E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Moderate to Severe Ulcerative Colitis
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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 |
Primary Objective for the Induction Phase
• To determine the effect of MLN0002 induction treatment on clinical response at 6 weeks
Primary Objective for the Maintenance Phase
• To determine the effect of MLN0002 maintenance treatment on clinical remission at 52 weeks
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives for the Induction Phase
• To determine the effect of MLN0002 induction treatment on clinical remission at 6 weeks
• To determine the effect of MLN0002 induction treatment on mucosal healing at 6 weeks
Secondary Objectives for the Maintenance Phase
• To determine the effect of MLN0002 maintenance treatment on durability of clinical response
• To determine the effect of MLN0002 maintenance treatment on mucosal healing at 52 weeks
• To determine the effect of MLN0002 maintenance treatment on durability of clinical remission
• To determine the effect of MLN0002 maintenance treatment on corticosteroid-free remission at 52 weeks
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age 18 to 80
2. Male or female patient who is voluntarily able to give informed consent
3. Female patients must: • be post-menopausal for at least 1 year before the screening visit, OR • be surgically sterile, OR • (if they are of childbearing potential) agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 6 months after the last dose of study drug, OR • agree to completely abstain from heterosexual contact. Male patients, even if surgically sterilized (ie, status post-vasectomy), must: • agree to practice effective barrier contraception during the entire study treatment period and through 6 months after the last dose of study drug, OR • agree to completely abstain from heterosexual contact.
4. Diagnosis of ulcerative colitis established at least 6 months prior to enrollment by clinical and endoscopic evidence and corroborated by a histopathology report.
5. Moderate to severe ulcerative colitis as determined by a Mayo score of 6 to 12 with an endoscopic subscore ≥2 during the screening period
6. Evidence of ulcerative colitis extending proximal to the rectum (≥15 cm of involved colon)
7. Patients with extensive colitis or pancolitis of >8 years duration or left-sided colitis of >12 years duration must have documented evidence of a surveillance colonoscopy within 12 months of the initial screening visit (may be performed during screening).
8. Patients with a family history of colorectal cancer, personal history of increased colorectal cancer risk, age >50 years, or other known risk factor must be up-to-date on colorectal cancer surveillance (may be performed during screening)
9. Demonstrated, over the previous 5 year period, an inadequate response to, loss of reponse to, or intolerance of at least one of the following agents as defined below: • Corticosteroids
i) Signs and symptoms of persistently active disease despite a history of at least one 4-week induction regimen that included a dose equivalent to prednisone 30 mg daily orally for 2 weeks or intravenously for 1 week OR ii) Recurrence of clinical symptoms upon tapering below a dose equivalent to prednisone 10 mg daily orally on two separate occasions OR iii) History of intolerance of corticosteroids (including, but not limited to Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, infection) • Immunomodulators i) Signs and symptoms of persistently active disease despite a history of at least one 8 week regimen of oral azathioprine (≥1.5 mg/kg) or 6-mercaptopurine mg/kg (≥0.75 mg/kg) OR ii) History of intolerance of at least one immunomodulator (including, but not limited to nausea/vomiting, abdominal pain, pancreatitis, LFT abnormalities, lymphopenia, TPMT genetic mutation, infection) • TNF antagonists i) Signs and symptoms of persistently active disease despite a history of at least one 4 week induction regimen of infliximab 5 mg/kg IV, 2 doses at least 2 weeks apart OR ii) Recurrence of symptoms during maintenance dosing following prior clinical benefit (discontinuation despite clinical benefit does not qualify) OR iii) History of intolerance of infliximab (including, but not limited to infusionrelated reaction, demyelination, congestive heart failure, infection)
10. May be receiving a therapeutic dose of the following drugs: • Oral 5-ASA compounds provided that the dose has been stable for the 2 weeks immediately prior to enrollment • Oral corticosteroid therapy (prednisone at a stable dose ≤30 mg/day, or equivalent steroid) provided that the dose has been stable for the 4 weeks immediately prior to enrollment if corticosteroids have just been initiated, or 2 weeks immediately prior to enrollment if corticosteroids were in the process of being tapered • Probiotics (eg, Culturelle, Saccharomyces boulardii) provided that the dose has been stable for the 2 weeks immediately prior to enrollment • Antidiarrheals (eg, loperamide, diphenoxylate with atropine) for control of chronic diarrhea • Azathioprine or 6-mercaptopurine provided that the dose has been stable for the 8 weeks immediately prior to enrollment
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E.4 | Principal exclusion criteria |
The exclusion criteria are divided into 3 categories: gastrointestinal exclusion criteria, infectious disease exclusion criteria, and general exclusion criteria. Patients meeting any of the following exclusion criteria are not to be enrolled in the study.
