Ulcerative Colitis
Conditions
Brief summary
Part 1 of this study is a 3-arm, randomized, active-controlled, parallel-group, multicenter, double-blind, double-dummy, 16-week study to compare the efficacy and safety of infliximab (IFX), as monotherapy or in combination with azathioprine (AZA) versus AZA monotherapy in adults with moderate to severe active ulcerative colitis (UC). Participants who qualify at the Baseline Visit will be eligible to be randomized to one of the three active treatment groups. Participants in the IFX/AZA combination therapy and IFX monotherapy cohorts will receive IFX infusions at Weeks 0, 2, and 6 and daily oral AZA/placebo, respectively; participants in the AZA cohort will receive daily oral AZA and placebo infusions at Weeks 0, 2, and 6. At Week 8, all participants will be evaluated for response. Participants responding to IFX treatment at Week 8, either as monotherapy or in combination with AZA, will receive one more IFX infusion at Week 14; non-responders to IFX therapy will receive placebo infusions at Weeks 8 and 10 and one additional IFX infusion at Week 14. Participants responding to AZA monotherapy at Week 8 will continue on AZA therapy and receive one placebo infusion at Week 14; nonresponders to AZA will be eligible to receive IFX at Weeks 8, 10, and 14. Part 2: Participants in remission on IFX monotherapy or IFX/AZA treatment at Week 16 will be randomized to either maintenance or intermittent open-label IFX treatment; randomization will be stratified based on oral AZA/placebo treatment in Part 1. Oral AZA/placebo treatment will continue to be double-blinded. All participants will continue to receive oral AZA/ placebo for the duration of the study. Participants randomized to maintenance IFX treatment will receive scheduled IFX infusions every 8 weeks beginning at Week 22 (Week 6 for direct entry). If participants lose response, or if treatment has to be discontinued because of an adverse event, these participants are considered treatment failures, and should be followed up for safety at the scheduled 6-month visits (Weeks 38, 62, and 94 \[Weeks 22, 46, and 78 for direct entry\]). These participants will receive standard of care per their personal physician. Participants randomized to intermittent IFX treatment will be evaluated every 8 weeks. Participants will receive IFX only upon relapse of disease. Treatment with IFX will be initiated at Weeks 0, 2, and 6 of the individual treatment cycle and will continue every 8 weeks until remission is regained. Throughout the study, individual treatment cycles will be repeated whenever a subject relapses. In addition, to facilitate enrollment into Part 2, participants who received treatment outside of Part 1 and who are in remission on IFX with or without AZA/6-mercaptopurine (6-MP) will be allowed to enter directly into Part 2. In the Czech Republic, direct entry into Part 2 of the study is not allowed. A higher than expected incidence of serious infusion reactions observed in the intermittent treatment arm of another study (Protocol P04563, NCT0358670) conducted in participants with moderate to severe psoriasis resulted in the termination of that study. Based on the similarities in study design between the intermittent treatment arm of P04563 and the intermittent treatment arm of Part 2 of this study, enrollment to Part 2 of this study was put on hold, for precautionary reasons. At the same time, all participants already enrolled in the intermittent treatment arm of Part 2 were asked to discontinue from the trial. In October 2009, a decision was made by the sponsor to terminate the whole study (Part 1 and 2). At that time, participants enrolled in Part 1 of the study were allowed to complete their treatment up to Week 16.
