| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Maintenance of remission of ulcerative colitis |
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| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The study will compare the safety and efficacy of 25 mg QD and 50 mg QD of OPC-6535 to 800 mg BID of Asacol® in the maintenance of remission in subjects with ulcerative colitis.
The primary efficacy measure is time to treatment failure, defined as (1) relapse of ulcerative colitis or (2) discontinuation from the study for any other reason. Relapse is defined as either (RB ≥ 1 and FS ≥1) or the need for other medication for treatment of an acute flare, as judged by the principal investigator. OPC-6535 25 mg QD and OPC-6535 50 mg QD will be compared to Asacol®. 800 mg BID for noninferiority and then for superiority—for a treatment duration of 26 weeks. |
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| E.2.2 | Secondary objectives of the trial |
Efficacy:
1.Time to relapse for a treatment duration of 26 weeks.
2.Proportion of randomized subjects at Week 26&52 who are not treatment failures
3.Time to treatment failure for a treatment duration of 26&52 weeks.
4.Proportion of randomized subjects at Week 52 with endoscopic relapse
5.Change from baseline in health related quality of life at Weeks 26 and 52, based on the Inflammatory Bowel Disease Questionnaire.
6.At Weeks 26&52, the proportion of randomized subjects who are not treatment failures and the times to treatment failure in 3 treatment groups.
7.Changes from baseline in the stool frequency, bleeding, bowel urgency, abdominal pain and general well being scores.
Safety: Vital signs, ECGs, laboratory studies (including hematology, clinical chemistry, and urinalysis), and adverse events.
Pharmacokinetics: OPC-6535 plasma concentrations.
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Male or female subjects, 18 to 80 years of age, inclusive, who provide written, informed consent prior to any study-related procedures and who are, in the opinion of the Investigator, likely to comply with all the requirements of the study.
2. Subjects with a prior diagnosis of ulcerative colitis, established by colonoscopy.
3. Subjects currently in remission, defined as rectal bleeding (RB) score of 0 and flexible sigmoidoscopy (FS) score of 0 (screening flexible sigmoidoscopy or colonoscopy).
4. Subjects who have undergone treatment for a flare of ulcerative colitis, with symptomatic onset of remission occurring no more than 52 weeks from the Screening Period.
5. If subjects are taking sulfasalazine or 5-ASA products prior to entry, the dose must be stable for at least 6 weeks prior to the Screening Period. NOTE: During the study, use of these drugs will be discontinued
6. Subjects having undergone colonoscopy with pan-colonic surveillance biopsies negative for dysplasia within 1 year of the Screening Visit if at increased risk of colorectal cancer (≥ 8 year history of ulcerative colitis). [Colonoscopy with pan-colonic surveillance biopsies for dysplasia will be substituted for flexible sigmoidoscopy during Screening if this inclusion criterion is not met.]
7. Female or male subjects who are surgically sterilized or who are prepared to and agree to practice a double-barrier form of birth control from the Screening Period through 30 days (females) and 90 days (males), respectively, from the last dose of study medication. Females who are more than 12 months post-menopausal are also eligible to participate in the study. [See Section 5.4 for a description of acceptable forms of birth control.]
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| E.4 | Principal exclusion criteria |
1. Subjects who have active disease, defined as a RB ≥ 1 or FS ≥ 1 during the Screening Period.
2. Subjects who have any other clinically significant disease(s) or condition/procedure(s) which, in the opinion of the Investigator, could compromise the subject’s involvement in the study and/or interfere with the absorption of the study drug or the overall interpretation of the data.
3. Subjects who have had major gastrointestinal surgery including, but not limited to, a colostomy, an ileostomy or previous colonic surgery other than appendectomy.
4. Subjects who have used oral or intravenous corticosteroids or intrarectal topical agents (corticosteroid or 5-ASA enemas, suppositories, foams) within 6 weeks of the Screening Period.
