Efficacy and Safety of Adalimumab in Subjects With Moderately to Severely Acute Ulcerative Colitis
NCT ID: NCT00385736
Last Updated: 2011-04-11
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
576 participants
INTERVENTIONAL
2006-11-30
2010-03-31
Brief Summary
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Detailed Description
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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 by flexible sigmoidoscopy with biopsy, were enrolled at 80 sites worldwide. The study enrolled 576 participants, including 186 participants under the original protocol and protocol Amendments 1 and 2, and 390 participants under protocol Amendments 3 and 4.
Participants enrolled in the study prior to Amendment 3 were randomized in a 1:1 ratio to receive adalimumab or placebo during the 12-week DB induction period. Participants received 4 injections of adalimumab 40 mg (160 mg) or 4 injections of placebo at Baseline (Week 0), followed by 2 injections of adalimumab 40 mg (80 mg) or 2 injections of placebo at Week 2, followed by 1 injection of adalimumab 40 mg or placebo at Weeks 4 and 6. At Week 8, participants randomized to placebo received 4 injections of adalimumab 40 mg (160 mg) followed by 2 injections of adalimumab 40 mg (80 mg) at Week 10. Participants randomized to adalimumab received 3 injections of placebo and 1 injection of adalimumab 40 mg at Week 8 and 1 injection of placebo and 1 injection of adalimumab 40 mg at Week 10. All participants continued to receive 1 injection of open-label (OL) adalimumab 40 mg every other week beginning at Week 12 up to Week 52 (or the early termination visit). Starting at Week 14, participants who had inadequate responses to treatment (as defined using partial Mayo scores) were permitted to dose escalate to adalimumab 40 mg weekly. Participants with persistent inadequate response while on weekly treatment could be discontinued from the study at the discretion of the investigator.
In August 2007, the study design was amended to incorporate an additional adalimumab induction dosing arm of 80/40 mg. Earlier that year, both 160/80-mg and 80/40-mg induction regimens had been approved in the EU as induction treatment for Crohn's disease. The adalimumab induction dosing regimen of 80/40 mg was therefore included so that both of these approved induction regimens would be evaluated for the induction of remission of UC.
Participants enrolled in the study after Amendment 3 were randomized in a 1:1:1 ratio to receive adalimumab (1 of 2 regimens) or placebo during the 8-week DB induction period. Participants received DB therapy from Baseline until Week 8 and OL therapy from Week 8 until the end of the study. In the first adalimumab dosing arm (adalimumab 80/40), participants received 2 injections of adalimumab 40 mg (80 mg) and 2 injections of placebo at Baseline followed by 1 injection of adalimumab 40 mg and 1 injection of placebo at Week 2, and 1 injection of adalimumab 40 mg every other week thereafter. In the second adalimumab DB induction dosing arm (adalimumab 160/80), participants received 4 injections of adalimumab 40 mg (160 mg) at Baseline followed by 2 injections of adalimumab 40 mg (80 mg) at Week 2, and 1 injection of adalimumab 40 mg every other week thereafter. Participants randomized to placebo received 4 injections of placebo at Baseline followed by 2 injections of placebo at Week 2, and 1 injection of placebo at Weeks 4 and 6. Beginning at Week 8, but after the Week 8 study assessments had been completed, all participants received 1 injection of OL adalimumab 40 mg every other week until Week 52 or early termination. Starting at Week 12, participants who had inadequate responses to treatment (as defined using partial Mayo scores) were permitted to dose escalate to adalimumab 40 mg weekly. Participants with persistent inadequate response while on weekly treatment could be discontinued from the study at the discretion of the investigator.
For the analysis of efficacy parameters during the DB Period through Week 8, only participants randomized under Protocol Amendment 3 or later were considered ("Efficacy Analysis Set - Induction" in the participant flow). For the analysis of efficacy parameters during the OL Period through Week 52, all randomized participants (under any version of the protocol) who received at least 1 dose of study drug were considered ("Efficacy Analysis Set - Maintenance" in the participant flow). For the analysis of safety parameters, all participants who received at least 1 dose of study drug were considered ("Safety Analysis Set" in the participant flow).
Twelve ranked secondary variables during the DB Period through Week 8 were to be tested in a hierarchical order to account for multiple testing. These variables are identified as "Ranked Secondary Endpoints" in the results section below. Additionally, non-ranked secondary variables during the OL Period through Week 52 were tested and are presented after the ranked secondary endpoints in the results section below.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Adalimumab 80/40
adalimumab
Prefilled syringe, 40 mg (loading dose then every other week dosing). 80 mg at Week 0, 40 mg at Week 2, and 40 mg every other week starting at Week 4.
Adalimumab 160/80/40
adalimumab
Prefilled syringe, 40 mg (loading dose then every other week dosing). 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week starting at Week 4.
Placebo
placebo
Placebo for 40 mg syringe. Matching placebo for loading dose and every other week dosing. Subjects received placebo at Weeks 0, 2, 4, and 6, followed by 160 mg adalimumab at Week 8, 80 mg adalimumab at Week 10, and 40 mg adalimumab eow thereafter (prior to Amendment 3) or 40 mg adalimumab eow starting at Week 8 (after Amendment 3).
Interventions
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adalimumab
Prefilled syringe, 40 mg (loading dose then every other week dosing). 80 mg at Week 0, 40 mg at Week 2, and 40 mg every other week starting at Week 4.
adalimumab
Prefilled syringe, 40 mg (loading dose then every other week dosing). 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week starting at Week 4.
placebo
Placebo for 40 mg syringe. Matching placebo for loading dose and every other week dosing. Subjects received placebo at Weeks 0, 2, 4, and 6, followed by 160 mg adalimumab at Week 8, 80 mg adalimumab at Week 10, and 40 mg adalimumab eow thereafter (prior to Amendment 3) or 40 mg adalimumab eow starting at Week 8 (after Amendment 3).
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Diagnosis of ulcerative colitis for greater than 90 days prior to Baseline
3. Diagnosis of active ulcerative colitis 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 dose of \>= 20 mg/day or equivalent) for at least 14 days prior to Baseline or stable oral corticosteroid dose (prednisone of \< 20 mg/day) for at least 40 days prior to Baseline.
and/or
* At least a consecutive 90 day course of azathioprine or 6-mercaptopurine (6 MP) prior to Baseline, with a dose of azathioprine \>= 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 was to 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 (azathioprine or 6-MP) during the previous 5 years and, in the judgment of the investigator, have failed to respond to or could not tolerate their treatment.
5. Had to be able to self-administer or has caregiver who can reliably administer subcutaneous injections.
6. Had to be able and willing to give written informed consent and to comply with the requirements of this study protocol.
7. 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 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 or intravaginal contraceptives for 90 days prior to study drug administration
* A vasectomized partner
8. The results of the serum pregnancy test performed at the Screening Visit and urine pregnancy test performed at the Baseline Visit had to be negative.
9. Judged to be in generally good health as determined by the principal investigator
Exclusion Criteria
2. Received infliximab or any other anti-TNF agent or any biological therapy in the past.
3. Received previous treatment with adalimumab or previous participation in an adalimumab clinical study.
4. Received cyclosporine, tacrolimus, or mycophenolate mofetil within 30 days prior to Baseline.
5. Received intravenous corticosteroids within 14 days prior to Screening or during the Screening Period.
6. Received therapeutic enema or suppository, other than required for endoscopy, within 14 days prior to the Screening endoscopy and during the remainder of the Screening Period.
7. Current diagnosis of fulminant colitis and/or toxic megacolon.
8. Participants with disease limited to the rectum (ulcerative proctitis).
9. Current diagnosis of indeterminate colitis.
10. Current diagnosis and/or history of Crohn's disease.
11. Currently receiving total parenteral nutrition.
12. Discontinued use of azathioprine or 6-MP within 28 days of Baseline.
13. Discontinued use of corticosteroid within 14 days of Baseline.
14. Participants using aminosalicylates for less than 90 days prior to Baseline, not on a stable dose for at least 28 days prior to Baseline, or discontinued use within 28 days of Baseline.
