Ulcerative Colitis
Conditions
Keywords
Ulcerative colitis
Brief summary
The purpose of this study is to compare Budesonide MMX™ 6 mg and Budesonide MMX™ 9 mg tablets to placebo and to Asacol 6x 400 mg tablets over an 8-week treatment period to determine if Budesonide MMX™ is effective in the treatment of ulcerative colitis.
Detailed description
Each patient will receive one of the following regimens in the morning after breakfast: 1. one budesonide-MMX™ 6 mg tablet plus two placebo Asacol® over encapsulated tablets, or 2. one budesonide-MMX™ 9 mg tablet plus two placebo Asacol® over encapsulated tablets, or 3. two placebo Asacol® over encapsulated tablets plus one placebo budesonide tablet, or 4. two Asacol® 400 mg over encapsulated tablets plus one placebo budesonide tablet, daily for 8 weeks. Each patient will also receive on each day after the midday meal and after the evening meal either: * two Asacol® 400 mg over-encapsulated tablets (Group 4), or * the equivalent placebo Asacol® over-encapsulated tablets, (Groups 1, 2 and 3) Hence, each patient is to take seven tablets per day of active or placebo study medication as per the randomization schedule. Placebo tablets of budesonide-MMX™ and placebo over-encapsulated tablets of Asacol® will be used to maintain the study blind using a double-dummy technique. During the study, five visits to the clinical center are scheduled: one at Screening and three in the double-blind treatment period (Day 1, Day 14, Day 28 and Day 56). A safety follow up visit will take place about 2 weeks after the final study visit. If a patient is withdrawn from the study before Day 56, they will be asked to attend the study center as soon as possible thereafter so that the Final visit assessments can be conducted.
Interventions
PROCEDUREBlood sampling, endoscopy
Blood sampling for hematology and biochemistry and endoscopy with biopsy for histological and endoscopic assessment scores
DRUGbudesonide-MMX® 6 mg
6 mg/day, 6 mg tablets
DRUGbudesonide-MMX® 9 mg
9 mg/day, 9 mg tablets
DRUGPlacebo
Placebo
DRUGAsacol® 400 mg
2400 mg/day, 400 mg tablets
Sponsors
Bausch Health Americas, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Patients fulfilling the following criteria at the screening visit are eligible for participation in the study: * Male and female patients, 18-75 years old, suffering from ulcerative colitis for at least 6 months. * Diagnosis of ulcerative colitis in active phase, of mild or moderate entity with Ulcerative Colitis Disease Activity Index (UCDAI) ≥ 4 and ≤ 10 according to Sutherland. * All females of child-bearing potential must have a negative serum pregnancy test immediately prior to enrollment. In addition, all females of child-bearing potential must agree to be completely abstinent or be using an accepted form of contraception throughout the entire study period. Accepted forms of contraception are defined as those with a failure rate \<1% when properly applied and include: combination oral pill, some intra-uterine devices, and a sterilised partner in a stable relationship. Female subjects must also not be actively breast-feeding through the entire study period. * Ability to comprehend the full nature and purpose of the study, including possible risks and side effects. * Ability to co-operate with the investigator and to comply with the requirements of the entire study. * Must be able to understand and voluntarily sign written informed consent prior to inclusion in the study.
Exclusion criteria
* Patients who meet any of the following criteria at screening visit are to be excluded from study participation: * Patients with limited distal proctitis (from anal verge up to 15 cm above the pectineal line). * Patients with severe ulcerative colitis (UCDAI \>10). * Patients with infectious colitis. * Evidence or history of toxic megacolon. * Severe anemia, leucopenia or granulocytopenia. * Use of oral or rectal steroids in the last 4 weeks. * Use of immuno-suppressive agents in the last 8 weeks before the study. * Use of anti tumor necrosis factor alpha (anti-TNFα) agents in the last 3 months. * Concomitant use of any rectal preparation. * Concomitant use of antibiotics. * Concurrent use of cytochrome P450 3A4 (CYP3A4) inducers or CYP3A4 inhibitors. * Patients with intolerance to salicylates. * Patients with verified, presumed or expected pregnancy or ongoing lactation. * Patients with liver cirrhosis, or evident hepatic or renal disease or insufficiency, and/or severe impairment of the bio-humoral parameters (i.e. 2 x upper limit of normal for alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\], gamma glutamyl transpeptidase \[GGT\] or creatinine). * Patient with severe diseases in other organs and systems. * Patients with local or systemic complications or other pathological states requiring a therapy with corticosteroids and/or immuno-suppressive agents. * Patients diagnosed with type 1 diabetes. * Patients diagnosed with, or with a family history of, glaucoma. * All patients with known hepatitis B, hepatitis C or with human immunodeficiency virus (HIV), according to the local privacy policy. * Participation in experimental therapeutic studies in the last 3 months. (Note: patients who participated in observational only studies are not excluded). * Any other medical condition that in the principal investigator's opinion would make the administration of the study drug or study procedures hazardous to the subject or obscure the interpretation of adverse events (AEs).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical and Endoscopic Remission. | 8 weeks | Clinical and endoscopic remission defined as a Ulcerative Colitis Disease Activity Index (UCDAI) score ≤ 1, with subscores of 0 for rectal bleeding, stool frequency, and mucosal appearance and with a ≥ 1 point reduction in the endoscopic index score. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Improvement. | 8 weeks | Clinical improvement, defined as a ≥ 3-point improvement in UCDAI from baseline to the end of Week 8. |
| Endoscopic Improvement | 8 weeks | Greater or equal to a 1 point improvement in the mucosal appearance subscore of the UCDAI, from baseline to week 8. As per the hierarchical testing procedure for secondary endpoints, because clinical improvement was not statistically significant in the ITT population, formal statistical comparisons for endoscopic improvement between the 2 budesonide MMX groups and placebo were not conducted. |
Countries
Canada, India, Mexico, United States
Participant flow
Recruitment details
Recruited from August 2008 until May 2010.
