mucosal Healing at Both Week 8 and Week 52
timeFrame: Week 8, Week 52
measure: Proportion of Participants Who Discontinued Corticosteroid Use Before Week 52 and Achieved Clinical Remission Per Mayo Score at Week 52
timeFrame: Baseline to Week 52
measure: Proportion of Participants With Physician's Global Assessment Subscore Indicative of Mild Disease (a Score of 0 or 1) at Week 8
timeFrame: Week 8
measure: Proportion of Participants With Stool Frequency Subscore Indicative of Mild Disease (a Score of 0 or 1) at Week 8
timeFrame: Week 8
measure: Proportion of Participants With Rectal Bleeding Subscore Indicative of Mild Disease (a Score of 0 or 1) at Week 8
timeFrame: Week 8
measure: Proportion of Participants Who Discontinued Corticosteroid Use for At Least 90 Days and Achieved Clinical Remission Per Mayo Score at Week 52
timeFrame: Baseline to Week 52
measure: Proportion of Participants Who Discontinued Corticosteroid Use and Achieved Clinical Remission Per Mayo Score (Sustained) at Both Weeks 32 and 52
timeFrame: Week 32, Week 52
measure: Proportion of Inflammatory Bowel Disease Questionnaire Responders at Week 52
timeFrame: Week 52
measure: Proportion of Inflammatory Bowel Disease Questionnaire Responders at Week 8
timeFrame: Week 8
Other outcomes:
Locations:
city: Anaheim
country: United States
facility: Site Ref # / Investigator 5394
state: California
city: Wheat Ridge
country: United States
facility: Site Ref # / Investigator 3753
state: Colorado
city: Hamden
country: United States
facility: Site Ref # / Investigator 3754
state: Connecticut
city: Gainesville
country: United States
facility: Site Ref # / Investigator 12903
state: Florida
city: Hollywood
country: United States
facility: Site Ref # / Investigator 3747
state: Florida
city: Jacksonville
country: United States
facility: Site Ref # / Investigator 5106
state: Florida
city: Naples
country: United States
facility: Site Ref # / Investigator 11601
state: Florida
city: Sarasota
country: United States
facility: Site Ref # / Investigator 6846
state: Florida
city: Winter Park
country: United States
facility: Site Ref # / Investigator 3742
state: Florida
city: Zephyrhills
country: United States
facility: Site Ref # / Investigator 3760
state: Florida
city: Atlanta
country: United States
facility: Site Ref # / Investigator 3739
state: Georgia
city: Macon
country: United States
facility: Site Ref # / Investigator 7658
state: Georgia
city: Moline
country: United States
facility: Site Ref # / Investigator 5397
state: Illinois
city: Topeka
country: United States
facility: Site Ref # / Investigator 7453
state: Kansas
city: Annapolis
country: United States
facility: Site Ref # / Investigator 3759
state: Maryland
city: Annapolis
country: United States
facility: Site Ref # / Investigator 3762
state: Maryland
city: Lutherville
country: United States
facility: Site Ref # / Investigator 3738
state: Maryland
city: Troy
country: United States
facility: Site Ref # / Investigator 7472
state: Michigan
city: Rochester
country: United States
facility: Site Ref # / Investigator 3744
state: Minnesota
city: St. Louis
country: United States
facility: Site Ref # / Investigator 6088
state: Missouri
city: Great Neck
country: United States
facility: Site Ref # / Investigator 3756
state: New York
city: Charlotte
country: United States
facility: Site Ref # / Investigator 3752
state: North Carolina
city: Jacksonville
country: United States
facility: Site Ref # / Investigator 3758
state: North Carolina
city: Cincinnati
country: United States
facility: Site Ref # / Investigator 3745
state: Ohio
city: Oklahoma City
country: United States
facility: Site Ref # / Investigator 7709
state: Oklahoma
city: Tulsa
country: United States
facility: Site Ref # / Investigator 3740
state: Oklahoma
city: Sayre
country: United States
facility: Site Ref # / Investigator 3765
state: Pennsylvania
city: Columbia
country: United States
facility: Site Ref # / Investigator 3741
