Ulcerative Colitis
Conditions
Brief summary
This study is a prospective clinical study to evaluate the safety and efficacy of two different doses of Asacol for the treatment of moderately active ulcerative colitis. In addition, a new tablet formulation will be evaluated at one of the two doses.
Interventions
DRUGAsacol 800 mg (mesalamine)
tablets, 4.8 g/day for 6 weeks, 2 - 800 mg Asacol tablets and 2 placebo tablets 3 times daily
DRUGAsacol 400 mg (mesalamine)
tablets, 2.4 g/day for 6 weeks, 2 - 400 mg Asacol tablets and 2 placebo tablets 3 times daily
Sponsors
Warner Chilcott
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* male or female between 18 and 75 years of age; * have a confirmed diagnosis of ulcerative colitis with the extent varying from proctitis to pancolitis; * currently demonstrating moderately active disease
Exclusion criteria
Patients will be excluded from admission to the study if they have/are: * a history of allergy or hypersensitivity to salicylates or aminosalicylates; * a history of extensive small bowel resection (\>1/2 the length of the small intestine) causing short bowel syndrome; * current renal or hepatic disease; * participated in any drug or device clinical study within 30 days of entry; * currently enrolled in any other clinical study; * received any oral, intravenous, intramuscular, or rectally administered corticosteroids within 1 month prior to the Baseline Visit; * received any other topical rectal therapy during the week prior to the Screening Visit; * received immunomodulatory therapy including, but not limited to, 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate within 3 months prior to the Baseline Visit; * received a dose of mesalamine-containing compound by any route from which more than 1.6 g/day of mesalamine was available within 1 week prior to the Screening Visit (NOTE: 4 g/day of sulfasalazine and 4.5 g/day of balsalazide are equivalent to 1.6 g/day of mesalamine); * received antibiotics, other than topical antibiotics, within 1 week prior to the Screening Visit; * received aspirin (except for cardioprotective reasons up to a maximum dose of 325 mg/day) or NSAIDs within 1 week prior to the Baseline Visit; * if female, positive pregnancy test, or lactating.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Treatment Success Patients at Week 6, ITT (Intent to Treat) Population | 6 Weeks | Treatment success defined as complete response (PGA score 0 and complete resolution of stool frequency, rectal bleeding, PFA (patient's functional assessment), normal sigmoidoscopy) or partial response (improvement from baseline PGA and improvement in 1 clinical assessment \[stool frequency, rectal bleeding, PFA, sigmoidoscopy\] and no worsening in any other clinical assessments) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Whose Rectal Bleeding & Sigmoidoscopy Score Both Improved From Baseline to Week 6, ITT Population | 6 Weeks | Rectal Bleeding - 0=no blood seen, 1=streaks of blood w/stool less than half of the time, 2=obvious blood w/stool most of the time, 3=blood alone passed Sigmoidoscopy Assessment Score - 0=normal (intact vascular pattern, no friability or granularity), 1=mild (erythema, diminished or absent vascular markings; mild granularity; friability), 2=moderate (marked erythema, granularity; absent vascular markings; bleeds with minimal trauma; no ulcerations) 3=severe (spontaneous bleeding, ulcerations) |
| Percentage of Patients Whose Sigmoidoscopy Score Improved From Baseline to Week 6, ITT Population | 6 Weeks | Sigmoidoscopy Assessment Score (0=normal intact vascular pattern, no friability or granularity, 1=mild erythema; diminished or absent vascular markings; mild granularity; friability, 2=moderate marked erythema, granularity; absent vascular markings; bleeds with minimal trauma; no ulcerations, 3=severe spontaneous bleeding, ulcerations) |
