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

NCT ID: NCT00408629

Last Updated: 2011-05-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 518 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-11-30
• Study Completion Date: 2010-03-31

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.

Conditions

Ulcerative Colitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

adalimumab group

Group Type: EXPERIMENTAL

adalimumab

Intervention Type: BIOLOGICAL

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.

placebo group

Group Type: EXPERIMENTAL

placebo

Intervention Type: BIOLOGICAL

Matching Placebo for prefilled syringe, 40 mg,

Interventions

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.

Intervention Type: BIOLOGICAL

placebo

Matching Placebo for prefilled syringe, 40 mg,

Intervention Type: BIOLOGICAL

Other Intervention Names

ABT-D2E7; Humira

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Abbott

INDUSTRY

Sponsor Role: lead

Responsible Party

Abbott

Principal Investigators

Roopal B Thakkar, M.D.

Role: STUDY_DIRECTOR

Abbott

Locations

Site Ref # / Investigator 5394

Anaheim, California, United States

Site Ref # / Investigator 3753

Wheat Ridge, Colorado, United States

Site Ref # / Investigator 3754

Hamden, Connecticut, United States

Site Ref # / Investigator 12903

Gainesville, Florida, United States

Site Ref # / Investigator 3747

Hollywood, Florida, United States

Site Ref # / Investigator 5106

Jacksonville, Florida, United States

Site Ref # / Investigator 11601

Naples, Florida, United States

Site Ref # / Investigator 6846

Sarasota, Florida, United States

Site Ref # / Investigator 3742

Winter Park, Florida, United States

Site Ref # / Investigator 3760

Zephyrhills, Florida, United States

Site Ref # / Investigator 3739

Atlanta, Georgia, United States

Site Ref # / Investigator 7658

Macon, Georgia, United States

Site Ref # / Investigator 5397

Moline, Illinois, United States

Site Ref # / Investigator 7453

Topeka, Kansas, United States

Site Ref # / Investigator 3759

Annapolis, Maryland, United States

Site Ref # / Investigator 3762

Annapolis, Maryland, United States

Site Ref # / Investigator 3738

Lutherville, Maryland, United States

Site Ref # / Investigator 7472

Troy, Michigan, United States

Site Ref # / Investigator 3744

Rochester, Minnesota, United States

Site Ref # / Investigator 6088

St Louis, Missouri, United States

Site Ref # / Investigator 3756

Great Neck, New York, United States

Site Ref # / Investigator 3752

Charlotte, North Carolina, United States

Site Ref # / Investigator 3758

Jacksonville, North Carolina, United States

Site Ref # / Investigator 3745

Cincinnati, Ohio, United States

Site Ref # / Investigator 7709

Oklahoma City, Oklahoma, United States

Site Ref # / Investigator 3740

Tulsa, Oklahoma, United States

Site Ref # / Investigator 3765

Sayre, Pennsylvania, United States

Site Ref # / Investigator 3741

Columbia, South Carolina, United States

Site Ref # / Investigator 3737

Germantown, Tennessee, United States

Site Ref # / Investigator 6077

Nashville, Tennessee, United States

Site Ref # / Investigator 5107

Nashville, Tennessee, United States

Site Ref # / Investigator 3743

Nashville, Tennessee, United States

Site Ref # / Investigator 5398

Ogden, Utah, United States

Site Ref # / Investigator 8064

Spokane, Washington, United States

Site Ref # / Investigator 3750

Spokane, Washington, United States

Site Ref # / Investigator 3761

West Bend, Wisconsin, United States

Site Ref # / Investigator 6853

Buenos Aires, , Argentina

Site Ref # / Investigator 13722

Garran, Australian Capital Territory, Australia

Site Ref # / Investigator 16141

Bankstown, New South Wales, Australia

Site Ref # / Investigator 13723

Herston, Queensland, Australia

Site Ref # / Investigator 10706

Bedford Park, South Australia, Australia

Site Ref # / Investigator 14882

Box Hill, Victoria, Australia

Site Ref # / Investigator 9002

Malvern, Victoria, Australia

Site Ref # / Investigator 10704

Fremantle, Western Australia, Australia

