Ulcerative Colitis
Conditions
Keywords
Ulcerative Colitis
Brief summary
This study is to compare the efficacy and safety of budesonide MMX 9 mg versus placebo as add-on therapy to an existing oral 5-ASA regimen for the induction of remission in participants with active mild or moderate ulcerative colitis (UC).
Detailed description
Eligible participants will be randomized to 1 of the following 2 treatment arms: 1. Budesonide MMX 9 mg (1 tablet) 2. Placebo (tablet indistinguishable from budesonide MMX 9 mg tablet) The assigned study drug will be taken as a single oral tablet each morning after breakfast. In addition to the study drug, all participants will continue their existing background oral 5-ASA regimen during the treatment period.
Interventions
DRUGBudesonide MMX®
Oral tablet taken daily in the morning after breakfast.
DRUGPlacebo
Matching budesonide MMX placebo oral tablet taken daily in the morning after breakfast.
DRUG5-ASA
Acceptable oral 5-ASA medications to be received during the study include: * Asacol®, Asacol® HD, Lialda®, Pentasa® (generic: mesalamine), minimum daily dose ≥2.4 grams (g) * Azulfidine® (generic: sulfasalazine), minimum daily dose ≥4.0 g * Dipentum® (generic: olsalazine), minimum daily dose ≥2.0 g * Colazal®, Colazide® (generic: balsalazide), minimum daily dose ≥6.75 g
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
1. Age 18 to 75 years, inclusive. 2. Established diagnosis of UC, based on clinical history, exclusion of infectious causes, and characteristic endoscopic and histologic findings. 3. Active mild or moderate UC with an ulcerative colitis disease activity index (UCDAI) score ≥4 and ≤10, with a mucosal appearance score of ≥1, and physician's rating of disease activity of 1 or 2. 4. Experiencing active UC (flare) despite a therapeutic dose of an oral 5-ASA (for example, mesalamine ≥2.4 g/day for ≥6 weeks prior to randomization, or equivalent). At screening, photographic evidence of active UC based on mucosal appearance must be obtained. 5. Women of childbearing potential or men of reproductive potential must be willing to use an acceptable form of contraception. 6. Able to comprehend the full nature and purpose of the study, including possible risks and side effects, and also able to comply with all requirements of the study. Must be able to understand and voluntarily sign an informed consent prior to any study procedures.
Exclusion criteria
1. Limited distal proctitis (from anal verge to 15 centimeters \[cm\] above the pectineal line). 2. Severe UC (UCDAI \>10 or physician global assessment \[PGA\] \>2), or non-active UC (UCDAI \<4). 3. Infectious colitis or any recent history of infectious colitis (within 30 days of Screening). 4. Active malignancy or carcinoma in situ within the last 5 years (treated non-melanoma skin cancers are not exclusionary). 5. Active ulcer or bleeding disorder that may affect evaluation of blood in the stool. 6. Evidence or history of toxic megacolon or bowel resection. 7. Crohn's disease or indeterminate colitis. 8. Known hypersensitivity to budesonide or any ingredients of the budesonide MMX tablets. 9. Active tuberculosis or other active systemic or local bacterial, fungal, or viral infection. 10. Liver cirrhosis, evident hepatic or renal disease or insufficiency, or significant impairment of the biohumoral parameters (≥2.5\*upper limit of normal \[ULN\] for alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, or ≥2\*ULN for creatinine). Elevations in bilirubin due to benign conditions such as Gilbert's syndrome are not exclusionary. 11. Severe diseases in other organs or systems. 12. Local or systemic complications or other pathological states requiring therapy with corticosteroids and/or immunosuppressive agents. 13. Type 1 diabetes. 14. Glaucoma or with a family history of glaucoma in first-degree relatives. 15. Known hepatitis B, hepatitis C, or human immunodeficiency virus (HIV), according to the local privacy policy. 16. Severe anemia (\<9 g/deciliter \[dL\] hemoglobin), leukopenia (\<2.5\*10\^9 white blood cells \[WBC\]/liter \[L\]), or granulocytopenia (\<1.2\*10\^9 cells/L). 17. Participants with a history of pancolitis (disease that extends to the hepatic flexure or beyond) for ≥8 years or left-sided colitis (disease confined to the left colon \[that is, distal to the splenic flexure\]) ≥15 years who have not yet completed a surveillance colonoscopy for dysplasia/colorectal cancer screening within the past year. 18. Prior budesonide MMX treatment. 19. Use of oral corticosteroids including other budesonide formulations within the last 4 weeks prior to randomization. 