| Percentage of Patients With an Improvement in Stool Frequency, ITT Population, Week 6 | 6 Weeks | 0=Normal stool frequency per day, 1=1-2 stools greater than normal per day, 2=3-4 stools greater than normal per day, 3=5 or more stools greater than normal per day |
| Percentage of Patients With Improvement in Rectal Bleeding, ITT Population, Week 6 | 6 Weeks | Rectal Bleeding (0=no blood seen, 1=streaks of blood with stool less than half of the time, 2=obvious blood with stool most of the time, 3=blood alone passed) |
| Percentage of Patients With Improvement in Patient's Functional Assessment (PFA), ITT Population, Week 6 | 6 Weeks | PFA - 0=generally well, 1=fair, 2=poor, 3=terrible |
| Change From Baseline in Ulcerative Colitis Disease Activity Index (UCDAI) at Week 6, ITT Population | 6 weeks | UCDAI - sum of clinical assessment scores (stool frequency score \[0=normal, 1=1-2 stools \> normal/day, 2=3-4 stools \> normal/day, 3=5 or more stools \> normal/day\], rectal bleeding score \[0=no blood seen, 1=streaks of blood with stool less than half of the time, 2=obvious blood with stool most of the time, 3=blood alone passed and PGA score \[0=quiescent disease, 1=mild, 2=moderate, 3=severe\]) and sigmoidoscopy score \[0=normal, 1=mild, 2=moderate, 3=severe\] |
| Mean Change From Baseline in Total Inflammatory Bowel Disease Questionnaire (IBDQ) at Week 3, All Randomized Patients | 3 Weeks | IBDQ-32 questions divided into 4 categories: bowel, systemic, emotional and social. Each question graded with the following responses: 1-more than ever before, 2-extremely frequently, 3-very frequently, 4-moderate increase in frequency, 5-some increase in frequency, 6-slight increase in frequency or 7-not at all/normal; 1/worst thru 7/best. Scoring 32 - 224 - higher score better. |
| Mean Change From Baseline in Total Inflammatory Bowel Disease Questionnaire (IBDQ) at Week 6, All Randomized Patients | 6 Weeks | IBDQ-32 questions divided into 4 categories: bowel, systemic, emotional and social. Each question graded with the following responses: 1-more than ever before, 2-extremely frequently, 3-very frequently, 4-moderate increase in frequency, 5-some increase in frequency, 6-slight increase in frequency or 7-not at all/normal; 1/worst thru 7/best. Scoring 32-224 - higher score better. |
| Percentage of Patients With Moderate, Left-Sided Disease at Baseline Classified as Treatment Success at Week 6, All Randomized Patients | 6 Weeks | Treatment success defined as complete response (PGA score 0 and complete resolution of stool frequency, rectal bleeding, PFA (patient's functional assessment), normal sigmoidoscopy) or partial response (improvement from baseline PGA and improvement in 1 clinical assessment \[stool frequency, rectal bleeding, PFA, sigmoidoscopy\] and no worsening in any other clinical assessments) |
| Percentage of Treatment Success Patients at Week 3, ITT Population | 3 Weeks | Treatment success defined as complete response (PGA score 0 and complete resolution of stool frequency, rectal bleeding, PFA (patient's functional assessment), normal sigmoidoscopy) or partial response (improvement from baseline PGA and improvement in 1 clinical assessment \[stool frequency, rectal bleeding, PFA, sigmoidoscopy\] and no worsening in any other clinical assessments) |
| Percentage of Patients With Improvement in Physician Global Assessment (PGA)Score, ITT Population, Week 6 | 6 Weeks | PGA -Physician's Global Assessment - 0=quiescent disease (all parameters 0), 1=mild disease (parameters mostly 1's) 2=moderate (parameters mostly 2's), 3=severe (parameters mostly 3's) \[parameters: combination of stool frequency, rectal bleeding, PFA & sigmoidoscopy findings\] If scoring equal default to physician judgement. |
Countries
Canada, Puerto Rico, United States
Participant flow
Recruitment details
Recruitment began Feb. 28, 2001. Randomized 386 patients of which 117 had mild disease and 268 had moderate disease at baseline. Analysis only includes patients with moderate disease at baseline.