5. Subjects who have used azathioprine, 6-mercaptopurine or methotrexate within 6 weeks of the screening period or other immunosuppressive agents including, but not limited to IL-10, IL-11, FK-506 [tacrolimus], mycophenalate, cyclosporin, anti-TNF-a or a monoclonal antibody within 8 weeks of the Screening Period.
6. Subjects who have a history or evidence of an active malignancy within the previous 5 years (surgically-treated basal cell, squamous cell or in-situ cervical carcinomas permissible), an intra-abdominal abscess, a toxic megacolon, or a clinical instability resulting from any other cause.
7. Subjects with a known or suspected history of sclerosing cholangitis.
8. Subjects with partial bowel obstruction, as documented by proximal small bowel dilatation during the Screening Period.
9. Female subjects who are pregnant or lactating.
10. Female subjects who are likely to undergo an in vitro fertilization (IVF ) procedure from the Screening Period through 30 days after the last dose of study medication, OR male subjects likely to participate in an IVF procedure from the Screening Period through 90 days after the last dose of study medication.
11. Subjects with compromised hepatic function, characterized by ALT and/or AST levels twice (2x) the upper normal limit and/or a serum bilirubin > 1.7 mg/dL (unless the subject has been diagnosed with Gilbert’s syndrome) based on clinical laboratory results.
12. Subjects with compromised renal function, characterized by serum creatinine levels 1.5 times the upper normal limit
13. Subjects with a platelet count <100,000 or >750,000/mm3 based on clinical laboratory results.
14. Subjects with severe anemia, defined as hemoglobin of <8.0 g/dL based on clinical laboratory results.
15. Subjects with a serum albumin <2.5 g/dL based on clinical laboratory results.
16. Subjects with a prothrombin time INR > 1.2 based on clinical laboratory results.
17. Subjects with a neutrophil count of <2000/mm3 based on clinical laboratory results.
18. Subjects taking > 325 mg aspirin/day or chronic (> 7 consecutive days) NSAID or COX-2 inhibitor use within 7 days of the Screening Period.
19. Subjects who have used antibiotics, other than topical antibiotics, within 14 days of the Screening Period. [NOTE: Oral antibiotic use will be permitted after randomization for up to 7 consecutive days for non-serious infections at the discretion of the investigator. See table 4.1-1]
20. Subjects taking warfarin (phenprocoumon) within 7 days of the Screening Period, or who are likely to take warfarin (phenprocoumon).
21. (Intentionally left blank)
22. Subjects taking pharmaceutical nicotine within 14 days of the Screening Period, or who are likely to take pharmaceutical nicotine.
23. Subjects with a history of known or suspected alcohol or drug abuse within 6 months of the Screening Period.
24. Subjects who receive any experimental drug or procedure within 30 days of the Screening Period, or who are likely to receive an experimental drug or procedure during the study through the 14-day period after the final administration of study drug. [An experimental agent is defined as any compound assessed under an IND.]
25. Subjects who have taken any experimental agents with documented or potential immunosuppressive effects within 90 days prior to Screening Period.
26. Subjects taking sulfasalazine or 5-ASA containing products who have undergone a dose change within 6 weeks of the Screening Period. NOTE: During the study, use of these drugs will be discontinued.
27. Subjects with Crohn’s Disease.
28. Subjects with allergies or intolerance to 5-ASA
29. Subjects with previous exposure to OPC-6535.
30. Subjects taking prescription or over-the-counter anti-diarrheal agents within 3 days of the Screening Period.
31. Subjects considered inappropriate by the Investigator for any reason(s).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Outcome Variable:
Efficacy: The primary efficacy measure is time to treatment failure, defined as (1) relapse of ulcerative colitis or (2) discontinuation from the study for any other reason. Relapse is defined as either (RB ≥ 1 and FS ≥ 1) or the need for other medication for treatment of an acute flare, as judged by the principal investigator. OPC-6535 25 mg QD and OPC-6535 50 mg QD will be compared to Asacol® 800 mg BID for non-inferiority and then for superiority—for a treatment duration of 26 weeks.
