| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderately to severely active Ulcerative Colitis |
|
| 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 | 10009900 |
| E.1.2 | Term | Colitis ulcerative |
|
| 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 primary objectives of this study are to evaluate the efficacy of a 3-dose induction regimen of infliximab in inducing clinical response in pediatric subjects with moderately to severely active UC and to evaluate the safety profile of infliximab during induction and maintenance treatment. |
|
| E.2.2 | Secondary objectives of the trial |
The major secondary objectives are:
1. To evaluate the efficacy of 2 infliximab maintenance dosing regimens (q8 and q12 weeks) in maintaining clinical remission.
2. To evaluate the efficacy of 2 infliximab maintenance dosing regimens (q8 and q12 weeks) in maintaining clinical response.
3. To evaluate the efficacy of a 3-dose induction regimen of infliximab in inducing clinical remission.
4. To evaluate the efficacy of a 3-dose induction regimen of infliximab in inducing mucosal healing. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Aged 6 to 16 years old, inclusive, if enrolled at a site that cannot treat and/or follow subjects once they become 18 years of age or aged 6 to 17 years old, inclusive, at all other sites.
2. Affected by moderately to severely active UC, defined as a baseline Mayo score of 6 to 12, inclusive.
3. Affected by UC diagnosed at least 3 months prior to screening..
4. Diagnosis of UC confirmed by the screening biopsy.
5. Affected by moderately to severely active UC confirmed during the screening sigmoidoscopy by a ≥ 2 endoscopy subscore of the Mayo score.
6. Must meet at least 1 of the following criteria:
a. Immunomodulators (6-MP or AZA): Be receiving adequate treatment with 6-MP or AZA, or have failed (within the last 5 years) to respond to an adequate dose of 6-MP or AZA, or have had medical complications and/or AEs from 6-MP or AZA (within the last 5 years) that, in the judgment of the subject’s physician, preclude the use of these medications at doses adequate to treat UC.
b. Oral Corticosteroids: Be receiving adequate treatment with oral corticosteroids or have failed (within the past 2 years) to respond to an adequate dose of corticosteroids or to successfully taper corticosteroids (ie, had a flare of disease on tapering to < 10 mg of prednisone on 2 separate occasions), or have had medical complications and/or AEs from corticosteroids (within the past 2 years) that, in the judgment of the subject’s physician, preclude the use of these medications.
7. Must be receiving (at no specific dose) 6-MP, AZA, or MTX because of the potential of these drugs to prevent the formation of antibodies to infliximab.
8. Must meet concomitant medication stability criteria, as appropriate for a. 6-MP, AZA, MTX, b. Corticosteroids, c. 5-ASA compounds, d. Bulking or stool softening agents.
9. Must have discontinued the use of antibiotics for the treatment of UC at least 3 weeks prior to Mayo screening procedures.
10. Must have a well-documented history of chicken pox or an uncertain history of chicken pox with a positive varicella antibody titer, or an history of varicella vaccination with positive varicella antibody titer.
11. If at increased risk for colon cancer must either have had a colonoscopy to assess the presence of dysplasia.
12. Have screening laboratory tests that meet the following criteria: Hemoglobin ≥ 8.5 g/dL; White blood cell count ≥ 3.5 x 109/L; Neutrophils ≥ 1.5 x 109/L; Platelets ≥ 100 x 109/L
13. Male subjects who are sexually active and female subjects of childbearing potential who are sexually active must agree to use adequate birth control measures.
14. Signed written consent from the parent/legal guardian and assent from the child (age at which assent is given may vary by IRB/EC) must be obtained prior to any protocol-specified procedures.
15 Are considered eligible according to the following TB screening criteria: have no history of latent or active TB prior to screening.; have no signs or symptoms suggestive of active TB upon medical history and/or physical examination, have had no recent close contact with a person with active TB, within 1 month prior to the first administration of study agent, have a negative tuberculin skin test, have a chest radiograph (posterior-anterior view), taken within 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. |
|
| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria may not be enrolled:
1. Have severe extensive colitis as evidenced.
2. Have UC limited to the rectum only or to < 20 cm of the colon.
3. Have a history of latent or active granulomatous infection.
4. Have had a Bacille Calmette-Guerin (BCG) vaccination within 12 months of screening.
5. Have had a chest radiograph within 3 months prior to the first administration of study agent that shows an abnormality suggestive of a malignancy or current active infection, including TB.
6. Have had a nontuberculous mycobacterial infection or opportunistic infection within 6 months prior to screening.
7. Have had a live viral or bacterial vaccination within 3 months prior to screening.
8. Have a positive stool culture for enteric pathogens.
9. Have or have had serious infection (such as hepatitis, pneumonia, or pyelonephritis) in the 3 months prior to screening. Less serious infections (such as acute upper respiratory tract infections [colds]) need not be considered exclusionary criteria at the discretion of the investigator.
10. Have immune deficiency syndrome.
11. Have documented HIV, AIDS-related complex, or AIDS and/or hepatitis B or hepatitis C.
12. Receiving total parenteral nutrition (TPN) within the 2 weeks prior to Mayo screening procedures.
13. Received parenteral corticosteroids within 2 weeks prior to Mayo screening procedures.
14. Require chronic and frequent use of antimotility agents for control of diarrhea .
15. Have used laxatives, except for preparation for endoscopy or other procedures, within 1 week prior to Mayo screening procedures.
16 Were treated with cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil (MMF) within 8 weeks prior to screening.
17. Have used any investigational drug within 4 weeks prior to screening or within 5 half-lives of the investigational agent, whichever is longer.
18. Have received prior treatment with infliximab or any other TNF antagonist.
19. Have known history of allergy to murine proteins or any previous treatment with murine products.
20. Have ever received natalizumab or other agents that target alpha-4-integrin.
21. Have ever received agents that deplete B cells (eg, rituximab) or T cells (eg, alemtuzamab).
22. Presence of a stoma.
23. Presence or history of a fistula.
24. Require, or required within the 2 months prior to screening, surgery for active gastrointestinal bleeding, peritonitis, intestinal obstruction, or intra-abdominal or pancreatic abscess or other conditions possibly confounding the evaluation of benefit from infliximab treatment.
25. Have severe, fixed symptomatic stenosis of the large or small intestine.
26. Presence or history of colonic obstruction within the 6 months prior to baseline.
27. History of extensive colonic resection.
28. History of colonic mucosal dysplasia.
29. 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.
30. Presence or history of any malignancy within 5 years of screening.
31. History of lymphoproliferative disease.
32. Concomitant diagnosis or history of CHF, including medically controlled asymptomatic CHF.
33. Have signs or symptoms of severe, progressive, or uncontrolled renal, hepatic, hematologic, endocrine, pulmonary, cardiac, neurologic, psychiatric, or cerebral diseases.
34. History of systemic lupus erythematosus.
35. Received an organ transplant.
36. History of demyelinating disease, such as multiple sclerosis or optic neuritis.
37. Are pregnant, nursing, or planning pregnancy (both males and females) within 18 months after screening. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Clinical response is defined as a decrease from baseline in the Mayo score by ≥ 30% and
≥ 3 points, with a decrease in the rectal bleeding subscore of ≥ 1 or a rectal bleeding
subscore of 0 or 1.
Clinical remission is defined as a Mayo score ≤ 2 points, with no individual subscore > 1.
By this definition, subjects in clinical remission will have a rectal bleeding subscore of
either 0 or 1. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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