Participants by arm
| Arm | Count |
|---|---|
| Asacol 2.4 g/Day Two 400 mg Asacol tablets and 2 placebo tablets (matching 800 mg formulation) taken 3 times daily (morning, midday, evening). | 139 |
| Asacol 4.8 g/Day Two 800 mg Asacol tablets and 2 placebo tablets (matching 400 mg formulation) taken 3 times daily (morning, midday, evening). | 129 |
| Total | 268 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 4 |
| Overall Study | Lack of Efficacy | 11 | 5 |
| Overall Study | Physician Decision | 3 | 1 |
| Overall Study | Protocol Violation | 2 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 5 |
Baseline characteristics
| Characteristic | Asacol 2.4 g/Day | Asacol 4.8 g/Day | Total |
|---|---|---|---|
| Age, Customized 18 - 64 years | 126 Participants | 118 Participants | 244 Participants |
| Age, Customized >= 65 years | 13 Participants | 11 Participants | 24 Participants |
| Race/Ethnicity, Customized Asian (Indian) | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian (Oriental) | 1 Participants | 3 Participants | 4 Participants |
| Race/Ethnicity, Customized Black or African American | 11 Participants | 14 Participants | 25 Participants |
| Race/Ethnicity, Customized Caucasian | 108 Participants | 96 Participants | 204 Participants |
| Race/Ethnicity, Customized Hispanic | 16 Participants | 11 Participants | 27 Participants |
| Race/Ethnicity, Customized Multi-racial/other | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Female | 77 Participants | 75 Participants | 152 Participants |
| Sex: Female, Male Male | 62 Participants | 54 Participants | 116 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 72 / 195 | 81 / 191 |
| serious Total, serious adverse events | 4 / 139 | 1 / 129 |
Outcome results
Primary
Percentage of Treatment Success Patients at Week 6, ITT (Intent to Treat) Population
Treatment success defined as complete response (PGA score 0 and complete resolution of stool frequency, rectal bleeding, PFA (patient's functional assessment), normal sigmoidoscopy) or partial response (improvement from baseline PGA and improvement in 1 clinical assessment \[stool frequency, rectal bleeding, PFA, sigmoidoscopy\] and no worsening in any other clinical assessments)
Time frame: 6 Weeks
Population: ITT Population with Moderate Disease \[PGA = 2\] at Baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Asacol 2.4 g/Day | Percentage of Treatment Success Patients at Week 6, ITT (Intent to Treat) Population | 59.2 Percentage of Participants |
| Asacol 4.8 g/Day | Percentage of Treatment Success Patients at Week 6, ITT (Intent to Treat) Population | 71.8 Percentage of Participants |
Comparison: It was assumed that true rate of improvement for 2.4 g/day treatment group is 40% and for the 4.8 g/day group is 60%. To detect a true difference of 20% between these 2 groups with 2-sided test, type I error of 0.05 (alpha = 0.05), and power of 80%, 120 patients with moderately active ulcerative colitis were required per group to complete the study.p-value: 0.035795% CI: [0.96, 24.12]Chi-squared
Secondary
Change From Baseline in Ulcerative Colitis Disease Activity Index (UCDAI) at Week 6, ITT Population
UCDAI - sum of clinical assessment scores (stool frequency score \[0=normal, 1=1-2 stools \> normal/day, 2=3-4 stools \> normal/day, 3=5 or more stools \> normal/day\], rectal bleeding score \[0=no blood seen, 1=streaks of blood with stool less than half of the time, 2=obvious blood with stool most of the time, 3=blood alone passed and PGA score \[0=quiescent disease, 1=mild, 2=moderate, 3=severe\]) and sigmoidoscopy score \[0=normal, 1=mild, 2=moderate, 3=severe\]
Time frame: 6 weeks
Population: ITT Population with Moderate Disease \[PGA = 2\] at Baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Asacol 2.4 g/Day | Change From Baseline in Ulcerative Colitis Disease Activity Index (UCDAI) at Week 6, ITT Population | -3.2 Scores on a Scale | Standard Error 0.27 |
| Asacol 4.8 g/Day | Change From Baseline in Ulcerative Colitis Disease Activity Index (UCDAI) at Week 6, ITT Population | -3.7 Scores on a Scale | Standard Error 0.27 |
p-value: 0.159495% CI: [-1.28, 0.21]ANOVA
p-value: <0.0001t-test, 2 sided
p-value: <0.0001t-test, 2 sided
Secondary
Mean Change From Baseline in Total Inflammatory Bowel Disease Questionnaire (IBDQ) at Week 3, All Randomized Patients
IBDQ-32 questions divided into 4 categories: bowel, systemic, emotional and social. Each question graded with the following responses: 1-more than ever before, 2-extremely frequently, 3-very frequently, 4-moderate increase in frequency, 5-some increase in frequency, 6-slight increase in frequency or 7-not at all/normal; 1/worst thru 7/best. Scoring 32 - 224 - higher score better.
Time frame: 3 Weeks
Population: All Randomized Patients with Moderate Disease\[PGA=2\] at Baseline. Questionnaire analyzable if patient answered 28 of 32 for total, 8/10 for bowel, 3/5 for systemic, 10/12 for emotional, 3/5 for social.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Asacol 2.4 g/Day | Mean Change From Baseline in Total Inflammatory Bowel Disease Questionnaire (IBDQ) at Week 3, All Randomized Patients | 30.4 Scores on a Scale | Standard Error 2.84 |
| Asacol 4.8 g/Day | Mean Change From Baseline in Total Inflammatory Bowel Disease Questionnaire (IBDQ) at Week 3, All Randomized Patients | 29.8 Scores on a Scale | Standard Error 2.6 |
p-value: 0.8308Wilcoxon (Mann-Whitney)
p-value: <0.0001t-test, 2 sided
p-value: <0.0001t-test, 2 sided
Secondary
Mean Change From Baseline in Total Inflammatory Bowel Disease Questionnaire (IBDQ) at Week 6, All Randomized Patients
IBDQ-32 questions divided into 4 categories: bowel, systemic, emotional and social. Each question graded with the following responses: 1-more than ever before, 2-extremely frequently, 3-very frequently, 4-moderate increase in frequency, 5-some increase in frequency, 6-slight increase in frequency or 7-not at all/normal; 1/worst thru 7/best. Scoring 32-224 - higher score better.
