| 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 |
| Moderately to Severely Active Crohn’s Disease |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| 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 |
- To evaluate the efficacy of ozanimod once daily in pediatric participants with moderately to severely active CD: clinical remission by PCDAI at Week 64
- To evaluate endoscopic remission at Week 64 by SES-CD |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of ozanimod once daily in pediatric participants with moderately to severely active CD: clinical remission by PCDAI at Week 12
- To evaluate endoscopic response by SES-CD
- To evaluate clinical response by PCDAI
- To evaluate symptomatic remission (adolescents only)
- To evaluate change in CD symptoms over time
- To evaluate clinical response by CDAI (adolescents only)
- To evaluate corticosteroid-free remission
- To evaluate endoscopic remission at Week 12
- To characterize the PK of 2 doses of oral ozanimod and its major active metabolites in pediatric participants with moderately to severely active CD
- To evaluate the PD effects of 2 dose levels of ozanimod (eg, effects on ALC) in pediatric participants with moderately to severely active CD
- To evaluate the safety and tolerability of 2 dose levels of oral ozanimod once daily in pediatric participants with moderately to severely active CD
For exploratory objectives, please refer to protocol
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants are eligible to be included in the study only if all of the following criteria apply:
1) Signed Written Informed Consent
2)Type of Participant and Target Disease Characteristics
a) Participant is willing and able to adhere to the study visit schedule and other protocol requirements including is willing and able to swallow a capsule until a sprinkle formulation of ozanimod is available.
b) Participant has been diagnosed with CD ≥ 3 months prior to the Screening Visit. The diagnosis should be confirmed by clinical and endoscopic evidence and corroborated by a histopathology report (Note: Histopathology may be performed during endoscopy at Screening if no prior report is readily available).
c) Participant has met each of the following 2 criteria:
i) A PCDAI score ≥ 30.
ii) Participant has a SES-CD score ≥ 6 (or SES-CD ≥ 4 in participants with isolated ileal disease).
d) Participant has an inadequate response, intolerance, or loss of response to at least 1 of the following treatments for CD.
i) corticosteroids (eg, oral prednisone, budesonide MMX, IV corticosteroids).
ii) immunomodulators (eg, AZA, 6-MP, cyclosporine, MTX).
iii) biologic therapy (eg, ustekinumab, abatacept, infliximab, etanercept, adalimumab, anakinra, rituximab, vedolizumab).
iv) other systemic immunomodulatory therapies for CD.
e) If the participant is taking the following background therapies for CD, a stable dose must be maintained as indicated below (dosage regimen can be adjusted to accommodate mg/kg/day dosing as appropriate):
i) Oral aminosalicylates (eg, mesalamine, sulfasalazine, olsalazine, balsalazide), the dose must have been stable starting 3 weeks prior to Screening endoscopy.
ii) Prednisone (≤ 0.5 mg/kg/day up to 20 mg/day), the dose must have been stable starting 2 weeks prior to Screening endoscopy and must remain stable through the first 5 weeks of treatment.
iii) Budesonide therapy (doses ≤ 9 mg per day) or beclomethasone (doses ≤ 5 mg per day), the dose must have been stable starting 3 weeks prior to Screening endoscopy and must remain stable through the first 5 weeks of treatment
f) Participant must have documentation of vaccinations per standard immunization schedule including complete varicella vaccination at least 30 days prior to randomization
3) Age of Participant
a) Participant must be age 2 to 17 years, inclusive (for the assigned cohort) at the time of informed consent/assent.
Please refer to Protocol for detailed list of Inclusion criteria |
|
| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
1) Medical Conditions
a) Participant has clinically relevant cardiovascular, hepatic, neurological, pulmonary, ophthalmological, endocrine, psychiatric, or other major systemic disease making implementation of the protocol or interpretation of the study difficult or that would put the participant at risk by participating in the study.
i) Clinically relevant pulmonary conditions include, but are not limited to, history of severe or chronic lung disease, bronchopulmonary dysplasia, cystic fibrosis, or severe asthma (ie, that interferes with normal activities of daily living).
b) Participant is likely to require, in the physician’s judgment, bowel resection within 12 weeks of entry into the study.
c) Participant has a diagnosis of UC, indeterminate colitis, radiation colitis, or ischemic colitis, or has strictures with prestenotic dilatation, requiring procedural intervention, or with obstructive symptoms. In addition, participants with colonic or ileal strictures that are not passable with an age-appropriate colonoscope that the endoscopist normally uses in clinical practice, or strictures in the ileum or ileocecal valve that are fibrotic in nature, will be excluded.
d) Participant has current stoma, ileal-anal pouch anastomosis, fistula that is likely to require, in the physician’s judgment, surgical or medical intervention within 12 weeks of entry into the study or need for ileostomy or colostomy.
e) Participant has extensive small bowel resection (> 100 cm) or known diagnosis of short bowel syndrome or participant requires total parenteral nutrition.
f) Participant has suspected or diagnosed intra-abdominal or perianal abscess that has not been appropriately treated.
g) Participant has documentation of positive test for toxigenic Clostridioides difficile (formerly Clostridium difficile [C difficile]) by polymerase chain reaction examination of the stool during Screening. If positive, participants may be rescreened after appropriate treatment and negative retest no earlier than 7 days after completion of treatment.
