| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderately to Severely Active Crohn's Disease |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10011401 |
| E.1.2 | Term | Crohn's disease |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
|
| 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 Crohn's disease
2. To evaluate the safety profile of ustekinumab in pediatric participants with moderately to severely active Crohn's disease.
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 | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
An optional Exposure Optimization Substudy, as described in Appendix 17 of the Protocol, for induction nonresponders who have a low steadystate, 8 weeks post-dose ustekinumab concentration, and for induction responders and delayed responders who lose response during maintenance and have a low steady-state, 8 weeks post-dose ustekinumab concentration.
Primary Objective:
- To determine if a q4w dose regimen in participants who have induction nonresponse or LOR and low 8-week steady-state ustekinumab trough concentrations during maintenance will result in steady-state ustekinumab trough exposures ≥1.4 ug/mL
- To evaluate the safety and immunogenicity of ustekinumab administered q4w in participants who have induction nonresponse or LOR and low ustekinumab exposure |
|
| 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. Criterion modified per Amendment 2
3.1 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, 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.
Crohn's Disease diagnosis and status
4. Criterion modified per Amendment 4
4.1 Have Crohn's disease or fistulizing Crohn's disease with active colitis, ileitis, or ileocolitis, confirmed at any time in the past by endoscopy and histology.
5. Criterion modified per Amendment 4
5.1 i. Must have moderately to severely active Crohn's disease (as defined by a baseline PCDAI score >30)
ii. Have ileocolonoscopy with evidence of active Crohn's disease defined as the presence of ulceration (which is equal to SES-CD score ≥3) during screening into the study*
*If unable to evaluate ulceration due to stricture or inadequate bowel preparation, at least one of the following criteria may instead be applied:
a. An abnormal CRP (>0.3mg/dL or 3.0 mg/L at screening)
OR
b. Fecal calprotectin of ≥250 mg/kg or ≥250 μg/g at screening
Allowed concomitant or prior medical therapies for Crohn's disease
6. Prior or current medication for Crohn's disease must include at least one of the following:
Have received biologic therapy for the treatment of pediatric Crohn's disease 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 and have a prior or current Crohn's disease 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 Crohn's disease)
OR
d. Have required more than 3 courses of oral or IV corticosteroids in the past year.
7. 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 for at least 2 weeks prior to Week I-0.
7.1 Criterion modified per Amendment 2
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 prednisone and must have been stable or discontinued for at least 2 weeks prior to Week I-0.
7.1 Criterion modified per Amendment 2
c. If IV, or rectal corticosteroids have recently been discontinued, they must have been stopped for at least 2 weeks prior to Week I-0.
5-ASA, MTX, 6-MP, and AZA compounds:
7.2 Criterion modified per Amendment 4
d. If receiving oral 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.
7.2 Criterion modified per Amendment 4
Antibiotics
h. If receiving a single antibiotic as a primary treatment of Crohn’s disease, the dosage of the medication/antibiotic must have been stable for at least 2 weeks prior to Week I-0. Participants cannot be receiving more than one antibiotic for the primary treatment of Crohn’s disease.
Enteral Nutrition
8. If receiving enteral nutrition, must have been on a stable regimen for at least 2 weeks prior to Week I-0.
Please refer to section 5.1 of the 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:
Crohn's disease diagnosis and status
1. Has complications of Crohn’s disease such as symptomatic strictures or stenosis, short gut syndrome, or any other manifestation that might be anticipated to require surgery, that could preclude the use of the PCDAI to assess response to therapy or would possibly confound the ability to assess the effect of treatment with ustekinumab.
2. Currently has or is suspected to have an abscess. Recent cutaneous and perianal abscesses are not exclusionary if drained and adequately treated at least 3 weeks prior to baseline, or 8 weeks prior to baseline for intra-abdominal abscesses, provided that there is no anticipated need for any further surgery. Participants with active fistulas may be included if there is no anticipation of a need for surgery and there are currently no abscesses identified.
3. Has had any kind of bowel resection within 6 months or any other intra-abdominal surgery within 3 months prior to Week I-0.
4. Presence of a stoma.
Concomitant or Previous Medical Therapies Received
5. Has received any of the following prescribed medications or therapies within the specified period:
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 LY3074828), and risankizumab.
c. Has ever received thalidomide or related agents.
d. Has received natalizumab within 12 months of Week I-0.
e. 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.
f. Has received vedolizumab without appropriate washout period prior to Week I-0.
g. Has received other immunomodulatory agents (eg, 6-thioguanine [6-TG], cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil) within 8 weeks prior to Week I-0.
h. Has received anti-TNFα biologic agents without an appropriate washout period prior to Week I-0.
i. 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.
j. Has used apheresis (ie, Adacolumn apheresis, Cellsorba apheresis) within 2 weeks prior to Week I-0.
k. Have used laxatives, except preparations for endoscopy or other procedures, within 1 week prior to screening procedures.
l. Has initiated enteral nutrition therapy <3 weeks prior to the first administration of study intervention at Week I-0. (Participants who are on a stable regimen ≥2 weeks prior to the anticipated first administration of study intervention at Week I-0 may be considered for enrollment.
m. Has an indwelling catheter.
n. 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, much have stopped therapy at least <3 weeks before baseline.
o. Is on rectal therapy for Crohn’s disease with either 5-ASA medications or corticosteroids.
p. Is on IV steroids
q. Is on more than one antibiotic prescribed for the treatment of Crohn’s disease
Infections or Predisposition to Infections
6. Have a history of latent or active granulomatous infection, including TB, histoplasmosis, or coccidioidomycosis, or have had a nontuberculous mycobacterial infection prior to screening.
7. 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.
8. Have clinically significant immune deficiency syndrome (eg, severe combined immunodeficiency syndrome, T-cell deficiency syndromes, B-cell deficiency syndromes, or chronic granulomatous disease) and/or monogenic cause of IBD. With children who carry a diagnosis of VEO-IBD, an evaluation for immunodeficiency and monogenic forms of IBD should have been performed.
9. Have a known history of infection with HIV or test positive at screening.
10. Has evidence of herpes zoster infection within 8 weeks prior to Week I-0.
Please refer to section 5.2 of the 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 remission at Week I-6
2. Clinical response at Week I-8.
3. Clinical response at Week I-6
4. Endoscopic response at Week M-8
5. Clinical response at Week M-8
The following endpoints will be evaluated for participants who are clinical responders at Week I-8
6. Clinical remission at Week M-44
7. Endoscopic response at Week M-44
8. Clinical response at Week M-44
9. Corticosteriod-free clinical remission at Week M-44
10. Corticosteriod-free clinical response at Week M-44
11. Durable clinical remission at Week M-44
US-specific
12. Clinical Remission at Week I-8
13. Clinical Remission at Week I-6
14. Clinical Response at Week I-8
15. Clinical response at Week I-6.
16. Endoscopic response at Week M-8.*
17. Clinical response at Week M-8.*
The following endpoints will be evaluated for participants who are clinical responders at Week I-8:
18. Endoscopic response at Week M-44.
19. Clinical response at Week M-44.
20. Corticosteroid-free clinical remission at Week M-44.
21. Corticosteroid-free clinical response at Week M-44.
22. Durable clinical remission at Week M-44. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1, 3, 13 and 15 Week I-6
2, 12 and 14 Week I-8
4, 5, 16 and 17 Week M-8
6 - 11 and 18 - 22 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 | 21 |
| 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 |
| Japan |
| Russian Federation |
| United States |
| Belgium |
| Germany |
| Hungary |
| Poland |
| United Kingdom |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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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