Interventions
BIOLOGICALInfliximab (IFX)
IFX intravenous (IV) infusion dosed at 5mg/kg of body weight
AZA 50 mg tablet dosed at 2.5 mg/kg of body weight orally every day
Placebo to AZA tablet orally every day
DRUGPlacebo infusion
Placebo to IFX intravenous (IV) infusion
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* must be \>=21 years of age at the time of informed consent, of either sex, and of any race; * must have endoscopic evidence of UC, as determined by sigmoidoscopy, within 14 days prior to Baseline; * must have a total Mayo score of 6 to 12 points at Baseline; * must have responded inadequately to corticosteroid treatment (ie, the last or current UC flare did not respond adequately to a standard course of corticosteroids) with or without 5 aminosalicylic acid (5-ASA); * must be off corticosteroids or on a stable dose of corticosteroid for at least 2 weeks prior to enrollment. The maximal daily dose of corticosteroid at Baseline must not exceed the equivalent of 30 mg of prednisone; * must be naïve to infliximab and other tumor necrosis factor-alpha (TNF-α) antagonists; * must be either naïve to AZA/6-MP or have not received AZA/6-MP for at least 3 months before enrollment in the study; * considered eligible according to the following tuberculosis (TB) screening criteria: * have no history of latent or active TB prior to Screening; * have no signs or symptoms suggestive of active TB upon medical history and/or physical examination; * have had no recent close contact with a person with active TB or, if there has been such contact, will be referred to a physician specializing in TB to undergo additional evaluation and, if warranted, receive appropriate treatment for latent TB prior to or simultaneously with the first administration of IFX; * within 1 month prior to the first administration of infliximab, either have negative tuberculin skin test OR have a newly identified positive tuberculin test during Screening in which active TB has been ruled out, and for which appropriate treatment for latent TB has been initiated either prior to or simultaneously with the first administration of IFX. * must have a chest X-ray (posterior-anterior and lateral views), taken within 3 months prior to the first administration of study agent and read by a qualified radiologist, with no evidence of current active TB or old active TB; * have had UC for more than 10 years should have had a full colonoscopy within 2 years prior to Screening for the surveillance of dysplasia; * screening and Baseline clinical laboratory tests (complete blood count \[CBC\] and blood chemistries) must be within predetermined parameters * had been on antibiotics for the treatment of UC (eg, ciprofloxacin and metronidazole) must have been discontinued from them at least 3 weeks prior to Screening; * must be free of any clinically significant condition or situation, other than UC that, in the opinion of the investigator, would interfere with the study evaluations or optimal participation in the study; * willing and able to adhere to the study visit schedule and other protocol requirements; * capable of providing written informed consent, which must be obtained prior to conducting any protocol-specified procedures; * women of child-bearing potential and all men must agree to use a medically accepted method of contraception prior to screening, while receiving protocol-specified medication, and for 6 months after stopping the medication. Acceptable methods of contraception include condoms (male or female) with or without a spermicidal agent, diaphragm or cervical cap with spermicide, medically prescribed intrauterine device (IUD), oral or injectable hormonal contraceptive, and surgical sterilization (eg, hysterectomy or tubal ligation). Women of child-bearing potential who are not currently sexually active must agree to use a medically accepted method of contraception should they become sexually active while participating in the study; * female participants of childbearing potential must have a negative serum pregnancy test (beta-human chorionic gonadotropin) at Screening and a negative urine pregnancy test at Baseline.
Exclusion criteria
* have severe extensive colitis as evidenced by: * investigator judgment that the participant is likely to require colectomy within 12 weeks of Baseline OR * at least 4 of these symptoms at Screening or Baseline visits, as follows: * diarrhea with \>=6 bowel movements/day with macroscopic blood in stool; * focal severe or rebound abdominal tenderness; * persistent fever (\>=37.5 degrees C) for at least 3 days prior to baseline; * tachycardia (\>100 beats/minute); * hemoglobin \<8.5 g/dL (5.3 mM/L). * require, or are required within the 2 months prior to baseline, surgery for active gastrointestinal bleeding, peritonitis, intestinal obstruction, or intra-abdominal or pancreatic abscess requiring surgical drainage or other conditions possibly confounding the evaluation of disease activity; * have severe, fixed symptomatic stenosis of the large or small intestine; * have current evidence of colonic obstruction or history within the 6 months prior to baseline, confirmed with objective radiographic or endoscopic evidence of a stricture with resulting obstruction (dilation of the colon proximal to the stricture on barium radiograph or an inability to traverse the stricture at endoscopy); * have a history of colonic mucosal dysplasia; * presence on screening endoscopy of adenomatous colonic polyps, if not removed prior to study entry, or history of adenomatous colonic polyps that were not removed; * have the presence of a stoma; * have a history of extensive colonic resection that would prevent adequate evaluation of clinical