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Efficacy and Safety of Adalimumab in Subjects With Moderately to Severely Active 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); placebo (Biological)

Phase: Phase 3

Status: Completed

Sponsored by: Abbott

Official(s) and/or principal investigator(s):
Roopal B Thakkar, M.D., Study Director, Affiliation: Abbott

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).

Clinical Details

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 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 Who Achieved Clinical Remission Per Mayo Score at Week 8

Proportion of Participants Who Achieved Clinical Remission Per Mayo Score at Week 52

Secondary outcome:

Proportion of Participants Who Achieved Sustained Clinical Remission Per Mayo Score at Both Week 8 and Week 52

Proportion of Participants Who Achieved Clinical Response Per Mayo Score at Week 8

Proportion of Participants Who Achieved Clinical Response Per Mayo Score at Week 52

Proportion of Participants Who Achieved Sustained Clinical Response Per Mayo Score at Both Week 8 and Week 52

Proportion of Participants Who Achieved Mucosal Healing at Week 8

Proportion of Participants Who Achieved Mucosal Healing at Week 52

Proportion of Participants Who Achieved Sustained Mucosal Healing at Both Week 8 and Week 52

Proportion of Participants Who Discontinued Corticosteroid Use Before Week 52 and Achieved Clinical Remission Per Mayo Score at Week 52

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

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

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

Proportion of Participants Who Discontinued Corticosteroid Use for At Least 90 Days and Achieved Clinical Remission Per Mayo Score at Week 52

Proportion of Participants Who Discontinued Corticosteroid Use and Achieved Clinical Remission Per Mayo Score (Sustained) at Both Weeks 32 and 52

Proportion of Inflammatory Bowel Disease Questionnaire Responders at Week 52

Proportion of Inflammatory Bowel Disease Questionnaire Responders at Week 8

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

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

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.