Pre-assignment details
Diary data for symptoms will be collected prior to randomization. Lab testing and a colonoscopy will be done prior to randomization. 510 patients were randomized. One patient was not treated and was not included in baseline characteristics, efficacy, and safety analyses. 509 patients received study drug and were included in safety analyses.
Participants by arm
| Arm | Count |
|---|---|
| 1: Budesonide-MMX® 6 mg One budesonide-MMX® 6 mg plus two placebo Asacol® overencapsulated tablets daily in the morning after breakfast and two placebo Asacol® overencapsulated tablets daily after the mid-day meal and the evening meal for eight weeks.
budesonide-MMX® 6 mg : 6 mg/day, 6 mg tablets
Blood sampling, endoscopy : Blood sampling for hematology and biochemistry and endoscopy with biopsy for histological and endoscopic assessment scores | 121 |
| 2: Budesonide-MMX® 9 mg One budesonide-MMX® 9 mg plus two placebo Asacol® overencapsulated tablets daily in the morning after breakfast and two placebo Asacol® overencapsulated tablets daily after the mid-day meal and the evening meal for eight weeks.
Blood sampling, endoscopy : Blood sampling for hematology and biochemistry and endoscopy with biopsy for histological and endoscopic assessment scores
budesonide-MMX® 9 mg : 9 mg/day, 9 mg tablets | 123 |
| 3: Placebo Two placebo Asacol® overencapsulated tablets plus one placebo Budesonide MMX® tablet daily in the morning after breakfast and two placebo Asacol® overencapsulated tablets daily after the mid-day meal and the evening meal for eight weeks.
Placebo : Placebo
Blood sampling, endoscopy : Blood sampling for hematology and biochemistry and endoscopy with biopsy for histological and endoscopic assessment scores | 121 |
| 4: Asacol® 400 mg Two Asacol® 400 mg overencapsulated tablets plus one placebo budesonide MMX® tablet daily in the morning after breakfast and two Asacol® 400 mg overencapsulated tablets daily after the mid-day meal and the evening meal for eight weeks.
Asacol® 400 mg : 2400 mg/day, 400 mg tablets
Blood sampling, endoscopy : Blood sampling for hematology and biochemistry and endoscopy with biopsy for histological and endoscopic assessment scores | 124 |
| Total | 489 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 6 | 10 | 7 |
| Overall Study | Infectious colitis, normal histology | 5 | 4 | 8 | 3 |
| Overall Study | Lack of Efficacy | 13 | 9 | 14 | 8 |
| Overall Study | Lost to Follow-up | 1 | 5 | 4 | 2 |
| Overall Study | Physician Decision | 3 | 2 | 2 | 2 |
| Overall Study | Protocol Violation | 1 | 1 | 2 | 1 |
| Overall Study | Randomization error, return to prior Rx | 0 | 0 | 3 | 0 |
| Overall Study | Sponsor decision | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 8 | 11 | 10 | 9 |
Baseline characteristics
| Characteristic | 2: Budesonide-MMX® 9 mg | 3: Placebo | 4: Asacol® 400 mg | Total | 1: Budesonide-MMX® 6 mg |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 6 Participants | 6 Participants | 17 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 122 Participants | 115 Participants | 118 Participants | 472 Participants | 117 Participants |
| Age, Continuous | 41.7 years STANDARD_DEVIATION 12.2 | 41.7 years STANDARD_DEVIATION 13.6 | 44 years STANDARD_DEVIATION 12.4 | 42.7 years STANDARD_DEVIATION 12.8 | 43.2 years STANDARD_DEVIATION 13 |
| Region of Enrollment Canada | 7 participants | 5 participants | 6 participants | 23 participants | 5 participants |
| Region of Enrollment India | 40 participants | 39 participants | 42 participants | 162 participants | 41 participants |
| Region of Enrollment United States | 76 participants | 77 participants | 76 participants | 304 participants | 75 participants |
| Sex: Female, Male Female | 46 Participants | 53 Participants | 55 Participants | 216 Participants | 62 Participants |
| Sex: Female, Male Male | 77 Participants | 68 Participants | 69 Participants | 273 Participants | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 35 / 126 | 36 / 127 | 34 / 129 | 31 / 127 |
| serious Total, serious adverse events | 2 / 126 | 3 / 127 | 3 / 129 | 4 / 127 |
Outcome results
Primary
Clinical and Endoscopic Remission.