disease activity (eg, less than 30 cm of colon remaining); * have had a positive stool culture for enteric pathogens, pathogenic ova or parasites within 4 months prior to Baseline unless participant has received treatment and had a negative stool examination 1 week or longer after the end of treatment; * have a concomitant diagnosis of congestive heart failure (CHF), including medically controlled asymptomatic subjects; * have had serious infections (eg, active hepatitis, pneumonia, or pyelonephritis) within 2 months of Screening. Less serious infections (such as acute upper respiratory tract infection \[colds\] or a simple urinary tract infection) need not be considered as an exclusion at the discretion of the investigator; * have had a nontuberculous mycobacterial infection or opportunistic infection (eg, cytomegalovirus, Pneumocystis carinii, aspergillosis) within 6 months prior to Screening; * have a known infection with human immunodeficiency virus (HIV) and/or hepatitis B or hepatitis C; * have a history of a known allergy to murine proteins or allergy/sensitivity to study drug or its excipients; * have current signs and symptoms of systemic lupus erythematosus, or severe, progressive, or uncontrolled renal, hepatic, hematologic, endocrine, pulmonary, cardiac, neurologic, or cerebral diseases; * have a known history of demyelinating disease suggestive of multiple sclerosis or optic neuritis; * presence of a transplanted organ (with the exception of a corneal transplant \>3 months prior to Screening); * have a history of lymphoproliferative disease including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy of unusual size or location (eg, nodes in the posterior triangle of the neck, infra-clavicular, epitrochlear, or periaortic areas), or splenomegaly; * have any current known malignancy or malignancy within 5 years prior to Screening (except for squamous or basal cell carcinoma of the skin that has been treated with no evidence of recurrence); * have poor tolerability of venipuncture or lack of adequate venous access for required blood sampling and infusion of study drug during the study period; * have had a known substance abuse or dependency (drug or alcohol) within 3 years of Screening; * require chronic (\>=1 month) and frequent use (\>=3 days per week)of nonsteroidal anti-inflammatory drugs (NSAIDs) except low-dose aspirin for prevention of heart attacks, unstable angina, or transient ischemic attacks; * have other inflammatory diseases that might interfere with the evaluation of the ulcerative colitis; * have a history of latent or active granulomatous infection, including TB, histoplasmosis, or coccidioidomycosis, prior to Screening. * have had a Bacille Calmette-Guerin (BCG) vaccination within 12 months of Screening. * have had a chest X-ray within the 3 months prior to the first administration of study agent that shows an abnormality suggestive of malignancy or current active infection, including TB. * have received any specified prohibited treatment more recently than the indicated washout period prior to Screening; * who are participating in any other clinical study or who have received treatment with any investigational drug or device within 3 months prior Screening; * who is part of the staff or a family member of the staff personnel directly involved with this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants in Steroid-free Remission at Week 16 | 16 weeks | Steroid-free remission is defined as a total Mayo score of 2 points or lower, with no individual sub-score exceeding 1 point, without the use of corticosteroids. The total Mayo score consists of the following 4 sub-scores: stool frequency, rectal bleeding, findings of endoscopy (sigmoidoscopy), and physician's global assessment. |
| Average Remission Rate During Part 2 of the Study | up to Week 94 (Week 78 for direct entry) | Due to the early termination of this study, evaluations of efficacy were not conducted for Part 2 of the study (Week 38 through Week 94 \[Week 22 through Week 78 for direct entry\]). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants in Response at Weeks 8 and 16 | Weeks 8 and 16 | Response at Week 8 is defined as a decrease in the partial Mayo score of ≥1 point. Response at Week 16 is defined as a decrease in total Mayo score of ≥3 points and at least 30% lower than baseline Mayo score. The partial Mayo score consists of the following 3 sub-scores: stool frequency, rectal bleeding, and physician's global assessment. The total Mayo score consists of the following 4 sub-scores: stool frequency, rectal bleeding, findings of endoscopy (sigmoidoscopy), and physician's global assessment. |
| Proportion of Participants Who Are in Steroid-free Remission During Part 2 of the Study | Weeks 38, 62 & 94 (Weeks 22, 46 and 78 for direct entry) | Due to the early termination of this study, evaluations of efficacy were not conducted for Part 2 of the study. |
| Proportion of Participants With Mucosal Healing at Week 16 | 16 weeks | Mucosal healing was defined as a Mayo endoscopy score of 0 or 1. |
| Proportion of Participants With Mucosal Healing During Part 2 of the Study | Weeks 38, 62 and 94 (Weeks 22, 46 and 78 for direct entry) | Due to the early termination of this study, evaluations of efficacy were not conducted for Part 2 of the study |
Participant flow
Pre-assignment details
2 participants were randomized but not treated. Part 1: 237 participants received ≥1 dose study medication. Part 2: Of 108 enrolled/randomized participants, 95 continued assigned treatment from Part 1 and 13 were randomized and entered into Part 2 of the study (10 participants from Part 1 and 3 participants who were enrolled directly into Part 2).
