| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderately to Severely Active Ulcerative Colitis |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045365 |
| E.1.2 | Term | Ulcerative colitis |
| E.1.2 | System Organ Class | 100000004856 |
|
| 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 |
Global:
1. To evaluate the efficacy of ustekinumab dosing in inducing clinical remission in pediatric participants with moderately to severely active UC.
2. To evaluate the safety profile of ustekinumab in pediatric participants with moderately to severely active UC.
3. To evaluate ustekinumab exposure (PK).
US specific:
4. To evaluate the efficacy of ustekinumab dosing in maintaining clinical remission among participants who were in clinical response in induction.
5. To evaluate the safety profile of ustekinumab.
6. To evaluate ustekinumab exposure (pharmacokinetics [PK]). |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the efficacy of IV ustekinumab during the induction period.
2. To evaluate the efficacy of SC ustekinumab during the maintenance period among participants who were in clinical response in induction. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
General
1. 2 to <18 years of age, inclusive (at the time of the first administration of study intervention at Week I-0) with a body weight ≥10 kg.
2. Medically stable on the basis of physical examination, medical history, and vital signs, performed at screening. Any abnormalities must be consistent with the underlying illness in the study population and this determination must be recorded in the participant's source documents and acknowledged by the investigator.
3. Medically stable on the basis of clinical laboratory tests performed at screening. If the results of the serum chemistry panel including liver enzymes, other specific tests, blood coagulation, or hematology are outside the normal reference ranges, the participant may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant or to be appropriate and reasonable for the population under study. This determination must be recorded in the participant's source documents and acknowledged by the investigator.
UC diagnosis and status
4. Must have had UC diagnosed for at least 1 month prior to screening.
5. Must have biopsy confirmation that is consistent with a diagnosis of UC (eg, crypt distortion, crypt abscess, and goblet cell depletion).
6. Have moderately to severely active UC, defined as a baseline Mayo score of 6 through 12, inclusive, with a screening Mayo endoscopy subscore ≥2 as determined by a central review of the video of the endoscopy.
Allowed concomitant or previous medical therapies for UC
7. Prior or current medication for UC must include at least one of the following:
Have received biologic therapy (ie, TNFα antagonist or vedolizumab) for the treatment of pediatric UC and have had an appropriate washout duration prior to first administration of study intervention and have a documented history of failure to respond to or not tolerate treatment;
OR
Be naïve to biologic therapy or have not demonstrated a history of failure to respond to, or tolerate a biologic therapy and have a prior or current UC medication history that includes at least 1 of the following:
a. Inadequate response to or failure to tolerate current treatment with oral or IV corticosteroids or immunomodulators (6-MP, AZA, or MTX)
OR
b. History of failure to respond to, or tolerate, at least 1 of the following therapies: oral or IV corticosteroids or immunomodulators (6-MP or AZA or MTX)
OR
c. History of corticosteroid dependence (ie, an inability to successfully taper corticosteroids without a return of the symptoms of UC)
OR
d. Have required more than 3 courses of oral or IV corticosteroids in the past year.
8. Must meet concomitant medication criteria prior to the first administration of study intervention:
Corticosteroids
a. If receiving budesonide or beclomethasone dipropionate, the dose must have been stable or discontinued for at least 2 weeks prior to Week I-0.
b. If receiving oral corticosteroids, other than budesonide or beclomethasone dipropionate, the dose must be ≤1.5 mg/kg/day prednisone or its equivalent (up to 40 mg/day) and must have been stable or discontinued for at least 2 weeks prior to Week I-0.
c. IV or rectal corticosteroids must have been discontinued for at least 2 weeks prior to Week I-0.
5-Aminosalicylates, MTX, 6-MP, and AZA Compounds
d. If receiving oral or rectal 5-ASA compounds, the dose must have been stable for at least 2 weeks prior to Week I-0.
e. If oral or rectal 5-ASA compounds have been discontinued, they must have been stopped for at least 2 weeks prior to Week I-0.
f. If receiving MTX, 6-MP, or AZA, the participant must have been taking them for ≥12 weeks and on a stable dose for at least 4 weeks prior to Week I-0.
g. If the MTX, 6-MP, or AZA have been recently discontinued, they must have been stopped for at least 4 weeks prior to Week I-0.
Antibiotics
h. If receiving a single antibiotic as a primary treatment of UC, the dose must have been stable or discontinued for at least 2 weeks prior to Week I-0. Participants cannot be receiving more than one antibiotic for the primary treatment of UC.
Enteral Nutrition
9. If previously receiving enteral nutrition providing more than 80% of daily caloric needs, therapy must have been stopped for at least 4 weeks prior to Week I-0.Malignancy or increased potential for malignancy
Please refer to protocol for all the inclusion criteria. |
|
| E.4 | Principal exclusion criteria |
Any potential participant who meets any of the following criteria will be excluded from participating in the study:
UC Diagnosis and Status
1. Have severe, extensive colitis as evidenced by:
a. Investigator judgment that the participant is likely to require a colectomy within 12 weeks of Week I-0.
OR
b. Symptom complex at screening or Week I-0 visit that includes at least 4 of the following:
• Diarrhea with ≥6 bowel movements/day with macroscopic blood in stool
• Focal severe or rebound abdominal tenderness
• Persistent fever (≥37.5°C) for more than 5 days
• Persistent tachycardia for more than 5 days
• Anemia (hemoglobin <8.5 g/dL)
2. Have UC limited to the rectum only or to <20 cm of the colon.
3. Presence of a stoma.
4. Presence or history of a fistula.
5. Have severe, fixed symptomatic stenosis of the large or small intestine.
6. Require, or required within the 2 months prior to screening, surgery for active GI bleeding, peritonitis, intestinal obstruction, or intra-abdominal or pancreatic abscess requiring surgical drainage, or other conditions possibly confounding the evaluation of benefit from study intervention treatment.