state: South Carolina
city: Germantown
country: United States
facility: Site Ref # / Investigator 3737
state: Tennessee
city: Nashville
country: United States
facility: Site Ref # / Investigator 6077
state: Tennessee
city: Nashville
country: United States
facility: Site Ref # / Investigator 5107
state: Tennessee
city: Nashville
country: United States
facility: Site Ref # / Investigator 3743
state: Tennessee
city: Ogden
country: United States
facility: Site Ref # / Investigator 5398
state: Utah
city: Spokane
country: United States
facility: Site Ref # / Investigator 8064
state: Washington
city: Spokane
country: United States
facility: Site Ref # / Investigator 3750
state: Washington
city: West Bend
country: United States
facility: Site Ref # / Investigator 3761
state: Wisconsin
city: Buenos Aires
country: Argentina
facility: Site Ref # / Investigator 6853
city: Garran
country: Australia
facility: Site Ref # / Investigator 13722
state: Australian Capital Territory
city: Bankstown
country: Australia
facility: Site Ref # / Investigator 16141
state: New South Wales
city: Herston
country: Australia
facility: Site Ref # / Investigator 13723
state: Queensland
city: Bedford Park
country: Australia
facility: Site Ref # / Investigator 10706
state: South Australia
city: Box Hill
country: Australia
facility: Site Ref # / Investigator 14882
state: Victoria
city: Malvern
country: Australia
facility: Site Ref # / Investigator 9002
state: Victoria
city: Fremantle
country: Australia
facility: Site Ref # / Investigator 10704
state: Western Australia
city: Vienna
country: Austria
facility: Site Ref # / Investigator 9802
city: Bonheiden
country: Belgium
facility: Site Ref # / Investigator 5256
city: Brussels
country: Belgium
facility: Site Ref # / Investigator 5253
city: Brussels
country: Belgium
facility: Site Ref # / Investigator 6225
city: Ghent
country: Belgium
facility: Site Ref # / Investigator 6079
city: Leuven
country: Belgium
facility: Site Ref # / Investigator 6078
city: Kelowna
country: Canada
facility: Site Ref # / Investigator 10423
state: British Columbia
city: Victoria
country: Canada
facility: Site Ref # / Investigator 3766
state: British Columbia
city: Hamilton
country: Canada
facility: Site Ref # / Investigator 3769
state: Ontario
city: Sudbury
country: Canada
facility: Site Ref # / Investigator 13556
state: Ontario
city: Toronto
country: Canada
facility: Site Ref # / Investigator 3736
state: Ontario
city: Montreal
country: Canada
facility: Site Ref # / Investigator 3771
state: Quebec
city: Montreal
country: Canada
facility: Site Ref # / Investigator 3764
state: Quebec
city: Montreal
country: Canada
facility: Site Ref # / Investigator 3768
state: Quebec
city: Quebec City
country: Canada
facility: Site Ref # / Investigator 3770
state: Quebec
city: Ceske Budejovice
country: Czech Republic
facility: Site Ref # / Investigator 7021
city: Hradec Kravlove 12
country: Czech Republic
facility: Site Ref # / Investigator 6307
city: Olomouc
country: Czech Republic
facility: Site Ref # / Investigator 6606
city: Prague 4
country: Czech Republic
facility: Site Ref # / Investigator 7481
city: Prague 5
country: Czech Republic
facility: Site Ref # / Investigator 7479
city: Hvidovre
country: Denmark
facility: Site Ref # / Investigator 6483
city: Odense C
country: Denmark
facility: Site Ref # / Investigator 7477
city: Clichy
country: France
facility: Site Ref # / Investigator 6231
city: Lille Cedex
country: France
facility: Site Ref # / Investigator 7476
city: Pessac Cedex
country: France
facility: Site Ref # / Investigator 7475
city: Toulouse
country: France
facility: Site Ref # / Investigator 7474
city: Hamburg
country: Germany
facility: Site Ref # / Investigator 15321
city: Hamburg
country: Germany
facility: Site Ref # / Investigator 9069
city: Magdeburg
country: Germany
facility: Site Ref # / Investigator 14642
city: Minden
country: Germany
facility: Site Ref # / Investigator 9067