Secondary Outcome Variables:
Efficacy:
1. Time to relapse (with non-relapse related discontinuations counted as censored data), with OPC-6535 25 mg QD and OPC-6535 50 mg QD compared to Asacol® 800 mg BID for non-inferiority and then for superiority—for a treatment duration of 26 weeks.
2. Proportion of randomized subjects at Week 26 who are not treatment failures, with OPC-6535 25 mg QD and OPC-6535 50 mg QD compared to Asacol® 800 mg BID for non- inferiority and then for superiority.
3. Time to treatment failure, with treatment failure defined as for the primary analysis, but with the OPC-6535 25 mg QD and OPC-6535 50 mg QD doses pooled together, compared to Asacol® 800 mg BID for non-inferiority and then for superiority—for a treatment duration of 26 weeks.
4. Proportion of randomized subjects at Week 26 who are not treatment failures, with treatment failure defined as for the primary analysis, but with the OPC-6535 25 mg QD and OPC-6535 50 mg QD doses pooled together, compared to Asacol® 800 mg BID for non-inferiority and then for superiority—for a treatment duration of 26 weeks.
5. Time to treatment failure, with treatment failure defined as for the primary
analysis, with OPC-6535 25 mg QD and OPC-6535 50 mg QD compared to Asacol® 800 mg BID for non-inferiority and then for superiority—for a treatment duration of 52 weeks.
6. Proportion of randomized subjects at Week 52 who are not treatment failures, with OPC-6535 25 mg QD and OPC-6535 50 mg QD compared to Asacol® 800 mg BID for non- inferiority and then for superiority.
7. Proportion of randomized subjects at Week 52 who have experienced endoscopic relapse, defined as FS ≥ 1, with OPC-6535 25 mg QD and OPC-6535 50 mg QD compared to Asacol® 800 mg BID for non-inferiority and then for superiority.
A flexible sigmoidoscopy may be triggered by a subject's rectal bleeding, but is also routinely scheduled in all subjects at Week 52 or upon early termination. For any flexible sigmoidoscopy, if inflammation is identified (FS >=1), endoscopic relapse will have occurred. Thus, subjects with endoscopic relapse may be either symptomatic (RB >=1) or asymptomatic (RB=0). Note, however, that asymptomatic endoscopic relapses are not counted as treatment failures.
8. Change from baseline in health related quality of life at Weeks 26 and 52, based on the Inflammatory Bowel Disease Questionnaire (IBDQ), with OPC-6535 25 mg QD and OPC-6535 50 mg QD compared to Asacol® 800 mg BID.
9. For each of the following categories, at Weeks 26 and 52, the proportion of randomized subjects who are not treatment failures will be reported for each treatment group:
(a) No 5-ASA taken prior to time of randomization;
(b) 5-ASA taken prior to time of randomization at a daily dose ≤ 1.6 g/day;
(c) 5-ASA taken prior to time of randomization at a daily dose > 1.6 g/day.
10. For each of the following categories, the times to treatment failure will be shown by plotting Kaplan-Meier curves for each treatment group:
(a) No 5-ASA taken prior to time of randomization;
(b) 5-ASA taken prior to time of randomization at a daily dose ≤ 1.6 g/day;
(c) 5-ASA taken prior to time of randomization at a daily dose > 1.6 g/day.
11. Changes from baseline in the stool frequency scores, bleeding scores, bowel urgency scores, abdominal pain scores and general well being scores recorded at Randomization, Weeks 1, 13, 26, 39, and 52, will be presented graphically by treatment group.
Safety: Vital signs, ECGs, laboratory studies (including hematology, clinical chemistry, and urinalysis), and adverse events.
Pharmacokinetics: OPC-6535 plasma concentrations.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| Last visit of last subject |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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