Ulcerative Colitis
Conditions
Keywords
ulcerative colitis, inflammatory bowel disease
Brief summary
The proposed study will test whether increasing Lialda dose can reduce fecal calprotectin (FCP) levels, a marker of intestinal inflammation that is highly predictive of the risk of relapse among patients with quiescent ulcerative colitis. Sixty patients with FCP levels \<50µg/g stool will be observed for 48 weeks. All patients will have FCP concentration measured using a commercially available assay at enrollment, 6 weeks and 12 weeks. All patients with persistently elevated FCP will receive one or both of the following interventions: change in the mesalamine formulation to Lialda and/or increase in the dose of Lialda. Reduction in FCP levels below 50µg/g stool 6 weeks after randomization will be the primary outcome. The proportion of patients achieving this outcome will be compared between groups using Fisher's exact test. All randomized patients as well as those who were excluded from the randomized trial because of a low FCP concentration at baseline will be followed to week 48 to determine the rate of clinical relapse.
Detailed description
Among patients with quiescent ulcerative colitis (UC), lower fecal concentrations of calprotectin are associated with lower rates of relapse. We performed an open-label, randomized controlled trial to investigate whether increasing doses of mesalamine reduce concentrations of fecal calprotectin (FC) in patients with quiescent UC. We screened 119 patients with UC in remission on the basis of Simple Clinical Colitis Activity Index scores, FC \>50 µg/g, and intake of no more than 3 g/day mesalamine. Participants taking mesalamine formulations other than multimatrix mesalamine were switched to multimatrix mesalamine (2.4 g/day) for 6 weeks; 52 participants were then randomly assigned (1:1) to a group that continued its current dose of mesalamine (controls, n = 26) or a group that increased its dose by 2.4 g/day for 6 weeks (n = 26). The primary outcome was continued remission with FC \<50 µg/g. Secondary outcomes were continued remission with FC \<100 µg/g or \<200 µg/g (among patients with pre-randomization values above these levels).
Interventions
DRUGmesalamine
Increase dose by 2.4gm per day over baseline dose
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Shire
James Lewis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Understand and sign the informed consent form. 2. Have documented ulcerative colitis on the basis of usual diagnostic criteria including clinical symptoms and findings from endoscopy, radiology studies, and histology. 3. Have a Simple Clinical Colitis Activity Index (SCCAI)55 score below 3 with no category value greater than 1 (Table 5). 4. Three or fewer bowel movements per 24 hours at the time of enrollment. 5. No visible blood in their bowel movements in the three days prior to enrollment. 6. Have either been on a stable dose of mesalamine medication (oral, rectal or a combination of oral and rectal, including sulfasalazine) or on no mesalamine medications for at least 4 weeks prior to enrollment. 7. Have been on either a stable dose of azathioprine, 6-mercaptopurine, or methotrexate or on none of these medications for at least 8 weeks prior to enrollment. 8. Have experienced at least one flare of ulcerative colitis in the 2 years prior to enrollment. A flare is defined as an increase in stool frequency, bleeding, urgency and/or abdominal discomfort sufficient to warrant a change in medication dose or addition of a new medication. 9. Most recently measured serum creatinine level in the preceding year less than 1.5 mg/dL.
Exclusion criteria
1. Age less than 18 2. Inability to speak and read English 3. Presence of an ostomy or prior total or subtotal colectomy 4. Current corticosteroid use or use within the two weeks prior to enrollment 5. Remission for less than 4 weeks prior to enrollment 6. Previous intolerance to mesalamine at doses greater than the current dose. 7. Use of rectally administered mesalamine or steroids within the 2 weeks prior to enrollment. 8. Currently taking more than 3.0 gm/day of mesalamine (oral or rectal). If on oral and rectal mesalamine, the combined dose is more than 3.0 gm/day. 9. Use of anti-TNFα therapies within the 8 weeks prior to enrollment and/or intent to use anti-TNFα therapies as maintenance therapy in the coming 12 weeks. 10. Pregnant or breast feeding women. 11. Use of an experimental therapy for ulcerative colitis in the 8 weeks prior to enrollment. 12. Any condition that the investigator feels will make completion of the study unlikely. 13. Use of cyclosporine in the two weeks prior to enrollment. 14. Moderate or severe abdominal tenderness on examination at time of enrollment.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Fecal Calprotectin Level <50µg/g | 6 weeks after randomization |
Secondary
| Measure | Time frame |
|---|---|
| Fecal Calprotectin Level <100 µg/g | at 6 weeks after randomization |
| Fecal Calprotectin <200 µg/g | at 6 weeks after randomization |
Countries
United States
Participant flow
Recruitment details
We screened 150 patients and enrolled 119 patients with UC in remission on the basis of SCCAI score. 58 patients had baseline fecal calprotectin(FC) \<50 µg/g. These patients were followed in an observational arm. 61 had FC \>= 50 µg/g,whose current mesalamine dose \<3g/day. See preassignment details.