Time frame: 6 Weeks
Population: All Randomized Patients with Moderate Disease \[PGA=2\] at Baseline. Questionnaire analyzable if patient answered 28 of 32 for total, 8/10 for bowel, 3/5 for systemic, 10/12 for emotional, 3/5 for social.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Asacol 2.4 g/Day | Mean Change From Baseline in Total Inflammatory Bowel Disease Questionnaire (IBDQ) at Week 6, All Randomized Patients | 43.1 Scores on a Scale | Standard Error 3.5 |
| Asacol 4.8 g/Day | Mean Change From Baseline in Total Inflammatory Bowel Disease Questionnaire (IBDQ) at Week 6, All Randomized Patients | 40.4 Scores on a Scale | Standard Error 3.08 |
p-value: 0.534Wilcoxon (Mann-Whitney)
p-value: <0.0001t-test, 2 sided
p-value: <0.0001t-test, 2 sided
Secondary
Percentage of Participants Whose Rectal Bleeding & Sigmoidoscopy Score Both Improved From Baseline to Week 6, ITT Population
Rectal Bleeding - 0=no blood seen, 1=streaks of blood w/stool less than half of the time, 2=obvious blood w/stool most of the time, 3=blood alone passed Sigmoidoscopy Assessment Score - 0=normal (intact vascular pattern, no friability or granularity), 1=mild (erythema, diminished or absent vascular markings; mild granularity; friability), 2=moderate (marked erythema, granularity; absent vascular markings; bleeds with minimal trauma; no ulcerations) 3=severe (spontaneous bleeding, ulcerations)
Time frame: 6 Weeks
Population: ITT Patients with Moderate Disease \[PGA=2\] at Baseline. Percentage of patients whose rectal bleeding AND sigmoidoscopy scores BOTH improved from baseline at Week 6
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Asacol 2.4 g/Day | Percentage of Participants Whose Rectal Bleeding & Sigmoidoscopy Score Both Improved From Baseline to Week 6, ITT Population | 59.8 Percentage of Participants |
| Asacol 4.8 g/Day | Percentage of Participants Whose Rectal Bleeding & Sigmoidoscopy Score Both Improved From Baseline to Week 6, ITT Population | 63.6 Percentage of Participants |
p-value: 0.577495% CI: [-9.43, 16.93]Chi-squared
Secondary
Percentage of Patients Whose Sigmoidoscopy Score Improved From Baseline to Week 6, ITT Population
Sigmoidoscopy Assessment Score (0=normal intact vascular pattern, no friability or granularity, 1=mild erythema; diminished or absent vascular markings; mild granularity; friability, 2=moderate marked erythema, granularity; absent vascular markings; bleeds with minimal trauma; no ulcerations, 3=severe spontaneous bleeding, ulcerations)
Time frame: 6 Weeks
Population: ITT Population with Moderate Disease \[PGA=2\] at Baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Asacol 2.4 g/Day | Percentage of Patients Whose Sigmoidoscopy Score Improved From Baseline to Week 6, ITT Population | 69.0 Percentage of Participants |
| Asacol 4.8 g/Day | Percentage of Patients Whose Sigmoidoscopy Score Improved From Baseline to Week 6, ITT Population | 75.2 Percentage of Participants |
p-value: 0.299195% CI: [-5.47, 17.86]Chi-squared
Secondary
Percentage of Patients With an Improvement in Stool Frequency, ITT Population, Week 6
0=Normal stool frequency per day, 1=1-2 stools greater than normal per day, 2=3-4 stools greater than normal per day, 3=5 or more stools greater than normal per day
Time frame: 6 Weeks
Population: ITT Patients with Moderate Disease \[PGA=2\] at Baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Asacol 2.4 g/Day | Percentage of Patients With an Improvement in Stool Frequency, ITT Population, Week 6 | 71.3 Percentage of Participants |
| Asacol 4.8 g/Day | Percentage of Patients With an Improvement in Stool Frequency, ITT Population, Week 6 | 74.0 Percentage of Participants |
p-value: 0.654395% CI: [-9.25, 14.73]Chi-squared
Secondary
Percentage of Patients With Improvement in Patient's Functional Assessment (PFA), ITT Population, Week 6
PFA - 0=generally well, 1=fair, 2=poor, 3=terrible
Time frame: 6 Weeks
Population: ITT Population with Moderate Disease \[PGA=2\] at Baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Asacol 2.4 g/Day | Percentage of Patients With Improvement in Patient's Functional Assessment (PFA), ITT Population, Week 6 | 70.5 Percentage of Participants |
| Asacol 4.8 g/Day | Percentage of Patients With Improvement in Patient's Functional Assessment (PFA), ITT Population, Week 6 | 69.6 Percentage of Participants |
p-value: 0.885995% CI: [-14.09, 12.17]Chi-squared
Secondary
Percentage of Patients With Improvement in Physician Global Assessment (PGA)Score, ITT Population, Week 6
PGA -Physician's Global Assessment - 0=quiescent disease (all parameters 0), 1=mild disease (parameters mostly 1's) 2=moderate (parameters mostly 2's), 3=severe (parameters mostly 3's) \[parameters: combination of stool frequency, rectal bleeding, PFA & sigmoidoscopy findings\] If scoring equal default to physician judgement.