20. Use of any rectal 5-ASA or corticosteroid formulations within the last 2 weeks prior to randomization. 21. Use of immunosuppressive agents within the last 8 weeks prior to randomization. 22. Use of anti-tumor necrosis factor-alpha (TNFα) agents or other biologic therapies within the last 3 months prior to randomization. 23. Participation in experimental therapeutic studies within 30 days of randomization (or within the last 3 months if in an anti-TNFα or biologic agent study). Note: participants who participated in observational-only studies (and who did not receive study therapy) are not excluded. 24. 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 participant or obscure the interpretation of adverse events (AEs) by the appropriate independent ethics committee/institutional review board.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved Clinical Remission at Day 56 | Baseline up to Day 56 | Clinical remission defined as a score of 0 for rectal bleeding and 0 for stool frequency components from the Ulcerative Colitis Disease Activity Index (UCDAI). UCDAI is the sum (0 to 12) of 4 severity scores (0 to 3). Stool frequency and rectal bleeding were based on information recorded in daily participant diaries. The diary entries were averaged for rectal bleeding and stool frequency for 3 days prior to (and closest to) Day 56 with non-missing diary data, within 5 days prior to (and closest to) Day 56. The 5 days did not include any days of the flexible sigmoidoscopy (or colonoscopy) or the preparation for the flexible sigmoidoscopy (or colonoscopy). These averages were rounded to integer values. If either subscore could not be calculated because of missing data, the score for that UCDAI component was set to missing. Participants with insufficient data at Day 56 were excluded from the analysis. Participants who had clinical remission at Baseline were classified as non-responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved UCDAI Remission at Day 56 | Baseline up to Day 56 | UCDAI remission was defined as a total UCDAI score ≤1 with subscores of 0 for rectal bleeding, stool frequency, and mucosal appearance of the colon. UCDAI is the sum (0 to 12) of 4 severity scores (0 to 3). Stool frequency and rectal bleeding were based on information recorded in daily participant diaries and mucosal appearance was based on endoscopy results. The diary entries were averaged for rectal bleeding and stool frequency for 3 days prior to (and closest to) Day 56 with non-missing diary data, within 5 days prior to (and closest to) Day 56. The 5 days did not include any days of the flexible sigmoidoscopy (or colonoscopy) or the preparation for the flexible sigmoidoscopy (or colonoscopy). These averages were rounded to integer values. If the subscore could not be calculated because of missing data, the score for that UCDAI component was set to missing. Participants with insufficient data at Day 56 were excluded from the analysis. |
| Number of Participants Who Achieved Endoscopic Remission at Day 56 | Screening and Day 56 | Endoscopic remission was defined as a score of 0 in the mucosal appearance component subscore of the UCDAI at Day 56. UCDAI is the sum (0 to 12) of 4 severity scores (0 to 3). Mucosal appearance was based on endoscopy results. If the mucosal appearance subscore could not be calculated because of missing data, endoscopic remission was set to missing. Participants with insufficient data at Day 56 were excluded from the analysis. |
| Number of Participants of Who Achieved Clinical Response at Day 56 | Baseline up to Day 56 | Clinical response defined as an improvement in UCDAI from Baseline of ≥3 points with a rectal bleeding score ≤1. UCDAI is the sum (0 to 12) of 4 severity scores (0 to 3). Rectal bleeding was based on information recorded in daily participant diaries. The diary entries were averaged for rectal bleeding for 3 days prior to (and closest to) Day 56 with non-missing diary data, within 5 days prior to (and closest to) Day 56. The 5 days did not include any days of the flexible sigmoidoscopy (or colonoscopy) or the preparation for the flexible sigmoidoscopy (or colonoscopy). These averages were rounded to integer values. If either subscore could not be calculated because of missing data, the score for that UCDAI component was set to missing. Participants with insufficient data at Day 56 were excluded from the analysis. |