city: Muenster
country: Germany
facility: Site Ref # / Investigator 14761
city: Munich
country: Germany
facility: Site Ref # / Investigator 14661
city: Munich
country: Germany
facility: Site Ref # / Investigator 9801
city: Regensburg
country: Germany
facility: Site Ref # / Investigator 5247
city: Budapest
country: Hungary
facility: Site Ref # / Investigator 7485
city: Budapest
country: Hungary
facility: Site Ref # / Investigator 5025
city: Debrecen
country: Hungary
facility: Site Ref # / Investigator 10625
city: Gyula
country: Hungary
facility: Site Ref # / Investigator 14104
city: Miskoic
country: Hungary
facility: Site Ref # / Investigator 4987
city: Miskolc
country: Hungary
facility: Site Ref # / Investigator 5036
city: Kfar Saba
country: Israel
facility: Site Ref # / Investigator 12744
city: Petah Tikva
country: Israel
facility: Site Ref # / Investigator 10623
city: Tel Aviv
country: Israel
facility: Site Ref # / Investigator 15361
city: Auckland
country: New Zealand
facility: Site Ref # / Investigator 13301
city: Auckland
country: New Zealand
facility: Site Ref # / Investigator 13181
city: Christchurch
country: New Zealand
facility: Site Ref # / Investigator 13148
city: Hamilton
country: New Zealand
facility: Site Ref # / Investigator 13482
city: Gjovik
country: Norway
facility: Site Ref # / Investigator 9561
city: Oslo
country: Norway
facility: Site Ref # / Investigator 5197
city: Oslo
country: Norway
facility: Site Ref # / Investigator 6297
city: Tromso
country: Norway
facility: Site Ref # / Investigator 5194
city: Trondheim
country: Norway
facility: Site Ref # / Investigator 5193
city: Lodz
country: Poland
facility: Site Ref # / Investigator 5242
city: Warsaw
country: Poland
facility: Site Ref # / Investigator 5266
city: Warsaw
country: Poland
facility: Site Ref # / Investigator 5265
city: Wroclaw
country: Poland
facility: Site Ref # / Investigator 15263
city: Faro
country: Portugal
facility: Site Ref # / Investigator 5264
city: Lisbon
country: Portugal
facility: Site Ref # / Investigator 7473
city: Lisbon
country: Portugal
facility: Site Ref # / Investigator 5263
city: Barcelona
country: Spain
facility: Site Ref # / Investigator 5211
city: Madrid
country: Spain
facility: Site Ref # / Investigator 5212
city: Basel
country: Switzerland
facility: Site Ref # / Investigator 10221
city: Bern
country: Switzerland
facility: Site Ref # / Investigator 10222
city: Zurich
country: Switzerland
facility: Site Ref # / Investigator 9162
Study officials:
affiliation: Abbott
name: Roopal B Thakkar, M.D.
role: STUDY_DIRECTOR
References:
citation: Ryan C, Sobell JM, Leonardi CL, Lynde CW, Karunaratne M, Valdecantos WC, Hendrickson BA. Safety of Adalimumab Dosed Every Week and Every Other Week: Focus on Patients with Hidradenitis Suppurativa or Psoriasis. Am J Clin Dermatol. 2018 Jun;19(3):437-447. doi: 10.1007/s40257-017-0341-6.
citation: Wolf D, D'Haens G, Sandborn WJ, Colombel JF, Van Assche G, Robinson AM, Lazar A, Zhou Q, Petersson J, Thakkar RB. Escalation to weekly dosing recaptures response in adalimumab-treated patients with moderately to severely active ulcerative colitis. Aliment Pharmacol Ther. 2014 Sep;40(5):486-97. doi: 10.1111/apt.12863. Epub 2014 Jul 15.
citation: Feagan BG, Sandborn WJ, Lazar A, Thakkar RB, Huang B, Reilly N, Chen N, Yang M, Skup M, Mulani P, Chao J. Adalimumab therapy is associated with reduced risk of hospitalization in patients with ulcerative colitis. Gastroenterology. 2014 Jan;146(1):110-118.e3. doi: 10.1053/j.gastro.2013.09.032. Epub 2013 Sep 22.
citation: Sandborn WJ, Colombel JF, D'Haens G, Van Assche G, Wolf D, Kron M, Lazar A, Robinson AM, Yang M, Chao JD, Thakkar R. One-year maintenance outcomes among patients with moderately-to-severely active ulcerative colitis who responded to induction therapy with adalimumab: subgroup analyses from ULTRA 2. Aliment Pharmacol Ther. 2013 Jan;37(2):204-13. doi: 10.1111/apt.12145. Epub 2012 Nov 23.