Clinical trial NCT00385736: Efficacy and Safety of Adalimumab in Subjects With Moderately to Severely Acute Ulcerative Colitis
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Ulcerative Colitis
Keywords: Moderate to Severe Ulcerative Colitis
Double-blind
Adalimumab
Induction of Clinical Remission
Lead sponsor: Abbott
Sponsor class: INDUSTRY
First posted: 2006-10-11
Enrollment: 576
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: 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.

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 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.

Primary outcomes:
measure: Proportion of Participants With Clinical Remission Per Mayo Score at Week 8
timeFrame: Week 8
Secondary outcomes:
measure: Ranked Secondary Endpoint #1: Proportion of Participants With Clinical Response Per Mayo Score at Week 8 (Adalimumab 160/80/40 Versus Placebo).
timeFrame: Week 8
measure: Ranked Secondary Endpoint #2: Proportion of Participants With Mucosal Healing at Week 8 (Adalimumab 160/80/40 Versus Placebo).
timeFrame: Week 8
measure: 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).
timeFrame: Week 8
measure: 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).
timeFrame: Week 8
measure: 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).
timeFrame: Week 8
measure: Ranked Secondary Endpoint #6: Proportion of Participants With Clinical Response Per Mayo Score at Week 8 (Adalimumab 80/40 Versus Placebo).
timeFrame: Week 8
measure: Ranked Secondary Endpoint #7: Proportion of Participants With Mucosal Healing at Week 8 (Adalimumab 80/40 Versus Placebo).
timeFrame: Week 8
measure: Ranked Secondary Endpoint #8: Proportion of Participants With Rectal Bleeding Subscore Indicative of Mild Disease (<= 1) at Week 8 (Adalimumab 80/40 Versus Placebo).
timeFrame: Week 8
measure: 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).
timeFrame: Week 8
measure: Ranked Secondary Endpoint #10: Proportion of Participants With Stool Frequency Subscore Indicative of Mild Disease (<= 1) at Week 8 (Adalimumab 80/40 Versus Placebo).
timeFrame: Week 8
measure: Ranked Secondary Endpoint #11: Proportion of IBDQ Responders at Week 8 (Adalimumab 160/80/40 Versus Placebo).
timeFrame: Week 8
measure: Ranked Secondary Endpoint #12: Proportion of IBDQ Responders at Week 8 (Adalimumab 80/40 Versus Placebo).
timeFrame: Week 8
measure: Proportion of Participants With Clinical Remission Per Mayo Score at Week 52
timeFrame: Week 52
measure: Proportion of Participants With Clinical Remission Per Partial Mayo Score at Week 52
timeFrame: Week 52
measure: Proportion of Participants With Clinical Response Per Mayo Score at Week 52
timeFrame: Week 52
measure: Proportion of Participants With Clinical Response Per Partial Mayo Score at Week 52
timeFrame: Week 52
measure: Proportion of Participants With Mucosal Healing at Week 52
timeFrame: Week 52
measure: Proportion of Participants With Rectal Bleeding Subscore Indicative of Mild Disease (<= 1) at Week 52
timeFrame: Week 52
measure: Proportion of Participants With Physician's Global Assessment Subscore Indicative of Mild Disease (<= 1) at Week 52
timeFrame: Week 52
measure: Proportion of Participants With Stool Frequency Subscore Indicative of Mild Disease (<= 1) at Week 52
timeFrame: Week 52
measure: Proportion of Participants With Clinical Remission Per Mayo Score at Week 52 Among Participants Who Were Systemic Corticosteroid-free at Week 52
timeFrame: Week 52
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Site Ref # / Investigator 2080
state: Alabama
city: Mobile
country: United States
facility: Site Ref # / Investigator 6034
state: Alabama
city: Fayetteville
country: United States
facility: Site Ref # / Investigator 5100
state: Arkansas
city: Orange
country: United States
facility: Site Ref # / Investigator 5390
state: California
city: San Diego
country: United States
facility: Site Ref # / Investigator 5392
state: California
city: Bridgeport
country: United States
facility: Site Ref # / Investigator 2245
state: Connecticut
city: Gainesville
country: United States
facility: Site Ref # / Investigator 2240
state: Florida
city: South Miami
country: United States
facility: Site Ref # / Investigator 2230
state: Florida
city: Atlanta
country: United States
facility: Site Ref # / Investigator 5393
state: Georgia
city: Atlanta
country: United States
facility: Site Ref # / Investigator 2231
state: Georgia
city: Chicago
country: United States
facility: Site Ref # / Investigator 2498
state: Illinois
city: Chevy Chase
country: United States
facility: Site Ref # / Investigator 2078
state: Maryland
city: Silver Springs
country: United States
facility: Site Ref # / Investigator 2238
state: Maryland
city: Boston
country: United States
facility: Site Ref # / Investigator 1971
state: Massachusetts
city: Rochester
country: United States
facility: Site Ref # / Investigator 2246
state: Minnesota
city: Kansas City
country: United States
facility: Site Ref # / Investigator 2243
state: Missouri
city: Mexico
country: United States
facility: Site Ref # / Investigator 2247
state: Missouri
city: Lincoln
country: United States
facility: Site Ref # / Investigator 2233
