Conventional Step-Up Versus Infliximab Monotherapy in Patients With Ulcerative Colitis (P05553 AM2)
Information source: Merck Sharp & Dohme Corp.
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Colitis, Ulcerative
Intervention: Infliximab (Biological); Prednisolone (Drug); 5-aminosalicylic acid (Drug); Azathioprine (Drug)
Phase: Phase 3
Status: Terminated
Sponsored by: Merck Sharp & Dohme Corp.
Summary
This study will be performed to compare the efficacy and safety of the classical "Step-Up"
approach for treatment of moderate-to-severe active ulcerative colitis using oral
prednisolone + oral 5-aminosalicylic acid (5-ASA) or oral prednisolone + oral azathioprine
(AZA) with a more intensive and early "Top-Hold" approach with intravenous infliximab (5
mg/kg) administered at Weeks 0, 2, and 6 and 8 weeks thereafter.
Clinical Details
Official title: Conventional Step-Up Versus Infliximab Monotherapy in Patients With Active Moderate to Severe Ulcerative Colitis. A Randomized, Open Label, Prospective, Multicenter Study
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Number of Participants With Response at Week 4 and Steroid-Free Remission at Week 50
Secondary outcome: Number of Participants Achieving Treatment Response
Detailed description:
Participants will be randomized to receive either intravenous (IV) infliximab monotherapy
(Top-Hold approach) starting at a dose of 5 mg/kg at Weeks 0, 2, and 6 and thereafter every
8 weeks in Level 1, or classical Step-Up treatment starting with oral prednisolone (40
mg/day for at least 3 days and at most 2 weeks followed by 1 mg/kg/day for a minimum of 7
days and up to 2 weeks in the case the participant does not show an improvement in clinical
symptoms under 40 mg/day treatment) + oral 5-aminosalicylic acid (5-ASA) at a dose of 2
g/day in Level 1.
Participants receiving Step-Up treatment who have not achieved adequate response during the
first 4 weeks of prednisolone treatment will directly enter Level 3 treatment after
endoscopy is performed to confirm treatment eligibility. Furthermore, participants that have
not achieved response at Week 4 will also directly enter Level 3 and be switched to
treatment with IV infliximab.
If a participant experiences a first flare after initial response, participants in the
Step-Up group will start prednisolone treatment at the last effective dose (i. e.,
participants that previously responded to prednisolone 40 mg/day will receive a dose of 40
mg/day for at least 3 days and up to 2 weeks; participants that previously responded to
prednisolone 1 mg/kg/day will receive a dose of 1 mg/kg/day for a minimum of 7 days and up
to 2 weeks). If the last effective dose was 40 mg/day and the participant does not respond
within 14 days, the dose will be adjusted to 1 mg/kg/day for a minimum of 7 days and up to 2
weeks. In case the participant does not respond to prednisolone (i. e., does not return to
their individual baseline partial Mayo score obtained at study Week 4), the participant will
enter Level 3 and receive treatment with IV infliximab.
If a participant experiences a second flare after initial response at Week 4 (Level 1), the
participant will enter treatment Level 2. In Level 2, participants will receive a
prednisolone induction at the same effective dose as previously used in Level 1 +
maintenance treatment with oral azathioprine (AZA) at a dose of 2. 0-2. 5 mg/kg/day.
Participants that do not respond to this treatment at Level 2 or that develop a further
flare after initial response at Level 2 will enter Level 3 and will receive treatment with
IV infliximab following endoscopy to confirm treatment eligibility.
If at any time during treatment, a participant becomes prednisolone dependent (i. e., flare
during tapering phase of prednisolone), the participant will enter Level 3 treatment with IV
infliximab.
Participants in Level 1 of the Top-Hold treatment group (IV infliximab at Week 0, 2, and 6
and every 8 weeks thereafter) that have not achieved response at Week 4 will receive IV
infliximab 5 mg/kg at reduced intervals of 4 weeks (Level 2) starting with the Week 10
infusion. Participants suffering a flare after initial response in Level 1 will be switched
to to Level 2. Participants that do not respond to treatment at reduced intervals after 3
infusions (12 weeks), or that develop a further flare after initial response at Level 2,
will be switched to treatment with oral prednisolone + AZA (Level 3) following colonoscopy
to confirm eligibility.
When a participant responds to treatment with IV infliximab in Level 2, they will return to
treatment with IV infliximab every 8 weeks when response is achieved at 3 consecutive
visits.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- Any race or ethnicity
- Must have a diagnosis of moderate-to-severe active ulcerative colitis (UC) with
inflammation present beyond the rectum and including more than 20 cm of the colon
(Mayo score of 6 to 12 points, inclusive ≥ 2 in the endoscopy subscore)
- Must have responded inadequately to oral (with or without topical) 5-ASA treatment
(prerequisite oral: at a minimum 4 g/d for 7 days) and must be considered for the
first course of systemic corticosteroids; Participants with a UC and a Mayo score of
≥ 9 are also eligible without prior 5-ASA treatment
- Must agree to use acceptable methods of contraception for at least 2 weeks prior to
starting any study treatment and to continue until at least 6 months after the last
doses of study drugs
- Laboratory results must be within specified limits
- Must be negative for colorectal cancer or any associated lesions
- Must have a negative tuberculosis (TB) test
- Must have a chest x-ray within the 3 months with no clinically significant
abnormality, or evidence of current active TB or latent TB
- Must have a negative stool culture
Exclusion Criteria:
- Pregnant, nursing, or planning pregnancy
- Had received previous treatment for UC with the corticosteroids, infliximab,
azathioprine/
6-mercaptopurine (6-MP), cyclosporine, tacrolimus, methotrexate, sirolimus,
mycophenolate, any tumor necrosis factor-alpha (TNF-α) inhibitor or receptor
constructs that bind to ΤΝF-α (e. g., etanercept or adalimumab) and any other biologic
agents
- Frequent (chronic) use of non-steroidal anti-inflammatory drugs (NSAIDs)
- Use of laxatives or any murine recombinant product
- Had surgery for active gastrointestinal bleeding, peritonitis, intestinal
obstruction, or intra-abdominal or pancreatic abscess requiring surgical drainage in
previous 2 months
- History of colonic obstruction within the previous 6 months
- History of mucosal dysplasia, fistula or colonic resection, adenomatous polyps or
stoma, severe, fixed symptomatic stenosis of the large or small intestine
- Had serious infection with previous 2 months, including human immunodeficiency virus
(HIV) and hepatitis
- Had organ transplant (with the exception of a corneal transplant)
- Any malignancy within 5 years, including lymphoma
- History of demyelinating disease such as multiple sclerosis or optic neuritis
- Presence or history of congestive heart failure
- Requires chronic and frequent use of antimotility agents for control of diarrhea
- Requires total parenteral nutrition
- Had participated in any other clinical trial within 30 days or intention to
participate in another clinical trial during participation in this study
Locations and Contacts
Additional Information
Starting date: November 2009
Last updated: October 30, 2014
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