Site Ref # / Investigator 9802

Vienna, , Austria

Site Ref # / Investigator 5256

Bonheiden, , Belgium

Site Ref # / Investigator 5253

Brussels, , Belgium

Site Ref # / Investigator 6225

Brussels, , Belgium

Site Ref # / Investigator 6079

Ghent, , Belgium

Site Ref # / Investigator 6078

Leuven, , Belgium

Site Ref # / Investigator 10423

Kelowna, British Columbia, Canada

Site Ref # / Investigator 3766

Victoria, British Columbia, Canada

Site Ref # / Investigator 13556

Greater Sudbury, Ontario, Canada

Site Ref # / Investigator 3769

Hamilton, Ontario, Canada

Site Ref # / Investigator 3736

Toronto, Ontario, Canada

Site Ref # / Investigator 3771

Montreal, Quebec, Canada

Site Ref # / Investigator 3764

Montreal, Quebec, Canada

Site Ref # / Investigator 3768

Montreal, Quebec, Canada

Site Ref # / Investigator 3770

Québec, Quebec, Canada

Site Ref # / Investigator 7021

České Budějovice, , Czechia

Site Ref # / Investigator 6307

Hradec Kravlove 12, , Czechia

Site Ref # / Investigator 6606

Olomouc, , Czechia

Site Ref # / Investigator 7481

Prague, , Czechia

Site Ref # / Investigator 7479

Prague, , Czechia

Site Ref # / Investigator 6483

Hvidovre, , Denmark

Site Ref # / Investigator 7477

Odense C, , Denmark

Site Ref # / Investigator 6231

Clichy, , France

Site Ref # / Investigator 7476

Lille, , France

Site Ref # / Investigator 7475

Pessac, , France

Site Ref # / Investigator 7474

Toulouse, , France

Site Ref # / Investigator 15321

Hamburg, , Germany

Site Ref # / Investigator 9069

Hamburg, , Germany

Site Ref # / Investigator 14642

Magdeburg, , Germany

Site Ref # / Investigator 9067

Minden, , Germany

Site Ref # / Investigator 14661

Munich, , Germany

Site Ref # / Investigator 9801

Munich, , Germany

Site Ref # / Investigator 14761

Münster, , Germany

Site Ref # / Investigator 5247

Regensburg, , Germany

Site Ref # / Investigator 7485

Budapest, , Hungary

Site Ref # / Investigator 5025

Budapest, , Hungary

Site Ref # / Investigator 10625

Debrecen, , Hungary

Site Ref # / Investigator 14104

Gyula, , Hungary

Site Ref # / Investigator 4987

Miskoic, , Hungary

Site Ref # / Investigator 5036

Miskolc, , Hungary

Site Ref # / Investigator 12744

Kfar Saba, , Israel

Site Ref # / Investigator 10623

Petah Tikva, , Israel

Site Ref # / Investigator 15361

Tel Aviv, , Israel

Site Ref # / Investigator 13301

Auckland, , New Zealand

Site Ref # / Investigator 13181

Auckland, , New Zealand

Site Ref # / Investigator 13148

Christchurch, , New Zealand

Site Ref # / Investigator 13482

Hamilton, , New Zealand

Site Ref # / Investigator 9561

Gjøvik, , Norway

Site Ref # / Investigator 5197

Oslo, , Norway

Site Ref # / Investigator 6297

Oslo, , Norway

Site Ref # / Investigator 5194

Tromsø, , Norway

Site Ref # / Investigator 5193

Trondheim, , Norway

Site Ref # / Investigator 5242

Lodz, , Poland

Site Ref # / Investigator 5266

Warsaw, , Poland

Site Ref # / Investigator 5265

Warsaw, , Poland

Site Ref # / Investigator 15263

Wroclaw, , Poland

Site Ref # / Investigator 5264

Faro, , Portugal

Site Ref # / Investigator 7473

Lisbon, , Portugal

Site Ref # / Investigator 5263

Lisbon, , Portugal

Site Ref # / Investigator 5211

Barcelona, , Spain

Site Ref # / Investigator 5212

Madrid, , Spain

Site Ref # / Investigator 10221

Basel, , Switzerland

Site Ref # / Investigator 10222

Bern, , Switzerland

Site Ref # / Investigator 9162

Zurich, , Switzerland

Countries

United States; Argentina; Australia; Austria; Belgium; Canada; Czechia; Denmark; France; Germany; Hungary; Israel; New Zealand; Norway; Poland; Portugal; Spain; Switzerland

References

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.

Reference Type: DERIVED

PMID: 29380251 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25041859 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 24067881 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 23173821 (View on PubMed)

Other Identifiers

2006-002782-40

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

M06-827

Identifier Type: -

Identifier Source: org_study_id