| Number of Participants With Treatment Failure at Day 56 | Baseline up to Day 56 | Treatment failure was defined as an unchanged, worsened, or missing UCDAI score at Day 56. UCDAI is the sum (0 to 12) of 4 severity scores (0 to 3). Stool frequency and rectal bleeding was based on information recorded in daily participant diaries and mucosal appearance was based on endoscopy results. The diary entries were averaged for rectal bleeding and stool frequency for 3 days prior to (and closest to) Day 56 with non-missing diary data, within 5 days prior to (and closest to) Day 56. The 5 days did not include any days of the flexible sigmoidoscopy (or colonoscopy) or the preparation for the flexible sigmoidoscopy (or colonoscopy). These averages were rounded to integer values. If the subscore could not be calculated because of missing data, the score for that UCDAI component was set to missing. Participants with insufficient data at Day 56 were excluded from the analysis. |
| Change From Baseline in Inflammatory Bowel Disease-Quality of Life (IBD-QoL) Questionnaire Scores | Baseline, Days 14, 28, and 56 | The IBD-QoL questionnaire was self-completed by the participant. The IBD-QoL is a disease-specific instrument to evaluate the quality of life of participants with UC. This 32-item questionnaire has 4 dimensions: bowel function, emotional function, systemic symptoms, and social function. The total score is presented, which ranges from 32 to 224, with higher scores indicating a better quality of life. The scores of participants in remission usually range from 170 to 190. If \>50% of the questionnaire answers for a particular dimension were missing, this dimension score was set to missing. The total score for the IBD-QoL was the sum of the domain scores, however, if any dimension score was missing, the total IBD-QoL score was set to missing. |
| Number of Participants Who Achieved Histologic Healing at Day 56 | Baseline and Day 56 | Participants achieved histologic healing if histologic assessments of all biopsy specimens were graded as 0 (normal mucosa). If the score for ≥1 sample was missing, the overall score at that visit was set to missing. Participants with insufficient data at Day 56 were excluded from analysis. |
Countries
Bulgaria, Canada, Czechia, Estonia, Hungary, Latvia, Lithuania, Poland, Russia, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Budesonide MMX Participants received 1 oral tablet of budesonide MMX 9 mg for 56 days. Additionally, participants continued to receive the same dose of their existing oral 5-ASA medication from their treating physician. | 255 |
| Placebo Participants received 1 oral tablet of matching budesonide MMX placebo for 56 days. Additionally, participants continued to receive the same dose of their existing oral 5-ASA medication from their treating physician. | 255 |
| Total | 510 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 9 |
| Overall Study | Lack of Efficacy | 4 | 1 |
| Overall Study | Lost to Follow-up | 3 | 4 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 16 | 2 |
Baseline characteristics
| Characteristic | Budesonide MMX | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 44.5 years STANDARD_DEVIATION 13.86 | 44.9 years STANDARD_DEVIATION 13.44 | 44.7 years STANDARD_DEVIATION 13.64 |
| Sex: Female, Male Female | 122 Participants | 108 Participants | 230 Participants |
| Sex: Female, Male Male | 133 Participants | 147 Participants | 280 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 255 | 14 / 255 |
| serious Total, serious adverse events | 10 / 255 | 2 / 255 |
Outcome results
Primary
Number of Participants Who Achieved Clinical Remission at Day 56
Clinical remission defined as a score of 0 for rectal bleeding and 0 for stool frequency components from the Ulcerative Colitis Disease Activity Index (UCDAI). UCDAI is the sum (0 to 12) of 4 severity scores (0 to 3). Stool frequency and rectal bleeding were based on information recorded in daily participant diaries. The diary entries were averaged for rectal bleeding and stool frequency for 3 days prior to (and closest to) Day 56 with non-missing diary data, within 5 days prior to (and closest to) Day 56. The 5 days did not include any days of the flexible sigmoidoscopy (or colonoscopy) or the preparation for the flexible sigmoidoscopy (or colonoscopy). These averages were rounded to integer values. If either subscore could not be calculated because of missing data, the score for that UCDAI component was set to missing. Participants with insufficient data at Day 56 were excluded from the analysis. Participants who had clinical remission at Baseline were classified as non-responders.
