E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Intravenous steroid-refractory ulcerative colitis (IVSR-UC) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10045365 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the efficacy, immunogenicity, and safety of three dose levels of Visilizumab in subjects with IVSR-UC, and to evaluate optimal dosing.
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E.2.2 | Secondary objectives of the trial | |
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Eligible subjects will be considered for inclusion in theis study if they meet all of the following criteria:
1) Males & females, 18 years of age or older.
2) Diagnosis of UC, as verified by endoscopy performed within 60 months prior to consent.
3) Severe active disease, as defined by MTWSI ≥11 at consent, with a confirmatory MTWSI ≥10 on or after the fifth consecutive day of IV steroids and within 1 day prior to randomization/registration.
4) Mayo score ≥10 and a Mayo mucosal subscore (finding of flexible proctosigmoidoscopy) of ≥2. The Mayo score will be calculated on the day of sigmoidoscopy by a blinded gastroenterologist, after a minium of 3 consecutive days (i.e. on or after the fourth consecutive day) of IV steroids.
5) Agreement to use adequate contraception by male or female subjects of reproductive potential throughout the study and for 3 months after receiving the last dose of study drug.
6) Negative serum pregnancy test at screening in female subjects of childbearing potential.
7) Negative Clostridium difficile test within 10 days prior to the first dose of study drug.
8) Ability to understanding the purpose and risks of the study and provide signed and dated informed consent. |
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E.4 | Principal exclusion criteria |
Subjects will be ineligible for this study if they meet any one of the following criteria:
1) UC requiring immediate surgical, endoscopic, or radiologic interventions, including massive hemorrhage, perforation and sepsis, suppurative complications (intra-abdominal or perianal abscesses), or toxic megacolon requiring imminent intervention.
2) History of total proctocolectomy, or subtotal colectomy with ileorectal anastomosis.
3) Presence of ileostomy.
4) White blood cell count less than 2.5 x 10 (E3)/mcL; platlet count less than 150 x 10 (E3)/mcL; or hemoglobin level less than 8g/dL. Note the following exceptions for WBC counts only (minimum platelet counts and hemoglobin levels are the same)
a) If subject is currently taking a stable dose of 6MP/AZA for 60 days or more, a WBC count <2.0 x 10 (E3)/mcL. b) If subject has initiated treatment with, or increased his/her dose of, 6MP, AZA or methotrexate (MTX) within 60 days prior to consent, a WBC count of ≤ 5 x 10 (E3)/mcL at the time of screening.
5) Active medically significant infections, particularly those of viral etiology, e.g. known CMV colitis. This includes any incidence of medically significant opportunistic infections(see Definitions) within the past 12 months.
6) Live vaccination within 6 weeks prior to randomization (Subjects may not receive any vaccine for 60 days after randomization).
7) Significant organ dysfunction, including cardiac, renal, liver, CNS, pulmonary, vascular, gastrointestinal, endocrine, or laboratory abnormality (e.g. creatinine ≥1.6 mg/dL; ALT or AST ≥ 2X the upper limit of normal [ULN]; alkaline phosphatase ≥ 1.5X ULN); a history of myocardial infarction, coronary artery disease, congestive heart failure, or arrhythmias within 6 months prior to consent.
8) History or treatment of lymphoproliferative disorder (LPD) or malignancy within the past 5 years (excluding nonmelanoma skin cancer or carcinoma in situ of the cervix).
9) Seropositive for infection with human immunodeficiency virus (HIV-1), hepatitis B virus (HBV) surface antigen, or hepatitis C virus (HCV) antibody.
10) Treatment with a first dose of infliximab or another anti-TNF- α drug within 4 weeks of randomization, or treatment with a subsequent dose of an anti-TNF-α drug within 2 weeks of randomization.
11) Treatment with cyclosporine or tacrolimus (FK506) within 2 weeks prior to randomization.
12) Treatment with any other investigational drug or therapy within 60 days prior to randomization, except those mentioned in the above two exclusion criteria.
13) Any condition that, in the investigator’s opinion, makes the subject unsuitable for study participation.
14) Unable or unwilling to discontinue all UC drugs, except for glucocorticoids and oral 5-ASA, immediately prior to randomization.
15) Pregnancy or nursing.
16) Nontherapeutic levels of chronic anti-seizure medications in subjects with a prior history of seizures, as tested within 4 days prior to randomization.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the comparison of the proportion of subjects in each of the three visilizumab dose groups who respond to treatment on Day 45 (± 4 days) in the dose-exploration portion of this study (Stage 1). A subject is defined as a responder if he or she has a ≥ 3-point reduction in the total Mayo score from baseline, with the rectal bleeding subscore reduced by at least 1 point, or an actual rectal bleeding subscore of 0 to 1.
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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 | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
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) | No |
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 | Yes |
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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The end of trial is defined as the last visit of the last subject in the trial |
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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 | 5 |
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 | 5 |