| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045365 |
| E.1.2 | Term | Ulcerative colitis |
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| 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 |
| There are 2 parts. The primary objective of Part 1 of this study is to compare the proportion of subjects with moderate to severe active UC who achieve remission at Wk 16 on IFX/AZA combination therapy versus AZA monotherapy. Clinical remission at Wk 16 is defined as a total Mayo score of 2 points or lower, with no individual subscore exceeding one point, without the use of corticosteroids. The primary objective of Part 2 of this study is to determine whether remission in UC is better sustained by maintenance (q8w) or intermittent (upon relapse) infliximab treatment. |
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| E.2.2 | Secondary objectives of the trial |
Part 1 of this study are:
- To compare the proportion of subjects with moderate to severe active UC who achieve remission at Wk 16 on infliximab monotherapy versus AZA monotherapy.
- To compare the proportion of subjects with moderate to severe active UC who achieve remission at Wk 16 on IFX/AZA combination therapy versus IFX monotherapy.
Secondary objectives for Part 2 are:
- To assess the long-term safety and efficacy of maintenance versus intermittent therapy with 5 mg/kg IFX in a moderate to severe active UC population.
-To assess mucosal healing
- To determine the number of colectomies.
- To determine the number of hospitalizations and unscheduled physician visits and surgeries due to UC.
- To determine the number and outcome of surgical procedures due to UC.
- To determine antibody formation to IFX in subjects who receive IFX monotherapy or IFX/AZA combination therapy as intermittent or maintenance IFX treatment in Part 2. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
The subject must meet ALL the criteria listed below for entry:
1. Must be ≥18 years of age at the time of informed consent, of either sex, and of any race;
2. Must have endoscopic evidence of UC, as determined by sigmoidoscopy, within 14 days prior to Baseline;
3. Must have a total Mayo score of 6 to 12 points at Baseline;
4. Must have responded inadequately to corticosteroid treatment (ie, the last or current UC flare did not respond adequately to a standard course of corticosteroids) with or without 5 aminosalicylic acid (5-ASA);
5. Must be off corticosteroids or on a stable dose of corticosteroid for at least 2 weeks prior to enrollment. The maximal daily dose of corticosteroid at Baseline must not exceed the equivalent of 30 mg of prednisone;
6. Must be naïve to infliximab and other tumor necrosis factor-alpha (TNF-α) antagonists;
7. Must be either naïve to AZA/6-MP or have not received AZA/6-MP for at least 3 months before enrollment in the study;
8 Are considered eligible according to the following tuberculosis (TB) screening criteria:
a. Have no history of latent or active TB prior to Screening;
b. Have no signs or symptoms suggestive of active TB upon medical history and/or physical examination;
c. Have had no recent close contact with a person with active TB or, if there has been such contact, will be referred to a physician specializing in TB to undergo additional evaluation and, if warranted, receive appropriate treatment for latent TB prior to or simultaneously with the first administration of infliximab;
d. Within 1 month prior to the first administration of inflixmab, either have negative tuberculin skin test, as outlined in Appendix 6 OR have a newly identified positive tuberculin test during screening in which active TB has been ruled out, and for which appropriate treatment for latent TB has been initiated either prior to or simultaneously with the first administration of infliximab.
e. Must have a chest X-ray (posterior-anterior and lateral views), taken within the 3 months prior to the first administration of study agent and read by a qualified radiologist, with no evidence of current active TB or old inactive TB.
9. Who have had UC for more than 10 years should have had a full colonoscopy within 2 years prior to Screening for the surveillance of dysplasia;
10. Subjects’ Screening and Baseline clinical laboratory tests (complete blood count [CBC] and blood chemistries) must be within the following parameters:
a. White blood cells (WBCs) ≥3.5 x 10 power of 9/L
b. Neutrophils ≥1.5 x 10 power of 9/L
c. Platelets ≥100 x 10 power of 9/L
d. Serum creatinine <1.5 mg/dL (or <133 µmol/L)
e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.5 x upper limit of normal (ULN), alkaline phosphatase and gamma-glutamyltransferase ≤2.5 x ULN
f. Total bilirubin ≤1 x ULN
11. Subjects who had been on antibiotics for the treatment of UC (eg, ciprofloxacin and metronidazole) must have been discontinued from them at least 3 weeks prior to Screening;
12. Must be free of any clinically significant condition or situation, other than UC that, in the opinion of the investigator, would interfere with the study evaluations or optimal participation in the study;
13. Are willing and able to adhere to the study visit schedule and other protocol requirements;
14. Are capable of providing written informed consent, which must be obtained prior to conducting any protocol-specified procedures;
15. Women of child-bearing potential and all men must agree to use a medically accepted method of contraception prior to screening, while receiving protocol-specified medication, and for 6 months after stopping the medication. Acceptable methods of contraception include condoms (male or female) with or without a spermicidal agent, diaphragm or cervical cap with spermicide, medically prescribed IUD, oral or injectable hormonal contraceptive, and surgical sterilization (eg, hysterectomy or tubal ligation). Women of child-bearing potential who are not currently sexually active must agree to use a medically accepted method of contraception should they become sexually active while participating in the study;
16. Female subjects of childbearing potential must have a negative serum pregnancy test (beta-hCG) at Screening and a negative urine pregnancy test at Baseline.
