| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045365 |
| E.1.2 | Term | Ulcerative colitis |
|
| 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 |
| to evaluate the efficacy of a 3-dose induction regimen of infliximab in inducing a clinical response, as measured by the Mayo score, 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 |
1. To evaluate the efficacy of 2 infliximab maintenance dosing regimens (q8 and q12 weeks) in maintaining remission, as measured by the PUCAI score.
2. To evaluate the efficacy of a 3-dose induction regimen of infliximab in inducing clinical remission, as measured by the Mayo score.
3. To evaluate the efficacy of a 3-dose induction regimen of infliximab in inducing remission, as measured by the PUCAI score.
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 | No |
| E.3 | Principal inclusion criteria |
| 1.Are 6-16 years, inclusive, if enrolled at a site that cannot treat and/or follow subjects once they become 18 years.OR Are 6 to 17 years, inclusive, at all other sites.2.Have moderately to severely active UC, defined as a baseline Mayo score of 6 to 12, inclusive.3.Had UC diagnosed or referral to the investigator to establish UC diagnosis initiated at least 2 weeks prior to screening.4.Must have the diagnosis of UC confirmed by the biopsy. 5.Must have moderately to severely active UC confirmed by a Mayo endoscopy subscore ≥ 2 at screening sigmoidoscopy.6.Must meet at least 1 of the following criteria:1) Be receiving adequate treatment* with 5-ASA compounds.OR 2)Have failed to (within the last 18 months) to respond to an adequate dose* of 5-ASA compounds. OR 3)Have had medical complications and/or AEs from 5-ASA compounds (within last 18 months) that, in the judgment of the subject’s physician, preclude the use of these medications.OR b.Immunomodulators (6-MP or AZA):1) Be receiving adequate treatment*with 6-MP or AZA.OR 2) Have failed (within last 5 years) to respond to an adequate dose*of 6-MP or AZA. OR 3) Have had medical complications and/or AEs from 6-MP or AZA (within last 5 years) that, in the judgment of the subject’s physician, preclude the use of these medications at doses adequate to treat UC. OR c.Oral or IV Corticosteroids:1) Be receiving adequate treatment* with corticosteroids. OR 2) Have failed (within 2 years) to respond to an adequate dose* of corticosteroids or to successfully taper corticosteroids. OR 3) 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. 8.Must meet concomitant medication stability criteria, as appropriate:b).Corticosteroids:1)If receiving oral or IV corticosteroids, the dose (in prednisone equivalents) must have been stable for at least 1 weeks prior to Mayo screening procedures.2)If receiving rectal corticosteroids, the dose must have been stable for at least 1 weeks prior to Mayo screening procedures.3)If oral, IV, or rectal corticosteroids have been recently discontinued, they must have been stopped at least 2 weeks prior to Mayo screening procedures.c. 5-ASA compounds:1)If receiving oral or rectal 5-ASA compounds, the dose must have been stable for at least 2 weeks prior to Mayo screening procedures.2)If oral or rectal 5-ASA compounds have been recently discontinued, they must have been stopped at least 2 weeks prior to Mayo screening.d.If using bulking or stool softening agents chronically, the dose must have been stable for at least 2 weeks prior to Mayo screening and a stable dose must be maintained until Week54.9.If receiving enteral nutrition, must have been on a stable regimen for 2 weeks prior to Mayo screening.10.Must have discontinued the use of antibiotics for the treatment of UC at least 1week prior to Mayo screening procedures.11.Must be able and willing to comply with protocol requirements for stable dosages of concomitant medication through Week 54. 12.Must have at least 1 of the following:documented history of chicken pox by medical chart review or careful interview of parents or guardian, OR An uncertain history of chicken pox with a positive varicella antibody titer OR A history of varicella vaccination with positive varicella antibody titer.13.If at increased risk for colon cancer must either have had a colonoscopy to assess the presence of dysplasia within 1 year prior to first infusion at Week 0 or a colonoscopy to assess the presence of malignancy at the screening visit 14.Have screening laboratory tests that meet the following criteria: a.Hemoglobin ≥ 7.5 g/dL b.White blood cell count ≥ 2.5x10E9/L c.Neutrophils ≥ 1.5x10E9/L d.Platelets ≥ 100x10E9/L e.AST, ALT, and alkaline phosphatase levels must be within 3 times the upper limit of normal range for the laboratory conducting the test.15. Sexually active Male and female subjects must agree to use adequate birth control measures during the study and 6 months after the last infusion. All female subjects who menstruate and/or who are 10 years old must have a negative serum pregnancy test at screening and a negative urine pregnancy test at Week 0. Female subjects who are younger than 10 must also have a negative serum pregnancy test and a negative urine pregnancy if the clinician suspects that puberty is imminent.16. Are considered eligible according to the following screening criteria: a. Have no history of latent or active TB. 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.d.Within 1 month to first administration of study agent, have a negative tuberculin skin test. e. Have a chest radiograph, taken within 3 months prior to the first administration of study agent and read |
|
| E.4 | Principal exclusion criteria |
Condensed:
1. Have severe extensive colitis as evidenced by:
a. Investigator judgment that the subject is a candidate for imminent colectomy.