Clinical and endoscopic remission defined as a Ulcerative Colitis Disease Activity Index (UCDAI) score ≤ 1, with subscores of 0 for rectal bleeding, stool frequency, and mucosal appearance and with a ≥ 1 point reduction in the endoscopic index score.
Time frame: 8 weeks
Population: Intent-to-Treat (ITT) population= primary population for efficacy/baseline characteristics analyses. ITT population= randomized patients who received study drug, and did not include patients with major entry criteria/GCP violations or normal histology at baseline (N= 509 randomized - 3\[infectious colitis\] - 17\[normal histology at baseline\] = 489).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1: Budesonide-MMX® 6 mg | Clinical and Endoscopic Remission. | 13.2 percentage of patients |
| 2: Budesonide-MMX® 9 mg | Clinical and Endoscopic Remission. | 17.9 percentage of patients |
| 3: Placebo | Clinical and Endoscopic Remission. | 7.4 percentage of patients |
| 4: Asacol® 400 mg | Clinical and Endoscopic Remission. | 12.1 percentage of patients |
Comparison: All p-values were based on the Chi-square test; comparisons of budesonide MMX and placebo were conducted at the α = 0.025 level of significance and the comparison of Asacol and placebo were conducted at the α = 0.05 level of significance. The study was not powered to show statistical significance for Asacol versus budesonide MMX.p-value: 0.139395% CI: [-1.8, 13.4]Chi-squared
Comparison: See comments from the budesonide 6 mg versus placebo comparison (statistical analysis 1).p-value: 0.014395% CI: [2.2, 18.7]Chi-squared
Comparison: See comments from the budesonide 6 mg versus placebo comparison (statistical analysis 1).p-value: 0.2295% CI: [-2.7, 12.1]Chi-squared
Secondary
Clinical Improvement.
Clinical improvement, defined as a ≥ 3-point improvement in UCDAI from baseline to the end of Week 8.
Time frame: 8 weeks
Population: Intent-to-Treat (ITT) population= primary population for efficacy/baseline characteristics analyses. ITT population= randomized patients who received study drug, and did not include patients with major entry criteria/GCP violations or normal histology at baseline (N= 509 randomized - 3\[infectious colitis\] - 17\[normal histology at baseline\] = 489).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1: Budesonide-MMX® 6 mg | Clinical Improvement. | 30.6 percentage of patients |
| 2: Budesonide-MMX® 9 mg | Clinical Improvement. | 33.3 percentage of patients |
| 3: Placebo | Clinical Improvement. | 24.8 percentage of patients |
| 4: Asacol® 400 mg | Clinical Improvement. | 33.9 percentage of patients |
Comparison: Clinical improvement and endoscopic improvement were analyzed hierarchically. If at least one primary endpoint comparison was statistically significant, clinical improvement was to be compared between each budesonide MMX group and placebo at the α = 0.025 level of significance. If at least one comparison of clinical improvement was statistically significant, endoscopic improvement was to be compared between each budesonide MMX dose group and placebo at the α = 0.025 level of significance.p-value: 0.314695% CI: [-5.5, 17]Chi-squared
Comparison: See comments from the budesonide 6 mg versus placebo comparison (statistical analysis 1).p-value: 0.14295% CI: [-2.8, 19.9]Chi-squared
Comparison: See comments from the budesonide 6 mg versus placebo comparison (statistical analysis 1).p-value: 0.118995% CI: [-2.3, 20.4]Chi-squared
Secondary
Endoscopic Improvement
Greater or equal to a 1 point improvement in the mucosal appearance subscore of the UCDAI, from baseline to week 8. As per the hierarchical testing procedure for secondary endpoints, because clinical improvement was not statistically significant in the ITT population, formal statistical comparisons for endoscopic improvement between the 2 budesonide MMX groups and placebo were not conducted.
Time frame: 8 weeks
Population: Intent-to-Treat (ITT) population= primary population for efficacy/baseline characteristics analyses. ITT population= randomized patients who received study drug, and did not include patients with major entry criteria/GCP violations or normal histology at baseline (N= 509 randomized - 3\[infectious colitis\] - 17\[normal histology at baseline\] = 489).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1: Budesonide-MMX® 6 mg | Endoscopic Improvement | 35.5 percentage of patients |
| 2: Budesonide-MMX® 9 mg | Endoscopic Improvement | 41.5 percentage of patients |
| 3: Placebo | Endoscopic Improvement | 33.1 percentage of patients |
| 4: Asacol® 400 mg | Endoscopic Improvement | 33.1 percentage of patients |
Comparison: As per the hierarchical testing procedure for secondary endpoints, because clinical improvement was not statistically significant in the ITT population, formal statistical comparisons for endoscopic improvement between the 2 budesonide MMX groups and placebo were not conducted. The statistical comparison between the Asacol and placebo groups is shown here.p-value: 0.999195% CI: [-11.8, 11.8]Chi-squared