Participants by arm
| Arm | Count |
|---|---|
| Infliximab (IFX) All treated participants. IFX 5 mg/kg IV infusions administered at Weeks 0, 2, and 6 and placebo to AZA daily for 16 weeks. Responders to IFX at Week 8, will receive one more IFX infusion at Week 14; non-responders to IFX will receive placebo infusions at Weeks 8 and 10 and an additional IFX infusion at Week 14. | 78 |
| Azathioprine (AZA) All treated participants. AZA 2.5 mg/kg orally for 16 weeks and placebo to IFX infusion at Weeks 0, 2, and 6. Responders to AZA monotherapy at Week 8 will continue on AZA therapy and receive one infliximab placebo infusion at Week 14; non-responders to AZA at Week 8 will be eligible to receive infliximab at Weeks 8, 10, and 14. This group included 20 participants who did not respond to AZA monotherapy at Week 8 had IFX added to their treatment regimen at Weeks 8, 10, and 14. | 79 |
| IFX/AZA All treated participants. IFX 5 mg/kg IV at Weeks 0, 2, and 6 plus AZA 2.5 mg/kg orally daily for 16 weeks.
Responders to IFX/AZA at Week 8 will receive one more infliximab infusion at Week 14; non-responders to IFX/AZA will receive placebo IFX infusions at Weeks 8 and 10 and one additional IFX infusion at Week 14. | 80 |
| Maintenance IFX/AZA (During Part 2) Participants enrolled directly and randomized to maintenance IFX/AZA received IFX 5 mg/kg of body weight every 8 weeks (beginning at Week 22, Week 6 for direct entry) plus AZA 2.5 mg/kg of body weight daily in Part 2 of the study (4 participants from Part 1 of the study and 1 participant enrolled directly into Part 2 of the study). | 1 |
| Intermittent IFX/AZA (During Part 2) Participants enrolled directly and randomized to intermittent IFX/AZA received IFX 5 mg/kg of body weight only upon relapse of disease (initiated at Weeks 0, 2, and 6 of individual treatment cycle and continued every 8 weeks until remission was regained) plus AZA 2.5 mg/kg of body weight daily in Part 2 of the study (3 participants from Part 1 of the study and 1 participant enrolled directly into Part 2 of the study). | 1 |
| Intermittent IFX (During Part 2) Participants enrolled directly and randomized to intermittent IFX received IFX 5 mg/kg of body weight only upon relapse of disease (initiated at Weeks 0, 2, and 6 of individual treatment cycle and continued every 8 weeks until remission was regained) and placebo to AZA daily in Part 2 of the study (1 participant from Part 1 of the study and 1 participant enrolled directly into Part 2 of the study). | 1 |
| Total | 240 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Part 1 | Administrative | 0 | 0 | 2 | 0 | 0 | 0 | 0 |
| Part 1 | Adverse Event | 7 | 11 | 8 | 0 | 0 | 0 | 0 |
| Part 1 | Did not meet protocol eligibility | 1 | 3 | 2 | 0 | 0 | 0 | 0 |
| Part 1 | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part 1 | Protocol defined clinical event | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part 1 | Protocol Violation | 1 | 5 | 1 | 0 | 0 | 0 | 0 |
| Part 1 | Withdrawal by Subject | 3 | 8 | 4 | 0 | 0 | 0 | 0 |
| Part 2 | Administrative | 16 | 8 | 24 | 3 | 1 | 4 | 1 |
| Part 2 | Adverse Event | 4 | 0 | 2 | 0 | 0 | 0 | 0 |
| Part 2 | Lost to Follow-up | 1 | 0 | 2 | 0 | 0 | 0 | 0 |
| Part 2 | Never entered follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Part 2 | Withdrawal by Subject | 5 | 1 | 4 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Infliximab (IFX) | Azathioprine (AZA) | IFX/AZA | Maintenance IFX/AZA (During Part 2) | Intermittent IFX/AZA (During Part 2) | Intermittent IFX (During Part 2) | Total |
|---|---|---|---|---|---|---|---|
| Age, Customized <18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized 18 years to <65 years | 77 Participants | 76 Participants | 78 Participants | 1 Participants | 1 Participants | 1 Participants | 234 Participants |
| Age, Customized 65 years and older | 1 Participants | 3 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 6 Participants |
| Sex: Female, Male Female | 36 Participants | 46 Participants | 32 Participants | 0 Participants | 1 Participants | 1 Participants | 116 Participants |
| Sex: Female, Male Male | 42 Participants | 33 Participants | 48 Participants | 1 Participants | 0 Participants | 0 Participants | 124 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 27 / 79 | 17 / 80 | 17 / 78 | 8 / 42 | 3 / 20 | 13 / 72 | 9 / 74 | 3 / 5 | 1 / 2 | 2 / 4 | 0 / 2 | 2 / 10 | 12 / 48 | 6 / 37 |
| serious Total, serious adverse events | 5 / 79 | 4 / 80 | 3 / 78 | 0 / 42 | 1 / 20 | 0 / 72 | 5 / 74 | 0 / 5 | 0 / 2 | 0 / 4 | 0 / 2 | 1 / 10 | 0 / 48 | 3 / 37 |
Outcome results
Primary
Average Remission Rate During Part 2 of the Study
Due to the early termination of this study, evaluations of efficacy were not conducted for Part 2 of the study (Week 38 through Week 94 \[Week 22 through Week 78 for direct entry\]).