Gastrointestinal Exclusion Criteria
1. Evidence of abdominal abscess or toxic megacolon at the initial screening visit 2. Extensive colonic resection, subtotal or total colectomy 3. Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine 4. Within 30 days prior to enrollment, have received any of the following for the treatment of underlying disease: • Non-biologic therapies (eg, cyclosporine, thalidomide) other than those permitted in Section 6.2 • A non-biologic investigational therapy • An approved non-biologic therapy in an investigational protocol 5. Within 60 days prior to enrollment, have received any of the following: • Infliximab • Other investigational or approved biological agent 6. Any prior exposure to natalizumab, efalizumab or rituximab 7. Use of topical (rectal) treatment with 5-ASA or corticosteroid enemas/suppositories within 2 weeks of the administration of the first dose of study drug 8. Evidence of or treatment for C. difficile infection within 60 days or other intestinal pathogen within 30 days prior to enrollment 9. Currently require or are anticipated to require surgical intervention for UC during the study 10. History or evidence of adenomatous colonic polyps that have not been removed 11. History or evidence of colonic mucosal dysplasia 12. Diagnosis of Crohn’s colitis or indeterminate colitis
Infectious Disease Exclusion Criteria
1. Any chronic hepatitis B or C infection 2. Active or latent tuberculosis, regardless of treatment history, as evidenced by any of the following: • History of tuberculosis • A positive diagnostic tuberculosis (TB) test within one month of enrollment defined as: i) a positive QuantiFERON test or 2 successive indeterminate QuantiFERON tests OR ii) a tuberculin skin test reaction ≥10 mm ( ≥5 mm in patients receiving the equivalent of > 15 mg/day prednisone). • Chest x-ray within 3 months of enrollment in which active or latent pulmonary tuberculosis cannot be excluded 3. Any identified congenital or acquired immunodeficiency (eg, common variable immunodeficiency, human immunodeficiency virus [HIV] infection, organ transplantation) 4. Any live vaccinations within 30 days prior to study drug administration except for the influenza vaccine 5. Clinically significant extra-intestinal infection (eg, pneumonia, pyelonephritis) within 30 days prior to enrollment
General Exclusion Criteria
1. Previous exposure to MLN0002 2. Female patients who are lactating or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 prior to study drug administration. 3. Any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, gastrointestinal, genitourinary, hematological, coagulation, immunological, endocrine/metabolic, or other medical disorder that, in the opinion of the investigator, would confound the study results or compromise patient safety 4. Had any surgical procedure requiring general anesthesia within 30 days prior to enrollment or is planning to undergo surgery during the study period 5. Any history of malignancy, except for the following: • adequately-treated non-metastatic basal cell skin cancer; • Squamous cell skin cancer that has been adequately treated and has not recurred for at least 1 year prior to enrollment; and • history of cervical carcinoma in situ that has been adequately treated and that has not recurred for at least 3 years prior to enrolment. Patients with remote history of malignancy (eg, >10 years since completion of curative therapy without recurrence) will be considered based on the nature of the malignancy and the therapy received and must be discussed with the sponsor on a case-by-case basis prior to enrollment. 6. History of any major neurological disorders, including stroke, multiple sclerosis, brain tumor, or neurodegenerative disease 7. Positive PML subjective symptom checklist prior to the administration of the first dose of study drug 8. Any of the following laboratory abnormalities during the screening period: • Hemoglobin level <8 g/dL • WBC count <3 × 10exp9/L • Lymphocyte count <0.5 × 10exp9/L • Platelet count <100 × 10exp9/L or >1200 × 10exp9/L • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × the upper limit of normal (ULN) • Alkaline phosphatase >3 × ULN • Serum creatinine >2 × ULN 9. Current or recent history (within one year prior to enrollment) of alcohol dependence or illicit drug use 10. Active psychiatric problems that, in the investigator’s opinion, may interfere with compliance with the study procedures 11. Unable to attend all the study visits or comply with study procedures |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Endpoint for the Induction Phase:
• Proportion of patients with clinical response at Week 6
Primary Endpoint for the Maintenance Phase:
• Proportion of patients in clinical remission at Week 52
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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 | Yes |
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 | Yes |
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 | 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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 104 |
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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End of Study
• Week 52 or Early Termination (ET) Visit (safety and efficacy assessments)
• Week 66 Visit (safety assessments)
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |