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

Information source: Abbott
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Ulcerative Colitis

Intervention: adalimumab (Biological); adalimumab (Biological); placebo (Biological)

Phase: Phase 3

Status: Completed

Sponsored by: Abbott

Official(s) and/or principal investigator(s):
Roopal Thakkar, MD, Study Director, Affiliation: Abbott

Summary

The objective of this study is to assess the efficacy and safety of adalimumab for the induction of clinical remission in subjects with moderately to severely active ulcerative colitis.

Clinical Details

Official title: A Multicenter, Randomized, Double-blind Placebo-controlled Study of the Human Anti-TNF Monoclonal Antibody Adalimumab for the Induction of Clinical Remission in Subjects With Moderately to Severely Active Ulcerative Colitis

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Proportion of Participants With Clinical Remission Per Mayo Score at Week 8

Secondary outcome:

Ranked Secondary Endpoint #1: Proportion of Participants With Clinical Response Per Mayo Score at Week 8 (Adalimumab 160/80/40 Versus Placebo).

Ranked Secondary Endpoint #2: Proportion of Participants With Mucosal Healing at Week 8 (Adalimumab 160/80/40 Versus Placebo).

Ranked Secondary Endpoint #3: Proportion of Participants With Rectal Bleeding Subscore Indicative of Mild Disease (<= 1) at Week 8 (Adalimumab 160/80/40 Versus Placebo).

Ranked Secondary Endpoint #4: Proportion of Participants With Physician's Global Assessment Subscore Indicative of Mild Disease (<= 1) at Week 8 (Adalimumab 160/80/40 Versus Placebo).

Ranked Secondary Endpoint #5: Proportion of Participants With Stool Frequency Subscore Indicative of Mild Disease (<= 1) at Week 8 (Adalimumab 160/80/40 Versus Placebo).

Ranked Secondary Endpoint #6: Proportion of Participants With Clinical Response Per Mayo Score at Week 8 (Adalimumab 80/40 Versus Placebo).

Ranked Secondary Endpoint #7: Proportion of Participants With Mucosal Healing at Week 8 (Adalimumab 80/40 Versus Placebo).

Ranked Secondary Endpoint #8: Proportion of Participants With Rectal Bleeding Subscore Indicative of Mild Disease (<= 1) at Week 8 (Adalimumab 80/40 Versus Placebo).

Ranked Secondary Endpoint #9: Proportion of Participants With Physician's Global Assessment Subscore Indicative of Mild Disease (<= 1) at Week 8 (Adalimumab 80/40 Versus Placebo).

Ranked Secondary Endpoint #10: Proportion of Participants With Stool Frequency Subscore Indicative of Mild Disease (<= 1) at Week 8 (Adalimumab 80/40 Versus Placebo).

Ranked Secondary Endpoint #11: Proportion of IBDQ Responders at Week 8 (Adalimumab 160/80/40 Versus Placebo).

Ranked Secondary Endpoint #12: Proportion of IBDQ Responders at Week 8 (Adalimumab 80/40 Versus Placebo).

Proportion of Participants With Clinical Remission Per Mayo Score at Week 52

Proportion of Participants With Clinical Remission Per Partial Mayo Score at Week 52

Proportion of Participants With Clinical Response Per Mayo Score at Week 52

Proportion of Participants With Clinical Response Per Partial Mayo Score at Week 52

Proportion of Participants With Mucosal Healing at Week 52

Proportion of Participants With Rectal Bleeding Subscore Indicative of Mild Disease (<= 1) at Week 52

Proportion of Participants With Physician's Global Assessment Subscore Indicative of Mild Disease (<= 1) at Week 52

Proportion of Participants With Stool Frequency Subscore Indicative of Mild Disease (<= 1) at Week 52

Proportion of Participants With Clinical Remission Per Mayo Score at Week 52 Among Participants Who Were Systemic Corticosteroid-free at Week 52

Detailed description: This was a Phase 3, multicenter, randomized, double-blind (DB), placebo-controlled trial designed to evaluate the efficacy and safety of the human anti-TNF monoclonal antibody adalimumab for the induction of clinical remission in participants with moderately to severely active ulcerative colitis (UC). 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.

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

The following eligibility criteria applied to participants enrolled following Amendment 3 to the study protocol. Inclusion Criteria: 1. Male and female participants >= 18 years of age 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: 1. History of subtotal colectomy with ileorectostomy or colectomy with ileoanal pouch, Koch pouch, or ileostomy for ulcerative colitis or is planning bowel surgery. 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.

