Ulcerative Colitis
Conditions
Keywords
Ulcerative colitis
Brief summary
This will be a multicentre, randomised, double-blind, double-dummy, parallel group comparative study in patients with mild or moderate, active ulcerative colitis. The study will compare budesonide-MMX™ 6 mg and budesonide-MMX™ 9 mg tablets to placebo and to Entocort® 3 x 3 mg capsules, in four parallel groups of patients over an 8 week treatment period. After the screening visit, patients will enter a washout period of 2 days, then they will be randomised to the following four treatment groups: budesonide-MMX™ tablets (6 mg), budesonide-MMX™ tablets (9 mg), Entocort® capsules (3 x 3 mg) and placebo (tablets and capsules), all administered once a day after breakfast. Hence, each patient will receive, in the morning after breakfast, either one budesonide-MMX™ 6 mg or budesonide MMX™ 9 mg tablet and 3 placebo Entocort® matching capsules, or three Entocort® 3 mg capsules and one placebo budesonide-MMX™ matching tablet, or one placebo budesonide-MMX™ matching tablet and three placebo Entocort® matching capsules.
Detailed description
Each patient will receive one of the following regimens in the morning after breakfast: 1. One budesonide MMX® 6 mg tablet plus three placebo Entocort enteric-coated (EC®) overencapsulated capsules, or 2. One budesonide MMX® 9 mg tablet plus three placebo Entocort EC® overencapsulated capsules, or 3. Three placebo Entocort EC® overencapsulated capsules plus one placebo budesonide MMX® tablet, or 4. Three Entocort EC® 3 mg overencapsulated capsules plus one placebo budesonide MMX® tablet, daily for eight weeks. Hence, each patient is to take four tablets/capsules per day of active or placebo study medication as per the randomization schedule. Placebo tablets of Budesonide MMX® and placebo overencapsulated capsules of Entocort EC® 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 If a patient is withdrawn from the study before Day 56, they will be asked to attend the study center as soon as possible thereafter so that the Final visit assessments can be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
DRUGEntocort EC® 3 mg
9 mg/day, 3 mg tablets
DRUGPlacebo
Placebo
Sponsors
Cosmo Technologies Ltd
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 anaemia, leucopaenia or granulocytopaenia. * 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 tumour 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 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-humoural 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 an 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
Australia, Belgium, Estonia, France, Israel, Italy, Latvia, Lithuania, Poland, Romania, Russia, Slovakia, Sweden, Ukraine, United Kingdom
Participant flow
Recruitment details
Recruited from July 2008 to February 2010.
Pre-assignment details
3 randomized patients were not treated and are excluded from all analyses. The safety population, N= 511: 509 randomized and treated + 2 nonrandomized and treated patients. The intent-to-treat (ITT) population, N=410: 511 - 101 patients who were not randomized, had major entry criteria violation, GCP violation, or normal histology at baseline.
Participants by arm
| Arm | Count |
|---|---|
| 1: Budesonide-MMX® 6 mg One budesonide-MMX® 6 mg plus three placebo Entocort EC® overencapsulated capsules daily in the morning after breakfast. | 109 |
| 2: Budesonide-MMX® 9 mg One budesonide-MMX® 9 mg plus three placebo Entocort EC® overencapsulated capsules daily in the morning after breakfast. | 109 |
| 3: Entocort EC® 3 mg Three Entocort EC® 3 mg overencapsulated capsules plus one placebo budesonide MMX® tablet daily in the morning after breakfast. | 103 |
| 4: Placebo Three placebo Entocort EC® overencapsulated capsules plus one placebo Budesonide MMX® tablet daily in the morning after breakfast. | 89 |
| Total | 410 |
Baseline characteristics
| Characteristic | 1: Budesonide-MMX® 6 mg | 2: Budesonide-MMX® 9 mg | 3: Entocort EC® 3 mg | 4: Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 2 Participants | 6 Participants | 7 Participants | 22 Participants |
| Age, Categorical Between 18 and 65 years | 102 Participants | 107 Participants | 97 Participants | 82 Participants | 388 Participants |
| Age, Continuous | 43.6 years STANDARD_DEVIATION 13.6 | 42.8 years STANDARD_DEVIATION 13.9 | 43.4 years STANDARD_DEVIATION 14 | 44.8 years STANDARD_DEVIATION 13 | 43.6 years STANDARD_DEVIATION 13.6 |
| Region of Enrollment Australia | 1 participants | 1 participants | 3 participants | 2 participants | 7 participants |
| Region of Enrollment Belgium | 2 participants | 0 participants | 0 participants | 0 participants | 2 participants |
| Region of Enrollment Estonia | 11 participants | 6 participants | 6 participants | 5 participants | 28 participants |
| Region of Enrollment France | 0 participants | 1 participants | 1 participants | 1 participants | 3 participants |
| Region of Enrollment Israel | 1 participants | 0 participants | 1 participants | 0 participants | 2 participants |