OR
b. Symptom complex at screening or baseline visits that includes at least 4 of the following:
1) diarrhea with ≥ 6 bowel movements/day with macroscopic blood in stool
2) focal severe or rebound abdominal tenderness
3) persistent fever
4) tachycardia (≥ 90 beats/minute)
5) anemia (≥ 8.5 g/dL)
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, including TB, histoplasmosis, or coccidioidomycosis, prior to screening.
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 stool culture or other examination positive for an enteric pathogen including Clostridium difficile toxin.
9. Have or have had serious infection in the 3 months prior to screening.
10. Have immune deficiency syndrome.
11. Have documented HIV, AIDS-related complex, or AIDS and/or hepatitis B or
hepatitis C.
12. Have signs or symptoms of any other medical condition that might predispose the
subject to significant infection.
13. removed by Amendment 1
14. removed by Amendment 1
15. Require chronic and frequent use of antimotility agents for control of diarrhea
16. Have used laxatives, except for preparation for endoscopy or other procedures,
within 1 week prior to Mayo screening procedures.
17. Were treated with cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil
within 8 weeks prior to screening.
18. Have used any investigational drug within 4 weeks prior to screening or within 5 half-lives of the investigational agent, whichever is longer, or have used apheresis (ie, Adacolumn® apheresis) within 2 weeks prior to screening.
19. Have received prior treatment with infliximab or any other TNF antagonist
20. Have known history of allergy to murine proteins or any previous treatment with
murine products.
21. Have ever received natalizumab or other agents that target alpha-4-integrin.
22. Have ever received agents that deplete B cells or T cells.
23. Presence of a stoma.
24. Presence or history of a fistula.
25. Require, or required within the 2 months prior to screening, 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 benefit from infliximab treatment.
26. Have severe, fixed symptomatic stenosis of the large or small intestine.
27. Presence or history of colonic obstruction within the 6 months prior to baseline,
confirmed by objective radiographic or endoscopic evidence of a stricture with
resulting obstruction.
28. History of extensive colonic resection that would prevent adequate evaluation of the effect of infliximab on clinical disease activity.
29. History of colonic mucosal dysplasia.
30. 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.
31. Presence or history of any malignancy within 5 years of screening.
32. History of. or current lymphoproliferative disease including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy of unusual size or location or clinically significant hepatic and/or splenic enlargement.
33. Concomitant diagnosis or history of CHF, including medically controlled asymptomatic CHF.
34. Have signs or symptoms of severe, progressive, or uncontrolled renal, hepatic,
hematologic, endocrine, pulmonary, cardiac, neurologic, psychiatric, or cerebral
diseases.
35. History of systemic lupus erythematosus.
36. Received an organ transplant.
37. History of demyelinating disease, such as multiple sclerosis or optic neuritis.
39. Have poor tolerability of venipuncture or lack of adequate venous access for
required blood sampling and infusion of study drug during the study period.
40. Are pregnant, nursing, or planning pregnancy within 18 months after screening.
41. Family history of lymphoproliferative disease or leukemia.
42. Receiving corticosteroids at a dose equivalent to > 50 mg prednisone per day.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Clinical response at Week 8, as measured by the Mayo score |
|
| 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 | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| 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 | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| 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 | 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
|
| The end of the study is defined as the final visit (Week 62) of the last subject. |
|
| 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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