Time frame: up to Week 94 (Week 78 for direct entry)
Primary
Proportion of Participants in Steroid-free Remission at Week 16
Steroid-free remission is defined as a total Mayo score of 2 points or lower, with no individual sub-score exceeding 1 point, without the use of corticosteroids. The total Mayo score consists of the following 4 sub-scores: stool frequency, rectal bleeding, findings of endoscopy (sigmoidoscopy), and physician's global assessment.
Time frame: 16 weeks
Population: Full Analysis Set (participants who were randomized, received at least one dose of study treatment, and had data available for baseline and at least one post baseline evaluation). Participants who dropped out prior to Week 16, had a missing Mayo score at Week 16, or were non-responders at Week 8 are considered failures (non-remission) at Week 16.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Infliximab (IFX) | Proportion of Participants in Steroid-free Remission at Week 16 | 0.22 Proportion of participants |
| Azathioprine (AZA) | Proportion of Participants in Steroid-free Remission at Week 16 | 0.24 Proportion of participants |
| IFX/AZA | Proportion of Participants in Steroid-free Remission at Week 16 | 0.40 Proportion of participants |
p-value: 0.032Chi-squared
Secondary
Proportion of Participants in Response at Weeks 8 and 16
Response at Week 8 is defined as a decrease in the partial Mayo score of ≥1 point. Response at Week 16 is defined as a decrease in total Mayo score of ≥3 points and at least 30% lower than baseline Mayo score. The partial Mayo score consists of the following 3 sub-scores: stool frequency, rectal bleeding, and physician's global assessment. The total Mayo score consists of the following 4 sub-scores: stool frequency, rectal bleeding, findings of endoscopy (sigmoidoscopy), and physician's global assessment.
Time frame: Weeks 8 and 16
Population: Full Analysis Set (participants who were randomized, received at least one dose of study treatment, and had data available for baseline and at least one post baseline evaluation). Participants who dropped out prior to Week 16, had a missing Mayo score at Week 16, or were non-responders at Week 8 are considered failures (non-responders) at Week 16.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Infliximab (IFX) | Proportion of Participants in Response at Weeks 8 and 16 | Week 8 | 0.88 Proportion of participants |
| Infliximab (IFX) | Proportion of Participants in Response at Weeks 8 and 16 | Week 16 | 0.69 Proportion of participants |
| Azathioprine (AZA) | Proportion of Participants in Response at Weeks 8 and 16 | Week 8 | 0.66 Proportion of participants |
| Azathioprine (AZA) | Proportion of Participants in Response at Weeks 8 and 16 | Week 16 | 0.50 Proportion of participants |
| IFX/AZA | Proportion of Participants in Response at Weeks 8 and 16 | Week 8 | 0.86 Proportion of participants |
| IFX/AZA | Proportion of Participants in Response at Weeks 8 and 16 | Week 16 | 0.77 Proportion of participants |
Secondary
Proportion of Participants Who Are in Steroid-free Remission During Part 2 of the Study
Due to the early termination of this study, evaluations of efficacy were not conducted for Part 2 of the study.
Time frame: Weeks 38, 62 & 94 (Weeks 22, 46 and 78 for direct entry)
Secondary
Proportion of Participants With Mucosal Healing at Week 16
Mucosal healing was defined as a Mayo endoscopy score of 0 or 1.
Time frame: 16 weeks
Population: Full Analysis Set (participants who were randomized, received at least one dose of study treatment, and had data available for baseline and at least one post baseline evaluation).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Infliximab (IFX) | Proportion of Participants With Mucosal Healing at Week 16 | 0.55 Proportion of participants |
| Azathioprine (AZA) | Proportion of Participants With Mucosal Healing at Week 16 | 0.37 Proportion of participants |
| IFX/AZA | Proportion of Participants With Mucosal Healing at Week 16 | 0.63 Proportion of participants |
Secondary
Proportion of Participants With Mucosal Healing During Part 2 of the Study
Due to the early termination of this study, evaluations of efficacy were not conducted for Part 2 of the study
Time frame: Weeks 38, 62 and 94 (Weeks 22, 46 and 78 for direct entry)