| Region of Enrollment Italy | 18 participants | 12 participants | 18 participants | 13 participants | 61 participants |
| Region of Enrollment Latvia | 2 participants | 2 participants | 0 participants | 2 participants | 6 participants |
| Region of Enrollment Lithuania | 19 participants | 17 participants | 11 participants | 12 participants | 59 participants |
| Region of Enrollment Poland | 7 participants | 14 participants | 13 participants | 9 participants | 43 participants |
| Region of Enrollment Romania | 2 participants | 5 participants | 1 participants | 3 participants | 11 participants |
| Region of Enrollment Russian Federation | 24 participants | 35 participants | 34 participants | 28 participants | 121 participants |
| Region of Enrollment Slovakia | 10 participants | 5 participants | 5 participants | 7 participants | 27 participants |
| Region of Enrollment Sweden | 3 participants | 1 participants | 0 participants | 2 participants | 6 participants |
| Region of Enrollment Ukraine | 7 participants | 6 participants | 7 participants | 5 participants | 25 participants |
| Region of Enrollment United Kingdom | 2 participants | 4 participants | 3 participants | 0 participants | 9 participants |
| Sex: Female, Male Female | 52 Participants | 45 Participants | 48 Participants | 32 Participants | 177 Participants |
| Sex: Female, Male Male | 57 Participants | 64 Participants | 55 Participants | 57 Participants | 233 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 | 77 / 128 | 67 / 128 | 68 / 126 | 52 / 129 |
| serious Total, serious adverse events | 3 / 128 | 4 / 128 | 1 / 126 | 5 / 129 |
Outcome results
Primary
Clinical and Endoscopic Remission.
Clinical and endoscopic remission defined as an 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: Efficacy endpoints were analyzed with the ITT population, defined as randomized patients who received study drug, had no entry criteria/GCP violation, and had abnormal mucosal histology at baseline. ITT population=410 patients: 511 - 101 patients who were not randomized, had entry criteria/GCP violation, or had normal histology at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1: Budesonide-MMX® 6 mg | Clinical and Endoscopic Remission. | 8.3 percentage of patients |
| 2: Budesonide-MMX® 9 mg | Clinical and Endoscopic Remission. | 17.4 percentage of patients |
| 3: Entocort EC® 3 mg | Clinical and Endoscopic Remission. | 12.6 percentage of patients |
| 4: Placebo | Clinical and Endoscopic Remission. | 4.5 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 Entocort EC and placebo were conducted at the α = 0.05 level of significance. The study was not powered to show statistical significance for Entocort EC versus budesonide MMX.p-value: 0.287695% CI: [-3, 10.5]Chi-squared
Comparison: See comments from the budesonide 6 mg versus placebo comparison (statistical analysis 1).p-value: 0.004795% CI: [4.6, 21.3]Chi-squared
Comparison: See comments from the budesonide 6 mg versus placebo comparison (statistical analysis 1).p-value: 0.048195% CI: [0.4, 15.9]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: Efficacy endpoints were analyzed with the ITT population, defined as randomized patients who received study drug, had no entry criteria/GCP violation, and had abnormal mucosal histology at baseline. ITT population=410 patients: 511 - 101 patients who were not randomized, had entry criteria/GCP violation, or had normal histology at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1: Budesonide-MMX® 6 mg | Clinical Improvement. | 25.7 percentage of patients |
| 2: Budesonide-MMX® 9 mg | Clinical Improvement. | 42.2 percentage of patients |
| 3: Entocort EC® 3 mg | Clinical Improvement. | 33.0 percentage of patients |
| 4: Placebo | Clinical Improvement. | 33.7 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: 0.2174Chi-squared
Comparison: See comments from the budesonide 6 mg versus placebo comparison (statistical analysis 1).p-value: 0.221595% CI: [-5, 22]Chi-squared
Comparison: See comments from the budesonide 6 mg versus placebo comparison (statistical analysis 1).p-value: 0.918595% CI: [-14.1, 12.7]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: Efficacy endpoints were analyzed with the ITT population, defined as randomized patients who received study drug, had no entry criteria/GCP violation, and had abnormal mucosal histology at baseline. ITT population=410 patients: 511 - 101 patients who were not randomized, had entry criteria/GCP violation, or had normal histology at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1: Budesonide-MMX® 6 mg | Endoscopic Improvement. | 25.7 percentage of patients |
| 2: Budesonide-MMX® 9 mg | Endoscopic Improvement. | 42.2 percentage of patients |
| 3: Entocort EC® 3 mg | Endoscopic Improvement. | 36.9 percentage of patients |
| 4: Placebo | Endoscopic Improvement. | 31.5 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 Entocort EC and placebo groups is shown here.p-value: 0.429395% CI: [-8, 18.8]Chi-squared