Time frame: Baseline up to Day 56
Population: Participants who received at least 1 dose of study drug and had active ulcerative colitis (UC) at study entry as a cause of their symptoms (Intent-To-Treat Population \[ITT\]) with evaluable clinical remission data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Budesonide MMX | Number of Participants Who Achieved Clinical Remission at Day 56 | 56 Participants |
| Placebo | Number of Participants Who Achieved Clinical Remission at Day 56 | 52 Participants |
Secondary
Change From Baseline in Inflammatory Bowel Disease-Quality of Life (IBD-QoL) Questionnaire Scores
The IBD-QoL questionnaire was self-completed by the participant. The IBD-QoL is a disease-specific instrument to evaluate the quality of life of participants with UC. This 32-item questionnaire has 4 dimensions: bowel function, emotional function, systemic symptoms, and social function. The total score is presented, which ranges from 32 to 224, with higher scores indicating a better quality of life. The scores of participants in remission usually range from 170 to 190. If \>50% of the questionnaire answers for a particular dimension were missing, this dimension score was set to missing. The total score for the IBD-QoL was the sum of the domain scores, however, if any dimension score was missing, the total IBD-QoL score was set to missing.
Time frame: Baseline, Days 14, 28, and 56
Population: Participants who received at least 1 dose of study drug and had active UC at study entry as a cause of their symptoms (ITT Population) with evaluable IBD-QoL data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Budesonide MMX | Change From Baseline in Inflammatory Bowel Disease-Quality of Life (IBD-QoL) Questionnaire Scores | Baseline | 132.8 scores on a scale | Standard Deviation 31.36 |
| Budesonide MMX | Change From Baseline in Inflammatory Bowel Disease-Quality of Life (IBD-QoL) Questionnaire Scores | Change at Day 14 | 24.4 scores on a scale | Standard Deviation 27.45 |
| Budesonide MMX | Change From Baseline in Inflammatory Bowel Disease-Quality of Life (IBD-QoL) Questionnaire Scores | Change at Day 28 | 31.8 scores on a scale | Standard Deviation 33.38 |
| Budesonide MMX | Change From Baseline in Inflammatory Bowel Disease-Quality of Life (IBD-QoL) Questionnaire Scores | Change at Day 56 | 31.1 scores on a scale | Standard Deviation 38.73 |
| Placebo | Change From Baseline in Inflammatory Bowel Disease-Quality of Life (IBD-QoL) Questionnaire Scores | Change at Day 56 | 31.7 scores on a scale | Standard Deviation 37.02 |
| Placebo | Change From Baseline in Inflammatory Bowel Disease-Quality of Life (IBD-QoL) Questionnaire Scores | Baseline | 134.1 scores on a scale | Standard Deviation 32.48 |
| Placebo | Change From Baseline in Inflammatory Bowel Disease-Quality of Life (IBD-QoL) Questionnaire Scores | Change at Day 28 | 25.7 scores on a scale | Standard Deviation 33.16 |
| Placebo | Change From Baseline in Inflammatory Bowel Disease-Quality of Life (IBD-QoL) Questionnaire Scores | Change at Day 14 | 21.3 scores on a scale | Standard Deviation 29.2 |
Secondary
Number of Participants of Who Achieved Clinical Response at Day 56
Clinical response defined as an improvement in UCDAI from Baseline of ≥3 points with a rectal bleeding score ≤1. UCDAI is the sum (0 to 12) of 4 severity scores (0 to 3). Rectal bleeding was based on information recorded in daily participant diaries. The diary entries were averaged for rectal bleeding for 3 days prior to (and closest to) Day 56 with non-missing diary data, within 5 days prior to (and closest to) Day 56. The 5 days did not include any days of the flexible sigmoidoscopy (or colonoscopy) or the preparation for the flexible sigmoidoscopy (or colonoscopy). These averages were rounded to integer values. If either subscore could not be calculated because of missing data, the score for that UCDAI component was set to missing. Participants with insufficient data at Day 56 were excluded from the analysis.
