Colitis, Ulcerative
Conditions
Brief 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.
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.
Interventions
BIOLOGICALInfliximab
Infliximab intravenous infusion at a dose of 5 mg/kg.
DRUGPrednisolone
Oral prednisolone 40 mg/day or 1 mg/kg/day depending upon participant response.
5-ASA administered orally at a dose of 2 g/day.
DRUGAzathioprine
AZA administered orally at a dose of 2.0-2.5 mg/kg/day.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Response at Week 4 and Steroid-Free Remission at Week 50 | Week 50 | Response at Week 4 was defined as a minimum decrease from baseline in Mayo score of 3 points and 30%. Steroid-free remission at Week 50 was defined as a total Mayo score (including endoscopic assessment) of 2 points or lower and no individual subscore exceeding 1. The Mayo score consists of the following 4 subscores: stool frequency; rectal bleeding; endoscopy results; physician's global assessment. Each subscore is rated on a scale from 0 (best) to 3 (worst). The total Mayo score is calculated as the sum of the 4 subscores and ranges from 0 (best) to 12 (worst). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieving Treatment Response | Up to Week 4 | Response was defined as a minimum decrease from baseline in total Mayo score of 3 points and 30% up to and including 4 weeks after the start of treatment. The Mayo score consists of the following 4 subscores: stool frequency; rectal bleeding; endoscopy results; physician's global assessment. Each subscore is rated on a scale from 0 (best) to 3 (worst). The total Mayo score is calculated as the sum of the 4 subscores and ranges from 0 (best) to 12 (worst). |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Top-Hold Level 1: Infliximab IV 5 mg/kg at Weeks 0, 2, and 6, and every 8 weeks thereafter. Level 2: Infliximab IV 5 mg/kg every 4 weeks. Level 3: Prednisolone induction + AZA 2.0-2.5 mg/kg/day. | 15 |
| Step-Up Level 1: Oral prednisolone (40 mg/day or 1 mg/kg/day in the case of non-response) + oral 5-aminosalicylic acid (5-ASA) 2 g/day. Level 2: Oral prednisolone (40 mg/day or 1 mg/kg/day in the case of non-response) + oral azathioprine (AZA) at a dose of 2.0-2.5 mg/kg/day. Level 3: Infliximab 5 mg/kg at Weeks 0, 2, and 6 and every 8 weeks thereafter. | 13 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Did Not Meet Randomization Criteria | 1 | 0 |
| Overall Study | Lack of Efficacy | 2 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Opportunistic Infection | 1 | 0 |
| Overall Study | Unknown Reason | 1 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Step-Up | Total | Top-Hold |
|---|---|---|---|
| Age, Continuous | 41.6 years STANDARD_DEVIATION 15.3 | 40.7 years STANDARD_DEVIATION 15 | 39.9 years STANDARD_DEVIATION 15.2 |
| Sex: Female, Male Female | 7 Participants | 17 Participants | 10 Participants |
| Sex: Female, Male Male | 6 Participants | 11 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 15 | 11 / 13 |
| serious Total, serious adverse events | 2 / 15 | 1 / 13 |
Outcome results
Primary
Number of Participants With Response at Week 4 and Steroid-Free Remission at Week 50
Response at Week 4 was defined as a minimum decrease from baseline in Mayo score of 3 points and 30%. Steroid-free remission at Week 50 was defined as a total Mayo score (including endoscopic assessment) of 2 points or lower and no individual subscore exceeding 1. The Mayo score consists of the following 4 subscores: stool frequency; rectal bleeding; endoscopy results; physician's global assessment. Each subscore is rated on a scale from 0 (best) to 3 (worst). The total Mayo score is calculated as the sum of the 4 subscores and ranges from 0 (best) to 12 (worst).
Time frame: Week 50
Population: The FAS consisted of all randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Top-Hold | Number of Participants With Response at Week 4 and Steroid-Free Remission at Week 50 | 5 Participants |
| Step-Up | Number of Participants With Response at Week 4 and Steroid-Free Remission at Week 50 | 5 Participants |
Secondary
Number of Participants Achieving Treatment Response
Response was defined as a minimum decrease from baseline in total Mayo score of 3 points and 30% up to and including 4 weeks after the start of treatment. The Mayo score consists of the following 4 subscores: stool frequency; rectal bleeding; endoscopy results; physician's global assessment. Each subscore is rated on a scale from 0 (best) to 3 (worst). The total Mayo score is calculated as the sum of the 4 subscores and ranges from 0 (best) to 12 (worst).
Time frame: Up to Week 4
Population: The full analysis set (FAS) consisted of all randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Top-Hold | Number of Participants Achieving Treatment Response | 10 Participants |
| Step-Up | Number of Participants Achieving Treatment Response | 10 Participants |