For direct entry into Part 2, the subject must meet ALL the criteria listed below for entry:
Use the inclusion criteria from Part 1 number 1, 2, 4, 8, 9, 10, 11, 12, 13, 14, 15, 16
The below are the additional criteria and the associated number as per the protocol
3. Subjects must be in remission based on the total Mayo score with sigmoidoscopy performed within 14 days before Baseline without the use of corticosteroids.
4. Subjects must have been on a scheduled IFX infusion every 8 Wks (± 1 Wk) for a maximum period of 6 mths.
5. If subjects are treated with AZA/6-MP, the dose must be stable.
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| E.4 | Principal exclusion criteria |
The subject will be excluded from entry if ANY of the criteria listed below are met:
1. Have severe extensive colitis as evidenced by:
a. Investigator judgment that the subject is likely to require colectomy within 12 wks of Baseline
OR
b. Subjects with at least 4 of these symptoms at Screening or Baseline visits as described in the protocol.
2. Require, or are required within the 2 mths prior to baseline, surgery for active gastrointestinal bleeding, peritonitis, intestinal obstruction, or intra-abdominal or pancreatic abscess requiring surgical drainage or other conditions possibly confounding the evaluation of disease activity;
3. Have severe, fixed symptomatic stenosis of the large or small intestine;
4. Have current evidence of colonic obstruction or history within the 6 mths prior to baseline, confirmed with objective radiographic or endoscopic evidence of a stricture with resulting
5. Have a history of colonic mucosal dysplasia;
6. Presence on screening endoscopy of adenomatous colonic polyps, if not removed prior to study entry, or history of adenomatous colonic polyps that were not removed;
7. Have the presence of a stoma;
8. Have a history of extensive colonic resection that would prevent adequate evaluation of clinical disease activity
9. Have a positive stool culture for enteric pathogens, pathogenic ova or parasites within 4 months prior to Baseline unless subject has received treatment and had a negative stool examination 1 wk or longer after the end of treatment;
10. Have a concomitant diagnosis of CHF, including medically controlled asymptomatic subjects;
11. Have had serious infections within 2 mths of screening. Less serious infections need not be considered as an exclusion at the discretion of the investigator;
12. Have had a nontuberculous mycobacterial infection or opportunistic infection within 6 months prior to screening;
13. Have a known infection with HIV and/or hepatitis B or hepatitis C;
14. Have a history of a known allergy to murine proteins or allergy/sensitivity to study drug or its excipients;
15. Have current signs and symptoms of systemic lupus erythematosus, or severe, progressive, or uncontrolled renal, hepatic, hematologic, endocrine, pulmonary, cardiac, neurologic, or cerebral diseases;
16. Have a known history of demyelinating disease suggestive of multiple sclerosis or optic neuritis;
17. Presence of a transplanted organ (with the exception of a corneal transplant >3 months prior to screening);
18. Have a history of lymphoproliferative disease including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy of unusual size or location (eg, nodes in the posterior triangle of the neck, infra-clavicular, epitrochlear, or periaortic areas), or splenomegaly;
19. Have any current known malignancy or malignancy within 5 years prior to screening (except for squamous or basal cell carcinoma of the skin that has been treated with no evidence of recurrence);
20. Have poor tolerability of venipuncture or lack of adequate venous access for required blood sampling and infusion of study drug during the study period;
21. Have had a known substance abuse or dependency (drug or alcohol) within 3 years of Screening;
22. Require chronic (≥1 month) and frequent use (≥3 days per wk) of NSAIDs except low-dose aspirin for prevention of heart attacks, unstable angina, or transient ischemic attacks;
23. Have other inflammatory diseases that might interfere with the evaluation of the ulcerative colitis;
24. Who have a history of latent or active granulomatous infection, including TB, histoplasmosis, or coccidioidomycosis, prior to screening.
25. Have had a Bacille Calmette-Guerin (BCG) vaccination within 12 mths of screening.
26. Have a chest X-ray within the 3 mths prior to the first administration of study agent that shows an abnormality suggestive of a malignancy or current active infection, including TB.
27. Have received any treatment listed in Table 2 (See Protocol) more recently than the indicated washout period prior to Screening;
28. Who are participating in any other clinical study or who have received treatment with any investigational drug or device within 3 mths prior to Screening;
29. Who is part of the staff or a family member of the staff personnel directly involved with this study.
Subject Exclusion Criteria for Direct Entry into Part 2
Use the exclusion criteria from Part 1 number 2 – 23, 28, 29. Use Table 2 from criteria 27 with the exception that Azathioprine or 6-MP is removed. All other prohibited meds apply.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint for Part 1 of the study is the proportion of subjects in remission at Wk 16 (ie, total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point, without the use of corticosteroids).The primary efficacy endpoint for Part 2 is the average remission rate over duration of treatment. |
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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 | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| 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 | Yes |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| 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 | Yes |
| 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.8.5.1 | Number of sites anticipated in the EEA | 84 |
| 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 | No |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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