| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderately to severely active Crohn's disease |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 |
- Evaluate the pharmacokinetics (PK) of ustekinumab in subjects from 2 through <18 years old and determine if it is similar to that observed in adults with moderately to severely active CD.
- Assess the safety and immunogenicity of ustekinumab in this population.
- Assess the efficacy of ustekinumab in the treatment of moderately to severely active CD, including assessment of improvement in the endoscopic appearance of the mucosa.
If feasible, the relationship between PK and the short-term efficacy of ustekinumab will be assessed in this population. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Be a pediatric subject 2 to <18 years old in the US, 6 to <18 years old elsewhere, of either gender.
2. Have CD or fistulizing CD of at least 3 months duration, with active colitis, ileitis, or ileocolitis, confirmed at any time in the past by radiography, histology, and/or endoscopy.
3. Must have moderately to severely active CD
4. Prior or current medication for CD must include at least 1 of the following:
a. Current treatment with at least 1 of the following therapies: oral corticosteroids, the
immunomodulators AZA, 6-MP, or MTX, or currently have or have had a history of corticosteroid dependency
OR
b. Have a history of failure to respond to, or tolerate, at least 1 of the following therapies:
oral or IV corticosteroids, the immunomodulators AZA, 6-MP, or MTX.
OR
c. Have required more than 3 courses of oral or IV corticosteroids in the past year.
5. Must meet the following requirements for current concomitant medications for CD criteria:
- Corticosteroids
- 5-aminosalyscilic (5-ASA) compounds
- Antibiotics
- Immunomodulators
6. If receiving total parenteral or enteral nutrition, must have been receiving for at least 2 weeks prior to baseline
7. Before randomization, a girl must be either:
- Not of childbearing potential
- Of childbearing potential
8. All girls of childbearing potential must have a negative highly sensitive serum pregnancy test (β-human chorionic gonadotropin [β-hCG]) at screening.
9. A girl must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction
during the study and for 6 months after receiving the last dose of study agent.
10. Have negative stool results for enteric pathogens. Stool studies must include a stool culture
and Clostridium difficile toxin assay. These must have been performed during screening or the current episode of disease exacerbation as long as the stool studies were performed within 4 months prior to the first administration of study agent.
Please refer to pages 23-26 of the protocol for the complete list of the the inclusion criteria
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| E.4 | Principal exclusion criteria |
Disease Characteristics
1. Has complications of CD such as symptomatic strictures or stenosis, short gut syndrome, or any other manifestation that might be anticipated to require surgery, 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. Subjects 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 baseline.
4. Has a draining (ie, functioning) stoma or ostomy.
Concomitant or Previous Medical Therapies Received
5. Has received any of the following prescribed medications or therapies within the specified
period:
a. IV corticosteroids <3 weeks prior to baseline.
b. Natalizumab within 12 months of baseline.
c. Anti-TNF biologic agents (eg, monoclonal antibody therapies) or other agents intended to suppress or eliminate TNF <8weeks prior to baseline.
d. Vedolizumab <16 weeks prior to baseline.
e. Other oral immunomodulatory agents (eg, 6-thioguanine [6-TG], cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil) within 8 weeks prior to baseline.
f. Nonautologous stem cell therapy (eg, Prochymal), efalizumab or biologic agents that deplete B or T cells (eg, rituximab, alemtuzumab, or visilizumab) within 12 months of baseline, or continue to manifest depletion of B or T cells more than 12 months after completion of therapy with lymphocyte depleting agents.
g. Have used any investigational drug within 4 weeks prior to baseline or within 5 half lives of the investigational agent, whichever is longer.
h. Have used apheresis within 2 weeks prior to baseline.
i. Other immunosuppressant biologic agents <12 weeks or within 5 half-lives of agent prior to baseline, whichever is longer.
6. Has previously received a biologic agent targeting IL-12 or IL-23, including but not limited to ustekinumab, briakinumab (ABT-874), or guselkumab.
Infections or Predisposition to Infections
7. Have a history of latent or active granulomatous infection, including TB, histoplasmosis, or
coccidioidomycosis, or have had a nontuberculous mycobacterial infection prior to screening.
8. Have a history of, or ongoing, chronic or recurrent infectious disease, including but not limited to, chronic renal infection, chronic chest infection, sinusitis, recurrent urinary tract infection, an open
draining, or infected skin wound, or an ulcer.
9. Have immune deficiency syndrome
10. Have a known history of infection with human immunodeficiency virus (HIV).
11. Has evidence of herpes zoster infection ≤8 weeks prior to baseline.
12. Have a known history of hepatitis C infection.
13. Subjects must undergo screening for hepatitis B virus
14. Have had a Bacille Calmette-Guerin vaccination within 12 months of screening.
15. Have received, or are expected to receive, any live virus or bacterial vaccination less than 2 weeks prior to the first administration of study agent, during the study, or within 15 weeks after the last administration of study agent.
16. Have had a clinically important opportunistic infection
17. If applicable, have 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.
18. Have had a serious infection have been hospitalized for an infection, or have been treated with parenteral antibiotics for an infection within 2 months prior to first administration of study agent. Less serious infections need not be considered exclusionary at the discretion of the investigator.
Please refer to pages 27-30 of the protocol for the complete list of the the inclusion criteria
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Pharmacokinetic endpoints:
- Serum ustekinumab concentrations over time.
- Maximum observed serum concentration (Cmax).
- Steady state trough concentration (Ctrough,ss).
- Area under the serum ustekinumab concentration versus time curve calculated from time 0 to a defined time t (AUC0-t).
- Elimination t1/2.
- Apparent clearance (CL/F).
- Apparent volume of distribution at steady state (Vss/F).
Efficacy endpoints:
- Clinical response and clinical remission as measured by the pediatric Crohn’s disease activity index (PCDAI) score.
- Change from baseline in the PCDAI score.
- Change from baseline in abdominal pain and stool frequency subscores of the PCDAI.
- Change from baseline in C-reactive protein (CRP) concentrations.
- Changes from baseline in fecal lactoferrin and calprotectin.
- Changes from baseline in height and weight z-scores.
- Change from baseline in the IMPACT III score.
- Fistula response.
Endoscopic endpoints:
- The change from baseline in the simplified endoscopic activity score for CD (SES-CD).
- Clinically meaningful endoscopic healing, defined as a reduction in SES-CD of ≥3 points from baseline.
- Endoscopic response, defined as ≥50% reduction from the SES-CD score at baseline.
- Endoscopic remission, defined as an SES-CD score ≤2. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Pharmacokinetic endpoints: At week 16
Efficacy endpoints: At weeks 8 and 16
Endoscopic endpoints: At week 16
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| E.5.2 | Secondary end point(s) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Comparing different doses of the IMP |
|
| 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
| Yes |
| 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 | 13 |
| 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 |
| Canada |
| United States |
| Belgium |
| France |
| Germany |
| Poland |
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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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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 | 14 |
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