15. Participants with positive Clostridium difficile stool assay.
16. Infections requiring treatment with intravenous (IV) antibiotics, IV antivirals, or IV antifungals within 30 days prior to Baseline or oral antibiotics, oral antivirals, or oral antifungals within 14 days prior to Baseline.
17. 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, the participant was not to be enrolled in the study.
18. History of listeria, histoplasmosis, chronic or active hepatitis B infection, human immunodeficiency virus, immunodeficiency syndrome, central nervous system demyelinating disease, or untreated tuberculosis (TB).
19. Female participants who was pregnant or breast-feeding or considering becoming pregnant during the study. There should be at least a 150-day period between the last dose of study drug and either conception or initiation of breast-feeding in women of childbearing potential.
20. Poorly controlled medical condition(s), such as uncontrolled diabetes, unstable ischemic heart disease, moderate to severe congestive heart failure, recent cerebrovascular accident and any other condition, which in the opinion of the investigator, would put the participant at risk by participation in the protocol.
21. Received any investigational agent within 30 days or 5 half lives prior to Baseline (whichever is longer).
22. History of clinically significant drug or alcohol abuse during the previous year.
23. Participants with known hypersensitivity to the excipients of adalimumab as stated in the label.
24. Participants with any prior exposure to Tysabri® (natalizumab).
25. Participants currently taking both budesonide and prednisone (or equivalent) simultaneously.
18 Years
ALL
No
Sponsors
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Abbott
INDUSTRY
Responsible Party
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Abbott
Principal Investigators
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Roopal Thakkar, MD
Role: STUDY_DIRECTOR
Abbott
Locations
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Site Ref # / Investigator 2080
Birmingham, Alabama, United States
Site Ref # / Investigator 6034
Mobile, Alabama, United States
Site Ref # / Investigator 5100
Fayetteville, Arkansas, United States
Site Ref # / Investigator 5390
Orange, California, United States
Site Ref # / Investigator 5392
San Diego, California, United States
Site Ref # / Investigator 2245
Bridgeport, Connecticut, United States
Site Ref # / Investigator 2240
Gainesville, Florida, United States
Site Ref # / Investigator 2230
South Miami, Florida, United States
Site Ref # / Investigator 5393
Atlanta, Georgia, United States
Site Ref # / Investigator 2231
Atlanta, Georgia, United States
Site Ref # / Investigator 2498
Chicago, Illinois, United States
Site Ref # / Investigator 2078
Chevy Chase, Maryland, United States
Site Ref # / Investigator 2238
Silver Springs, Maryland, United States
Site Ref # / Investigator 1971
Boston, Massachusetts, United States
Site Ref # / Investigator 2246
Rochester, Minnesota, United States
Site Ref # / Investigator 2243
Kansas City, Missouri, United States
Site Ref # / Investigator 2247
Mexico, Missouri, United States
Site Ref # / Investigator 2233
Lincoln, Nebraska, United States
Site Ref # / Investigator 2236
Cedar Knolls, New Jersey, United States
Site Ref # / Investigator 2072
New York, New York, United States
Site Ref # / Investigator 2241
Charlotte, North Carolina, United States
Site Ref # / Investigator 2232
Raleigh, North Carolina, United States
Site Ref # / Investigator 11801
Wilmington, North Carolina, United States
Site Ref # / Investigator 2074
Cincinnati, Ohio, United States
Site Ref # / Investigator 2126
Cleveland, Ohio, United States
Site Ref # / Investigator 6090
Germantown, Tennessee, United States
Site Ref # / Investigator 2076