Locations and Contacts

Site Ref # / Investigator 4936, Graz 8036, Austria

Site Ref # / Investigator 6224, Hall 6060, Austria

Site Ref # / Investigator 3830, Innsbruck A-6020, Austria

Site Ref # / Investigator 7508, Linz A-4010, Austria

Site Ref # / Investigator 3829, Salzburg A-5020, Austria

Site Ref # / Investigator 3831, Vienna 1090, Austria

Site Ref # / Investigator 4937, Vienna 1030, Austria

Site Ref # / Investigator 3861, Bonheiden 2820, Belgium

Site Ref # / Investigator 3859, Liege 4000, Belgium

Site Ref # / Investigator 3862, Roeselare 8800, Belgium

Site Ref # / Investigator 3858, Brno 62500, Czech Republic

Site Ref # / Investigator 3856, Olomouc 77520, Czech Republic

Site Ref # / Investigator 3857, Ostrava 708 52, Czech Republic

Site Ref # / Investigator 3854, Prague 1 118 83, Czech Republic

Site Ref # / Investigator 3855, Prague 7 17000, Czech Republic

Site Ref # / Investigator 3832, Berlin 13353, Germany

Site Ref # / Investigator 13983, Essen D-45239, Germany

Site Ref # / Investigator 3834, Jena 07747, Germany

Site Ref # / Investigator 3833, Kiel 24105, Germany

Site Ref # / Investigator 3878, Mainz 55131, Germany

Site Ref # / Investigator 3897, Munich 81377, Germany

Site Ref # / Investigator 3850, Budapest H-1125, Hungary

Site Ref # / Investigator 3852, Budapest H-1076, Hungary

Site Ref # / Investigator 3849, Gyor H-9024, Hungary

Site Ref # / Investigator 3876, Bologna 40138, Italy

Site Ref # / Investigator 3848, Milan 20157, Italy

Site Ref # / Investigator 3845, Palermo 90146, Italy

Site Ref # / Investigator 3846, Rome 00152, Italy

Site Ref # / Investigator 6232, Rome 00133, Italy

Site Ref # / Investigator 3873, Eindhoven 5623 EJ, Netherlands

Site Ref # / Investigator 3875, Leiden 2333 ZA, Netherlands

Site Ref # / Investigator 8061, Lodz 90-153, Poland

Site Ref # / Investigator 13804, Sopot 81-756, Poland

Site Ref # / Investigator 8055, Warsaw 02-507, Poland

Site Ref # / Investigator 2392, Ponce 00717, Puerto Rico

Site Ref # / Investigator 2393, San Juan 00936-5067, Puerto Rico

Site Ref # / Investigator 3839, Banska Bystrica 97 401, Slovakia

Site Ref # / Investigator 3838, Bratislava 811 07, Slovakia

Site Ref # / Investigator 3841, Bratislava 833 05, Slovakia

Site Ref # / Investigator 3842, Nitra 94 901, Slovakia

Site Ref # / Investigator 14721, Presov 08001, Slovakia

Site Ref # / Investigator 14521, Trencin 91101, Slovakia

Site Ref # / Investigator 3840, Trnava 917 01, Slovakia

Site Ref # / Investigator 8503, Gothenburg 41345, Sweden

Site Ref # / Investigator 8504, Linkoping 581 85, Sweden

Site Ref # / Investigator 8502, Lund 22185, Sweden

Site Ref # / Investigator 2080, Birmingham, Alabama 35209, United States

Site Ref # / Investigator 6034, Mobile, Alabama 36617, United States

Site Ref # / Investigator 2224, Calgary, Alberta T2N 4Z6, Canada

Site Ref # / Investigator 2227, Edmonton, Alberta T6G 2X8, Canada

Site Ref # / Investigator 5100, Fayetteville, Arkansas 72703, United States

Site Ref # / Investigator 2226, Vancouver, British Columbia V6Z-2K5, Canada

Site Ref # / Investigator 5390, Orange, California 92868, United States

Site Ref # / Investigator 5392, San Diego, California 92123, United States

Site Ref # / Investigator 2245, Bridgeport, Connecticut 06606, United States

Site Ref # / Investigator 2240, Gainesville, Florida 32610, United States

Site Ref # / Investigator 2230, South Miami, Florida 33143, United States

Site Ref # / Investigator 2231, Atlanta, Georgia 30342, United States

Site Ref # / Investigator 5393, Atlanta, Georgia 30308, United States

Site Ref # / Investigator 2498, Chicago, Illinois 60637, United States

Site Ref # / Investigator 2223, Winnipeg, Manitoba R3A 1R9, Canada

Site Ref # / Investigator 2078, Chevy Chase, Maryland 20815, United States

Site Ref # / Investigator 2238, Silver Springs, Maryland 20901, United States

Site Ref # / Investigator 1971, Boston, Massachusetts 02114, United States

Site Ref # / Investigator 2246, Rochester, Minnesota 55905, United States

Site Ref # / Investigator 2243, Kansas City, Missouri 64131, United States

Site Ref # / Investigator 2247, Mexico, Missouri 65265, United States

Site Ref # / Investigator 2233, Lincoln, Nebraska 68503, United States

Site Ref # / Investigator 2236, Cedar Knolls, New Jersey 07927, United States

Site Ref # / Investigator 2072, New York, New York 10028, United States

Site Ref # / Investigator 2241, Charlotte, North Carolina 28211, United States

Site Ref # / Investigator 2232, Raleigh, North Carolina 27612, United States

Site Ref # / Investigator 11801, Wilmington, North Carolina 28403, United States

Site Ref # / Investigator 2074, Cincinnati, Ohio 45219, United States

Site Ref # / Investigator 2126, Cleveland, Ohio 44106-5066, United States

Site Ref # / Investigator 2138, Toronto, Ontario M3N 2V7, Canada

Site Ref # / Investigator 6090, Germantown, Tennessee 38138, United States

Site Ref # / Investigator 2076, Nashville, Tennessee 37203, United States

Site Ref # / Investigator 2229, Bellevue, Washington 98004, United States

Site Ref # / Investigator 2077, Milwaukee, Wisconsin 53215, United States

Additional Information

Starting date: November 2006
Last updated: April 7, 2011

Page last updated: August 23, 2015

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