h) Participant has documentation of positive examination for pathogens (ova, parasites, and bacteria). If positive, participants may be treated and rescreened.
i) Participant requires or is expected to undergo apheresis (eg, Adacolumn apheresis) within 2 weeks of randomization.
j) Participant is pregnant, lactating, or has a positive serum β-subunit human chorionic gonadotropin measured during Screening.
k) Participant has a history or presence of the following clinically relevant cardiovascular conditions:
i) Structural cardiac disease (eg, hypertrophic obstructive cardiomyopathy, unrepaired congenital heart defects). Participants with repaired congenital heart defects should be discussed with the Clinical Trial Physician or designee prior to enrollment.
ii) Cardiac events (eg, myocardial infarction) or diseases that predispose to cardiac complications.
iii) History of stroke, heart failure, or symptomatic bradycardia defined as <5th percentile of normal sinus rhythm HR for age.29
iv) Second degree (Mobitz type II) AV block or higher, sick sinus syndrome, or sino-atrial block.
v) Prolonged QT interval corrected for HR using Fridericia’s formula > 450 msec for both males and females (at either Screening or Day 1 Predose assessment), or is at additional risk for QT interval prolongation (eg, hypokalemia, hypomagnesemia, congenital long-QT syndrome).
vi) During either Screening or Day 1 pre-dose assessment, resting HR < 55 beats per minute (bpm) in participants 12 to 17 years old, resting HR < 65 bpm in participants 6 to 11 years old, or resting HR < 75 bpm in participants 2 to 5 years old (one retest is allowed).
vii) Severe untreated sleep apnea.
l) Participant has a history of diabetes mellitus (DM) type 1, or uncontrolled DM type 2 (hemoglobin A1c [HbA1c] > 9%) or is a diabetic participant with significant comorbid conditions such as retinopathy or nephropathy.
m) Participant has a history of uveitis within the last year prior to Screening, or history or evidence of retinal disease (eg, macular edema).
n) Participant has any known active bacterial, viral, fungal (excluding fungal infection of nail beds, minor upper respiratory tract infections, and minor skin infections), mycobacterial infection (including tuberculosis [TB] or atypical mycobacterial disease), or any other infection that required hospitalization or treatment with IV antibiotics within 30 days of Screening or oral antibiotics within 14 days of Screening.
Please refer to Protocol for detailed list of exclusion criteria.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
-Proportion of participants who achieve PCDAI < 10 at Week 64
- Proportion of participants achieving SES-CD ≤ 2 or SES-CD ≤ 4 points with no SES-CD subscore > 1 point at Week 64 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Proportion of participants who achieve PCDAI < 10 at Week 12
- Proportion of participants who achieve SES-CD decrease from Baseline of ≥ 50% (ER-50) at Week 64; Week 12
- Proportion of participants who achieve reduction in PCDAI score ≥ 12.5 and a total PCDAI score of < 30 points at Week 64; Week 12
- Proportion of adolescents who achieve an average daily abdominal pain score ≤ 1 point and an average daily stool frequency ≤ 3 points with abdominal pain and stool frequency no worse than Baseline at Week 64; Week 12
- Change from Baseline in stool frequency score over time
- Change from Baseline in abdominal pain over time
- Proportion of adolescents who achieve CDAI score < 150 at Week 64; Week 12
- Proportion of adolescents who achieve CDAI reduction from Baseline of ≥ 100 points or CDAI score < 150 at Week 64; Week 12
- Proportion of participants who achieve a PCDAI score < 10 at Week 64 while remaining corticosteroid free in the prior 12 weeks
- Proportion of participants who achieve a CDAI score < 150 at Week 64 while remaining corticosteroid free in the prior 12 weeks (adolescents only)
- Proportion of participants achieving SES-CD ≤ 2 or SES-CD ≤ 4 points with no SES-CD subscore > 1 point at Week 12
- Steady state systemic exposures of ozanimod and CC112273 at Week 20 and throughout the study
- Absolute and percent change from Baseline in ALC at Week 64, Week 12, and throughout the study
- Number and proportion of participants experiencing AEs, SAEs, AEs leading to discontinuation from treatment, and AESIs throughout the study
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Week 12
- Week 12
- Week 12
- Week 12
- Change from Baseline in stool frequency score over time
- Change from Baseline in abdominal pain over time
- Week 12
- Week 12
- Week 64 while remaining corticosteroid free in the prior 12 weeks
- Week 64 while remaining corticosteroid free in the prior 12 weeks (adolescents only)
- Week 12
- Week 20 and throughout the study
- Week 12, and throughout the study
- throughout the study
|
|
| 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 | Yes |
| 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) | Yes |
| 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 | 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 |
| Different dosage of the same 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
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| Australia |
| Canada |
| Israel |
| United Kingdom |
| United States |
| Belgium |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Spain |
|
| 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
|
| End of trial is defined as the last participant last visit or the date of receipt of the last data point from the last participant that is required for primary, secondary, and/or exploratory analysis, as pre-specified in the protocol, whichever is the later date. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 12 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| 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 | 19 |
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