Pre-assignment details
Among 61 pts with FC \>=50 µg/g at week 0, 26 were taking non-MMX mesalamine at baseline and switched to MMX mesalamine 2.4g/day. Of these, by week 6, 2 had a repeat FC \<50 µg/g, 3 had a flare of UC and 4 were noncompliant with study protocol or no longer interested in participating. The remaining 52 patients were included in the randomized trial.
Participants by arm
| Arm | Count |
|---|---|
| Increase Mesalamine Dose Participants were randomized to increase dose of mesalamine by 2.4 gm per day over their baseline dose | 26 |
| Maintain Mesalamine Dose Participants were randomized to maintain their baseline mesalamine dose | 26 |
| Total | 52 |
Baseline characteristics
| Characteristic | Increase Mesalamine Dose | Total | Maintain Mesalamine Dose |
|---|---|---|---|
| Age, Continuous | 43.8 years | 46.5 years | 48.8 years |
| Current rectal mesalamine No | 24 participants | 48 participants | 24 participants |
| Current rectal mesalamine Yes | 2 participants | 4 participants | 2 participants |
| Current thiopurine No | 20 participants | 42 participants | 22 participants |
| Current thiopurine Yes | 6 participants | 10 participants | 4 participants |
| Currrent oral mesalamine MMX formulation | 14 participants | 26 participants | 12 participants |
| Currrent oral mesalamine None | 4 participants | 9 participants | 5 participants |
| Currrent oral mesalamine Non-MMX formulation | 8 participants | 17 participants | 9 participants |
| Extent of disease Extensive | 9 participants | 20 participants | 11 participants |
| Extent of disease Left-sided | 9 participants | 21 participants | 12 participants |
| Extent of disease Other | 0 participants | 1 participants | 1 participants |
| Extent of disease Proctitis | 8 participants | 10 participants | 2 participants |
| Median duration of UC | 11.9 years | 8.9 years | 6.5 years |
| Median fecal calprotectin immediately before randomization | 174 µg/g | 195 µg/g | 214 µg/g |
| Median of duration of remission at baseline | 0.3 years | 0.4 years | 0.5 years |
| Prior anti-tumor necrosis factor agent No | 24 participants | 50 participants | 26 participants |
| Prior anti-tumor necrosis factor agent Yes | 2 participants | 2 participants | 0 participants |
| Prior corticosteroids No | 15 participants | 24 participants | 9 participants |
| Prior corticosteroids Yes | 11 participants | 28 participants | 17 participants |
| Prior cyclosporine No | 26 participants | 51 participants | 25 participants |
| Prior cyclosporine Yes | 0 participants | 1 participants | 1 participants |
| Prior rectal corticosteroids No | 20 participants | 39 participants | 19 participants |
| Prior rectal corticosteroids Yes | 6 participants | 13 participants | 7 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 22 Participants | 43 Participants | 21 Participants |
| Region of Enrollment United States | 26 participants | 52 participants | 26 participants |
| Sex: Female, Male Female | 11 Participants | 24 Participants | 13 Participants |
| Sex: Female, Male Male | 15 Participants | 28 Participants | 13 Participants |
| Tobacco use Current | 0 participants | 2 participants | 2 participants |
| Tobacco use Never | 20 participants | 36 participants | 16 participants |
| Tobacco use Prior | 6 participants | 14 participants | 8 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 26 | 7 / 26 |
| serious Total, serious adverse events | 0 / 26 | 0 / 26 |
Outcome results
Primary
Fecal Calprotectin Level <50µg/g
Time frame: 6 weeks after randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Increase Mesalamine Dose by 2.4g/Day | Fecal Calprotectin Level <50µg/g | 7 participants |
| Maintain Mesalmine Dose | Fecal Calprotectin Level <50µg/g | 1 participants |
Secondary
Fecal Calprotectin <200 µg/g
Time frame: at 6 weeks after randomization
Population: 25 participants with baseline FC\>=200ug/g
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Increase Mesalamine Dose by 2.4g/Day | Fecal Calprotectin <200 µg/g | 10 participants |
| Maintain Mesalmine Dose | Fecal Calprotectin <200 µg/g | 2 participants |
Secondary
Fecal Calprotectin Level <100 µg/g
Time frame: at 6 weeks after randomization
Population: 38 participants with baseline FC\>=100ug/g
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Increase Mesalamine Dose by 2.4g/Day | Fecal Calprotectin Level <100 µg/g | 10 participants |
| Maintain Mesalmine Dose | Fecal Calprotectin Level <100 µg/g | 3 participants |