state: Nebraska
city: Cedar Knolls
country: United States
facility: Site Ref # / Investigator 2236
state: New Jersey
city: New York
country: United States
facility: Site Ref # / Investigator 2072
state: New York
city: Charlotte
country: United States
facility: Site Ref # / Investigator 2241
state: North Carolina
city: Raleigh
country: United States
facility: Site Ref # / Investigator 2232
state: North Carolina
city: Wilmington
country: United States
facility: Site Ref # / Investigator 11801
state: North Carolina
city: Cincinnati
country: United States
facility: Site Ref # / Investigator 2074
state: Ohio
city: Cleveland
country: United States
facility: Site Ref # / Investigator 2126
state: Ohio
city: Germantown
country: United States
facility: Site Ref # / Investigator 6090
state: Tennessee
city: Nashville
country: United States
facility: Site Ref # / Investigator 2076
state: Tennessee
city: Bellevue
country: United States
facility: Site Ref # / Investigator 2229
state: Washington
city: Milwaukee
country: United States
facility: Site Ref # / Investigator 2077
state: Wisconsin
city: Graz
country: Austria
facility: Site Ref # / Investigator 4936
city: Hall
country: Austria
facility: Site Ref # / Investigator 6224
city: Innsbruck
country: Austria
facility: Site Ref # / Investigator 3830
city: Linz
country: Austria
facility: Site Ref # / Investigator 7508
city: Salzburg
country: Austria
facility: Site Ref # / Investigator 3829
city: Vienna
country: Austria
facility: Site Ref # / Investigator 4937
city: Vienna
country: Austria
facility: Site Ref # / Investigator 3831
city: Bonheiden
country: Belgium
facility: Site Ref # / Investigator 3861
city: Liege
country: Belgium
facility: Site Ref # / Investigator 3859
city: Roeselare
country: Belgium
facility: Site Ref # / Investigator 3862
city: Calgary
country: Canada
facility: Site Ref # / Investigator 2224
state: Alberta
city: Edmonton
country: Canada
facility: Site Ref # / Investigator 2227
state: Alberta
city: Vancouver
country: Canada
facility: Site Ref # / Investigator 2226
state: British Columbia
city: Winnipeg
country: Canada
facility: Site Ref # / Investigator 2223
state: Manitoba
city: Toronto
country: Canada
facility: Site Ref # / Investigator 2138
state: Ontario
city: Brno
country: Czech Republic
facility: Site Ref # / Investigator 3858
city: Olomouc
country: Czech Republic
facility: Site Ref # / Investigator 3856
city: Ostrava
country: Czech Republic
facility: Site Ref # / Investigator 3857
city: Prague 1
country: Czech Republic
facility: Site Ref # / Investigator 3854
city: Prague 7
country: Czech Republic
facility: Site Ref # / Investigator 3855
city: Berlin
country: Germany
facility: Site Ref # / Investigator 3832
city: Essen
country: Germany
facility: Site Ref # / Investigator 13983
city: Jena
country: Germany
facility: Site Ref # / Investigator 3834
city: Kiel
country: Germany
facility: Site Ref # / Investigator 3833
city: Mainz
country: Germany
facility: Site Ref # / Investigator 3878
city: Munich
country: Germany
facility: Site Ref # / Investigator 3897
city: Budapest
country: Hungary
facility: Site Ref # / Investigator 3852
city: Budapest
country: Hungary
facility: Site Ref # / Investigator 3850
city: Gyor
country: Hungary
facility: Site Ref # / Investigator 3849
city: Bologna
country: Italy
facility: Site Ref # / Investigator 3876
city: Milan
country: Italy
facility: Site Ref # / Investigator 3848
city: Palermo
country: Italy
facility: Site Ref # / Investigator 3845
city: Rome
country: Italy
facility: Site Ref # / Investigator 6232
city: Rome
country: Italy
facility: Site Ref # / Investigator 3846
city: Eindhoven
country: Netherlands
facility: Site Ref # / Investigator 3873
city: Leiden
country: Netherlands
facility: Site Ref # / Investigator 3875
city: Lodz
country: Poland
facility: Site Ref # / Investigator 8061
city: Sopot
country: Poland
facility: Site Ref # / Investigator 13804
city: Warsaw
country: Poland
facility: Site Ref # / Investigator 8055
city: Ponce
country: Puerto Rico
facility: Site Ref # / Investigator 2392
city: San Juan
country: Puerto Rico
facility: Site Ref # / Investigator 2393
city: Banska Bystrica
country: Slovakia
facility: Site Ref # / Investigator 3839
city: Bratislava
country: Slovakia
facility: Site Ref # / Investigator 3838
city: Bratislava
country: Slovakia
facility: Site Ref # / Investigator 3841
city: Nitra
country: Slovakia
facility: Site Ref # / Investigator 3842
city: Presov
country: Slovakia
facility: Site Ref # / Investigator 14721
city: Trencin
country: Slovakia
facility: Site Ref # / Investigator 14521
city: Trnava
country: Slovakia
facility: Site Ref # / Investigator 3840
city: Gothenburg
country: Sweden
facility: Site Ref # / Investigator 8503
city: Linkoping
country: Sweden
facility: Site Ref # / Investigator 8504
city: Lund
country: Sweden
facility: Site Ref # / Investigator 8502
Study officials:
affiliation: Abbott
name: Roopal Thakkar, MD
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: 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: 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.
citation: 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.