Time frame: Baseline up to Day 56
Population: Participants who received at least 1 dose of study drug and had active UC at study entry as a cause of their symptoms (ITT Population) with evaluable clinical response data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Budesonide MMX | Number of Participants of Who Achieved Clinical Response at Day 56 | 101 Participants |
| Placebo | Number of Participants of Who Achieved Clinical Response at Day 56 | 86 Participants |
Secondary
Number of Participants Who Achieved Endoscopic Remission at Day 56
Endoscopic remission was defined as a score of 0 in the mucosal appearance component subscore of the UCDAI at Day 56. UCDAI is the sum (0 to 12) of 4 severity scores (0 to 3). Mucosal appearance was based on endoscopy results. If the mucosal appearance subscore could not be calculated because of missing data, endoscopic remission was set to missing. Participants with insufficient data at Day 56 were excluded from the analysis.
Time frame: Screening and Day 56
Population: Participants who received at least 1 dose of study drug and had active UC at study entry as a cause of their symptoms (ITT Population) with evaluable endoscopic response data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Budesonide MMX | Number of Participants Who Achieved Endoscopic Remission at Day 56 | 46 Participants |
| Placebo | Number of Participants Who Achieved Endoscopic Remission at Day 56 | 28 Participants |
Secondary
Number of Participants Who Achieved Histologic Healing at Day 56
Participants achieved histologic healing if histologic assessments of all biopsy specimens were graded as 0 (normal mucosa). If the score for ≥1 sample was missing, the overall score at that visit was set to missing. Participants with insufficient data at Day 56 were excluded from analysis.
Time frame: Baseline and Day 56
Population: Participants who received at least 1 dose of study drug and had active UC at study entry as a cause of their symptoms (ITT Population) with evaluable histologic healing data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Budesonide MMX | Number of Participants Who Achieved Histologic Healing at Day 56 | 62 Participants |
| Placebo | Number of Participants Who Achieved Histologic Healing at Day 56 | 40 Participants |
Secondary
Number of Participants Who Achieved UCDAI Remission at Day 56
UCDAI remission was defined as a total UCDAI score ≤1 with subscores of 0 for rectal bleeding, stool frequency, and mucosal appearance of the colon. UCDAI is the sum (0 to 12) of 4 severity scores (0 to 3). Stool frequency and rectal bleeding were based on information recorded in daily participant diaries and mucosal appearance was based on endoscopy results. The diary entries were averaged for rectal bleeding and stool frequency for 3 days prior to (and closest to) Day 56 with non-missing diary data, within 5 days prior to (and closest to) Day 56. The 5 days did not include any days of the flexible sigmoidoscopy (or colonoscopy) or the preparation for the flexible sigmoidoscopy (or colonoscopy). These averages were rounded to integer values. If the subscore could not be calculated because of missing data, the score for that UCDAI component was set to missing. Participants with insufficient data at Day 56 were excluded from the analysis.
Time frame: Baseline up to Day 56
Population: Participants who received at least 1 dose of study drug and had active UC at study entry as a cause of their symptoms (ITT Population) with evaluable UCDAI remission data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Budesonide MMX | Number of Participants Who Achieved UCDAI Remission at Day 56 | 30 Participants |
| Placebo | Number of Participants Who Achieved UCDAI Remission at Day 56 | 17 Participants |
Secondary
Number of Participants With Treatment Failure at Day 56
Treatment failure was defined as an unchanged, worsened, or missing UCDAI score at Day 56. UCDAI is the sum (0 to 12) of 4 severity scores (0 to 3). Stool frequency and rectal bleeding was based on information recorded in daily participant diaries and mucosal appearance was based on endoscopy results. The diary entries were averaged for rectal bleeding and stool frequency for 3 days prior to (and closest to) Day 56 with non-missing diary data, within 5 days prior to (and closest to) Day 56. The 5 days did not include any days of the flexible sigmoidoscopy (or colonoscopy) or the preparation for the flexible sigmoidoscopy (or colonoscopy). These averages were rounded to integer values. If the subscore could not be calculated because of missing data, the score for that UCDAI component was set to missing. Participants with insufficient data at Day 56 were excluded from the analysis.
Time frame: Baseline up to Day 56
Population: Participants who received at least 1 dose of study drug and had active UC at study entry as a cause of their symptoms (ITT Population) with evaluable UCDAI data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Budesonide MMX | Number of Participants With Treatment Failure at Day 56 | 45 Participants |
| Placebo | Number of Participants With Treatment Failure at Day 56 | 61 Participants |