Time frame: 6 Weeks
Population: ITT Population with Moderate Disease \[PGA=2\] at Baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Asacol 2.4 g/Day | Percentage of Patients With Improvement in Physician Global Assessment (PGA)Score, ITT Population, Week 6 | 73.5 Percentage of Participants |
| Asacol 4.8 g/Day | Percentage of Patients With Improvement in Physician Global Assessment (PGA)Score, ITT Population, Week 6 | 83.2 Percentage of Participants |
p-value: 0.075895% CI: [-0.94, 20.4]Chi-squared
Secondary
Percentage of Patients With Improvement in Rectal Bleeding, ITT Population, Week 6
Rectal Bleeding (0=no blood seen, 1=streaks of blood with stool less than half of the time, 2=obvious blood with stool most of the time, 3=blood alone passed)
Time frame: 6 Weeks
Population: ITT Population with Moderate Disease \[PGA=2\] at Baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Asacol 2.4 g/Day | Percentage of Patients With Improvement in Rectal Bleeding, ITT Population, Week 6 | 77.5 Percentage of Participants |
| Asacol 4.8 g/Day | Percentage of Patients With Improvement in Rectal Bleeding, ITT Population, Week 6 | 78.5 Percentage of Participants |
p-value: 0.854295% CI: [-10.19, 12.29]Chi-squared
Secondary
Percentage of Patients With Moderate, Left-Sided Disease at Baseline Classified as Treatment Success at Week 6, All Randomized Patients
Treatment success defined as complete response (PGA score 0 and complete resolution of stool frequency, rectal bleeding, PFA (patient's functional assessment), normal sigmoidoscopy) or partial response (improvement from baseline PGA and improvement in 1 clinical assessment \[stool frequency, rectal bleeding, PFA, sigmoidoscopy\] and no worsening in any other clinical assessments)
Time frame: 6 Weeks
Population: All Randomized Patients with Moderate Disease \[PGA=2\] at Baseline. Left Sided Disease = proctitis, proctosigmoiditis or left-sided colitis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Asacol 2.4 g/Day | Percentage of Patients With Moderate, Left-Sided Disease at Baseline Classified as Treatment Success at Week 6, All Randomized Patients | 60.0 Percentage of Participants |
| Asacol 4.8 g/Day | Percentage of Patients With Moderate, Left-Sided Disease at Baseline Classified as Treatment Success at Week 6, All Randomized Patients | 71.1 Percentage of Participants |
p-value: 0.096695% CI: [-1.87, 24.14]Chi-squared
Secondary
Percentage of Treatment Success Patients at Week 3, ITT Population
Treatment success defined as complete response (PGA score 0 and complete resolution of stool frequency, rectal bleeding, PFA (patient's functional assessment), normal sigmoidoscopy) or partial response (improvement from baseline PGA and improvement in 1 clinical assessment \[stool frequency, rectal bleeding, PFA, sigmoidoscopy\] and no worsening in any other clinical assessments)
Time frame: 3 Weeks
Population: ITT Patients with Moderate Disease \[PGA = 2\] at Baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Asacol 2.4 g/Day | Percentage of Treatment Success Patients at Week 3, ITT Population | 51.5 Percentage of Participants |
| Asacol 4.8 g/Day | Percentage of Treatment Success Patients at Week 3, ITT Population | 61.3 Percentage of Participants |
p-value: 0.117395% CI: [-2.39, 21.89]Chi-squared