Locations and Contacts

Site Ref # / Investigator 6853, Buenos Aires C1181ACH, Argentina

Site Ref # / Investigator 9802, Vienna 1090, Austria

Site Ref # / Investigator 5256, Bonheiden 2820, Belgium

Site Ref # / Investigator 5253, Brussels 1070, Belgium

Site Ref # / Investigator 6225, Brussels 1200, Belgium

Site Ref # / Investigator 6079, Ghent 9000, Belgium

Site Ref # / Investigator 6078, Leuven 3000, Belgium

Site Ref # / Investigator 7021, Ceske Budejovice 370 87, Czech Republic

Site Ref # / Investigator 6307, Hradec Kravlove 12 500 12, Czech Republic

Site Ref # / Investigator 6606, Olomouc 775 20, Czech Republic

Site Ref # / Investigator 7481, Prague 4 140 21, Czech Republic

Site Ref # / Investigator 7479, Prague 5 15006, Czech Republic

Site Ref # / Investigator 6483, Hvidovre DK-2650, Denmark

Site Ref # / Investigator 7477, Odense C 5000, Denmark

Site Ref # / Investigator 6231, Clichy 92110, France

Site Ref # / Investigator 7476, Lille Cedex 59037, France

Site Ref # / Investigator 7475, Pessac Cedex 33600, France

Site Ref # / Investigator 7474, Toulouse 31059, France

Site Ref # / Investigator 15321, Hamburg 20148, Germany

Site Ref # / Investigator 9069, Hamburg 22559, Germany

Site Ref # / Investigator 14642, Magdeburg 39120, Germany

Site Ref # / Investigator 9067, Minden 32423, Germany

Site Ref # / Investigator 14761, Muenster 48159, Germany

Site Ref # / Investigator 14661, Munich 80639, Germany

Site Ref # / Investigator 9801, Munich 81377, Germany

Site Ref # / Investigator 5247, Regensburg 93053, Germany

Site Ref # / Investigator 5025, Budapest H-1135, Hungary

Site Ref # / Investigator 7485, Budapest H-1076, Hungary

Site Ref # / Investigator 10625, Debrecen 4032, Hungary

Site Ref # / Investigator 14104, Gyula 5700, Hungary

Site Ref # / Investigator 4987, Miskoic H-3051, Hungary

Site Ref # / Investigator 5036, Miskolc H-3526, Hungary

Site Ref # / Investigator 12744, Kfar Saba 44281, Israel

Site Ref # / Investigator 10623, Petah Tikva 49100, Israel

Site Ref # / Investigator 15361, Tel Aviv 64239, Israel

Site Ref # / Investigator 13181, Auckland 1148, New Zealand

Site Ref # / Investigator 13301, Auckland 0620, New Zealand

Site Ref # / Investigator 13148, Christchurch 8011, New Zealand

Site Ref # / Investigator 13482, Hamilton, New Zealand

Site Ref # / Investigator 9561, Gjovik 2819, Norway

Site Ref # / Investigator 5197, Oslo 0027, Norway

Site Ref # / Investigator 6297, Oslo 0514, Norway

Site Ref # / Investigator 5194, Tromso 9038, Norway

Site Ref # / Investigator 5193, Trondheim 7006, Norway

Site Ref # / Investigator 5242, Lodz 90-153, Poland

Site Ref # / Investigator 5265, Warsaw 02-507, Poland

Site Ref # / Investigator 5266, Warsaw 02 781, Poland

Site Ref # / Investigator 15263, Wroclaw 54-144, Poland

Site Ref # / Investigator 5264, Faro 8000-386, Portugal

Site Ref # / Investigator 5263, Lisbon 1769-001, Portugal

Site Ref # / Investigator 7473, Lisbon 1150-314, Portugal

Site Ref # / Investigator 5211, Barcelona 08036, Spain

Site Ref # / Investigator 5212, Madrid 28040, Spain

Site Ref # / Investigator 10221, Basel 4031, Switzerland

Site Ref # / Investigator 10222, Bern 3010, Switzerland

Site Ref # / Investigator 9162, Zurich 8091, Switzerland

Site Ref # / Investigator 13722, Garran, Australian Capital Territory 2605, Australia

Site Ref # / Investigator 10423, Kelowna, British Columbia B1Y 1Z9, Canada

Site Ref # / Investigator 3766, Victoria, British Columbia V8T 5G4, Canada

Site Ref # / Investigator 5394, Anaheim, California 92801, United States

Site Ref # / Investigator 3753, Wheat Ridge, Colorado 80033, United States

Site Ref # / Investigator 3754, Hamden, Connecticut 06518, United States

Site Ref # / Investigator 12903, Gainesville, Florida 32607, United States

Site Ref # / Investigator 3747, Hollywood, Florida 33021, United States

Site Ref # / Investigator 5106, Jacksonville, Florida 32256, United States

Site Ref # / Investigator 11601, Naples, Florida 34102, United States

Site Ref # / Investigator 6846, Sarasota, Florida 34239, United States

Site Ref # / Investigator 3742, Winter Park, Florida 32789, United States

Site Ref # / Investigator 3760, Zephyrhills, Florida 33542, United States

Site Ref # / Investigator 3739, Atlanta, Georgia 30342, United States

Site Ref # / Investigator 7658, Macon, Georgia 31201, United States

Site Ref # / Investigator 5397, Moline, Illinois 61265, United States

Site Ref # / Investigator 7453, Topeka, Kansas 66606, United States

Site Ref # / Investigator 3759, Annapolis, Maryland 21401, United States

Site Ref # / Investigator 3762, Annapolis, Maryland 21401, United States

Site Ref # / Investigator 3738, Lutherville, Maryland 21093, United States

Site Ref # / Investigator 7472, Troy, Michigan 48098, United States

Site Ref # / Investigator 3744, Rochester, Minnesota 55905, United States

Site Ref # / Investigator 6088, St. Louis, Missouri 63128, United States

Site Ref # / Investigator 16141, Bankstown, New South Wales NSW 2200, Australia

Site Ref # / Investigator 3756, Great Neck, New York 11021, United States

Site Ref # / Investigator 3752, Charlotte, North Carolina 28207, United States

Site Ref # / Investigator 3758, Jacksonville, North Carolina 28546, United States

Site Ref # / Investigator 3745, Cincinnati, Ohio 45219, United States

Site Ref # / Investigator 7709, Oklahoma City, Oklahoma 73104, United States

Site Ref # / Investigator 3740, Tulsa, Oklahoma 74104, United States

Site Ref # / Investigator 3769, Hamilton, Ontario L8N 3Z5, Canada

Site Ref # / Investigator 13556, Sudbury, Ontario P3E 2N8, Canada

Site Ref # / Investigator 3736, Toronto, Ontario M5G 1X5, Canada

Site Ref # / Investigator 3765, Sayre, Pennsylvania 18840, United States

Site Ref # / Investigator 3764, Montreal, Quebec H3G 1A4, Canada

Site Ref # / Investigator 3768, Montreal, Quebec H3T 1E2, Canada

Site Ref # / Investigator 3771, Montreal, Quebec H3A 1A1, Canada

Site Ref # / Investigator 3770, Quebec City, Quebec G1S 4L8, Canada

Site Ref # / Investigator 13723, Herston, Queensland 4029, Australia

Site Ref # / Investigator 10706, Bedford Park, South Australia SA 5042, Australia

Site Ref # / Investigator 3741, Columbia, South Carolina 29204, United States

Site Ref # / Investigator 3737, Germantown, Tennessee 38138, United States

Site Ref # / Investigator 3743, Nashville, Tennessee 37212-1610, United States

Site Ref # / Investigator 5107, Nashville, Tennessee 37205, United States

Site Ref # / Investigator 6077, Nashville, Tennessee 37203, United States

Site Ref # / Investigator 5398, Ogden, Utah 84405, United States

Site Ref # / Investigator 14882, Box Hill, Victoria 3128, Australia

Site Ref # / Investigator 9002, Malvern, Victoria 3144, Australia

Site Ref # / Investigator 3750, Spokane, Washington 99204, United States

Site Ref # / Investigator 8064, Spokane, Washington 99202, United States

Site Ref # / Investigator 10704, Fremantle, Western Australia 6160, Australia

Site Ref # / Investigator 3761, West Bend, Wisconsin 53095, United States

Additional Information

Starting date: November 2006
Last updated: April 28, 2011

Page last updated: August 23, 2015

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