Nashville, Tennessee, United States
Site Ref # / Investigator 2229
Bellevue, Washington, United States
Site Ref # / Investigator 2077
Milwaukee, Wisconsin, United States
Site Ref # / Investigator 4936
Graz, , Austria
Site Ref # / Investigator 6224
Hall in Tirol, , Austria
Site Ref # / Investigator 3830
Innsbruck, , Austria
Site Ref # / Investigator 7508
Linz, , Austria
Site Ref # / Investigator 3829
Salzburg, , Austria
Site Ref # / Investigator 4937
Vienna, , Austria
Site Ref # / Investigator 3831
Vienna, , Austria
Site Ref # / Investigator 3861
Bonheiden, , Belgium
Site Ref # / Investigator 3859
Liège, , Belgium
Site Ref # / Investigator 3862
Roeselare, , Belgium
Site Ref # / Investigator 2224
Calgary, Alberta, Canada
Site Ref # / Investigator 2227
Edmonton, Alberta, Canada
Site Ref # / Investigator 2226
Vancouver, British Columbia, Canada
Site Ref # / Investigator 2223
Winnipeg, Manitoba, Canada
Site Ref # / Investigator 2138
Toronto, Ontario, Canada
Site Ref # / Investigator 3858
Brno, , Czechia
Site Ref # / Investigator 3856
Olomouc, , Czechia
Site Ref # / Investigator 3857
Ostrava, , Czechia
Site Ref # / Investigator 3854
Prague, , Czechia
Site Ref # / Investigator 3855
Prague, , Czechia
Site Ref # / Investigator 3832
Berlin, , Germany
Site Ref # / Investigator 13983
Essen, , Germany
Site Ref # / Investigator 3834
Jena, , Germany
Site Ref # / Investigator 3833
Kiel, , Germany
Site Ref # / Investigator 3878
Mainz, , Germany
Site Ref # / Investigator 3897
Munich, , Germany
Site Ref # / Investigator 3852
Budapest, , Hungary
Site Ref # / Investigator 3850
Budapest, , Hungary
Site Ref # / Investigator 3849
Győr, , Hungary
Site Ref # / Investigator 3876
Bologna, , Italy
Site Ref # / Investigator 3848
Milan, , Italy
Site Ref # / Investigator 3845
Palermo, , Italy
Site Ref # / Investigator 6232
Rome, , Italy
Site Ref # / Investigator 3846
Rome, , Italy
Site Ref # / Investigator 3873
Eindhoven, , Netherlands
Site Ref # / Investigator 3875
Leiden, , Netherlands
Site Ref # / Investigator 8061
Lodz, , Poland
Site Ref # / Investigator 13804
Sopot, , Poland
Site Ref # / Investigator 8055
Warsaw, , Poland
Site Ref # / Investigator 2392
Ponce, , Puerto Rico
Site Ref # / Investigator 2393
San Juan, , Puerto Rico
Site Ref # / Investigator 3839
Banská Bystrica, , Slovakia
Site Ref # / Investigator 3838
Bratislava, , Slovakia
Site Ref # / Investigator 3841
Bratislava, , Slovakia
Site Ref # / Investigator 3842
Nitra, , Slovakia
Site Ref # / Investigator 14721
Prešov, , Slovakia
Site Ref # / Investigator 14521
Trenčín, , Slovakia
Site Ref # / Investigator 3840
Trnava, , Slovakia
Site Ref # / Investigator 8503
Gothenburg, , Sweden
Site Ref # / Investigator 8504
Linköping, , Sweden
Site Ref # / Investigator 8502
Lund, , Sweden
Countries
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References
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Reinisch W, Sandborn WJ, Panaccione R, Huang B, Pollack PF, Lazar A, Thakkar RB. 52-week efficacy of adalimumab in patients with moderately to severely active ulcerative colitis who failed corticosteroids and/or immunosuppressants. Inflamm Bowel Dis. 2013 Jul;19(8):1700-9. doi: 10.1097/MIB.0b013e318281f2b7.
Reinisch W, Sandborn WJ, Hommes DW, D'Haens G, Hanauer S, Schreiber S, Panaccione R, Fedorak RN, Tighe MB, Huang B, Kampman W, Lazar A, Thakkar R. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut. 2011 Jun;60(6):780-7. doi: 10.1136/gut.2010.221127. Epub 2011 Jan 5.
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.
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.
Other Identifiers
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2006-002781-20
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
M06-826
Identifier Type: -
Identifier Source: org_study_id
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