7. Presence or history of colonic or small bowel obstruction within 6 months prior to screening, confirmed by objective radiographic or endoscopic evidence of a stricture with resulting obstruction (dilation of the colon or small bowel proximal to the strictureon barium radiograph or an inability to traverse the stricture at endoscopy).
8. History of extensive colonic resection (eg, less than 30 cm of colon remaining) that would prevent adequate evaluation of the effect of study intervention on clinical disease activity.
9. 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.
10. Have evidence of Crohn’s disease:
a. Small intestinal or ileal disease by upper GI small bowel follow-through, ileocolonoscopy with histology, video capsule endoscopy, or magnetic resonance enterography
b. Noncaseating and non-mucin granulomas that are suggestive of a diagnosis of Crohn’s disease on colonoscopy
c. Skip lesions on colonoscopy including absolute rectal sparing, with a normal rectum both endoscopically and histologically
d. Perianal disease
Concomitant or previous medical therapies received
11. Have received the following concomitant or previous medical therapies:
a. Has ever received ustekinumab or a biologic agent targeting IL-12/23 or IL-23, including but not limited to briakinumab, brazikumab, guselkumab, mirikizumab (formerly LY-3074828), and risankizumab.
b. Has ever received thalidomide or related agents.
c. Has received natalizumab within 12 months of Week I-0.
d. Has received agents that deplete B or T cells (eg, rituximab, alemtuzumab, or visilizumab) within 12 months of Week I-0 or continue to manifest depletion of B or T cells more than 12 months after completion of therapy with lymphocyte depleting agents.
e. Has received vedolizumab without an appropriate washout period prior to Week I-0.
f. Has received other oral immunomodulatory agents (eg, 6-thioguanine [6-TG], cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil [MMF]) within 8 weeks prior to Week I-0.
g. Has received anti-TNFα biologic agents without an appropriate washout period prior to Week I-0.
h. Has used any investigational intervention within 4 weeks prior to Week I-0 or within 5 half-lives of the investigational intervention, whichever is longer.
i. Has used apheresis (ie, Adacolumn apheresis, Cellsorba apheresis) within 2 weeks prior to Week I-0.
j. Has used laxatives, except preparations for endoscopy or other procedures, within 1 week prior to screening procedures.
k. Has an indwelling catheter.
l. Is on total (complete) or partial (supplemental) parenteral nutrition or anticipated to require during enrollment in the study. If recently on total (complete) or partial (supplemental) parenteral nutrition, must have stopped therapy at least <3 weeks before baseline.
m. Is on rectal therapy for UC with either 5-ASA medications or corticosteroids.
n. Is on IV steroids
o. Is on more than one antibiotic prescribed for the treatment of UC.
Infections or predisposition to infections
12. Have a history of latent or active granulomatous infection, including TB, histoplasmosis, or coccidioidomycosis, or have had a nontuberculous mycobacterial infection prior to screening.
13. Have a history of, or ongoing, chronic or recurrent infectious disease, including but not limited to, chronic renal infection, chronic chest infection (eg, bronchiectasis), sinusitis, recurrent urinary tract infection (eg, recurrent pyelonephritis, chronic cystitis), an open, draining, or infected skin wound, or a skin ulcer.
Please refer to protocol for all the exclusion criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Global
1. Clinical remission at Induction Week 8 (Week I-8).
US-specific
2. Clinical remission at Maintenance Week (Week M-44). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints are:
Global
1. Clinical response at Week I-8.
2. Symptomatic remission at Week I-8.
3. Clinical remission at Week I-8 as assessed by the Pediatric Ulcerative Colitis Activity Index (PUCAI) score.
4. Endoscopic improvement at Week I-8.
5. Clinical remission at Maintenance Week (Week M-44.)
6. Symptomatic remission at Week M-44.
7. Clinical remission at Week M-44 as assessed by the PUCAI score.
8. Endoscopic improvement at Week M-44.
9. Clinical remission at Week M-44 and not receiving corticosteroids for at least 90 days prior to Week M-44 among participants who received corticosteroids at Week M-0.
10. Clinical remission at Week M-44 for participants who are in clinical remission at Week I-8.
US-specific
11. Clinical remission at Induction Week 8 (Week I-8).
12. Clinical response at Week I-8.
13. Symptomatic remission at Week I-8.
14. Clinical remission at Week I-8 as assessed by the PUCAI score.
15. Endoscopic improvement at Week I-8.
16. Symptomatic remission at Week M-44.
17. Clinical remission at Week M-44 as assessed by the PUCAI score.
18. Endoscopic improvement at Week M-44.
19. Clinical remission at Week M-44 and not receiving corticosteroids for at least 90 days prior to Week M-44 among participants who received corticosteroids at Week M-0.
20. Clinical remission at Week M-44 for participants who are in clinical remission at Week I-8.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 to 4. and 11 to 15. Week I-8
5 to 10. and 16 to 20. Week M-44 |
|
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Maintenance Period: Randomized, double-blind, parallel group 2-arm study |
|
| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 | No |
| 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 |
| Belgium |
| Germany |
| Hungary |
| Japan |
| Poland |
| Russian Federation |
| United Kingdom |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 5 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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