| 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] - 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 |
| Demonstrate the efficacy of ozanimod compared to placebo on the induction of clinical remission |
|
| E.2.2 | Secondary objectives of the trial |
- Demonstrate the efficacy of ozanimod compared to placebo on induction of clinical response, endoscopic response, endoscopic remission, and histologic improvement
- Evaluate the efficacy of ozanimod compared to placebo, in subjects who had previously received biologic therapy (eg, anti-IL-12, anti-IL-23, anti-TNF, or anti-integrin therapy)
- Demonstrate the efficacy of ozanimod compared to placebo on the induction of clinical remission and clinical response in adolescent subjects (aged 12 to 17 years, inclusive)
- Characterize the population pharmacokinetics (PK) and PK/pharmacodynamics (PD) relationship of ozanimod
- Demonstrate the safety and tolerability of ozanimod as induction therapy |
|
| 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 |
A twenty-four (24)-hour ambulatory blood pressure monitoring substudy will be conducted on a total of approximately 75 adult subjects (~50
active and ~25 placebo subjects) at selected sites, with assessments at 24 hours pre-baseline (ie, between Screening and before Day 1) and 24
hours post-dose on Day 8. At these participating sites, monitoring will be hourly during the day and every two hours at night. Heart rate will also
be assessed throughout the 24 hour period at both time points (ie, prebaseline and day 8). Paper diary will be used to collect information on all
subjects during the 24 hour period for symptoms associated with changes in blood pressure. |
|
| E.3 | Principal inclusion criteria |
1. Male or female subjects aged 12 to 75 years (at Screening), inclusive
with adolescents in selected countries or sites (12 to 17) with a body
weight ≥ 45 kg.
Note: Countries or sites with local restrictions that prohibit enrollment of
adolescents (aged 12 to 17 years) will only enroll subjects who are 18
years of age or older. Enrollment of adolescent subjects will begin only
after the applicable regulatory requirements for enrolling subjects in
that age group have been satisfied and the necessary health authority
agreements have been granted. Where national or regional guidelines
for the definition of adolescence differ from the definition stated above,
the national or regional guidelines may be used to determine eligibility.
2. Subjects should not have any constraints under local regulations and
must provide written informed consent prior to any study-related
procedures, and have the ability to comply with the Table of Events.
3. Subject has signs and symptoms consistent with a diagnosis of CD for
at least 3 months (prior to first IP administration). The diagnosis should
be confirmed by clinical and endoscopic evidence and corroborated by a
histology report. (Note: endoscopy and histopathology confirmation may
be obtained during Screening if no prior report is readily available).
4. Subject has met each of the following 2 criteria:
a CDAI score ≥ 220 and ≤ 450
an average daily stool frequency ≥ 4 points and/or an abdominal pain of
≥ 2 points
5. Subject has a SES-CD score of ≥ 6 (or SES-CD ≥ 4 in subjects with
isolated ileal disease).
6. Subject has an inadequate response or loss of response to or is
intolerant of at least 1 of the following systemic CD treatments:
corticosteroids, immunomodulators, biologic therapies (eg,
ustekinumab, TNFα antagonists, or vedolizumab)
7. If the subject is taking the following background therapies for CD, a
stable dose must be maintained throughout the study as indicated
below:
oral aminosalicylates (eg, mesalamine, sulfasalazine, olsalazine,
balsalazide) with a stable dose for at least 3 weeks prior to Screening
endoscopy
prednisone (doses ≤ 20 mg per day) or equivalent with a stable dose for
at least 2 weeks prior to Screening endoscopy
budesonide therapy (doses ≤ 9 mg per day) or beclomethasone doses ≤
5 mg/per day at a stable dose for at least 2 weeks prior to the Screening
endoscopy
8. Subject at high risk (ie, family history, CD duration) for colonic
malignancy has documented evidence of having had a surveillance
colonoscopy within the last 2 years or according to local and national
medical guidelines to evaluate for polyps, dysplasia, or malignancy. If
there is no recent history of surveillance colonoscopy, this can be done
as part of the colonoscopy performed during Screening. Any visualized
adenomatous polyps must be removed and any suspicious lesion
confirmed free of cancer and/or dysplasia prior to randomization.
9. Female subjects of childbearing potential (FCPB):
Note: For the purposes of this study, a female patient is considered to be
of childbearing potential if she is ≥ 12 years of age or has reached
menarche, whichever occurred first, and 1) has not undergone a
hysterectomy (the surgical removal of the uterus) or bilateral
oophorectomy (the surgical removal of both ovaries) or 2) has not been
postmenopausal for at least 24 consecutive months (that is, has had
menses at any time during the preceding 24 consecutive months).
Must agree to practice a highly effective method of contraception
throughout the study until completion of the 90-day Safety Follow-Up
Visit. Highly effective methods of contraception are those that alone or
in combination result in a failure rate of a Pearl Index of less than 1%
per year when used consistently and correctly.
Periodic abstinence (calendar, symptothermal, post-ovulation methods),
withdrawal (coitus interruptus), spermicides only, and lactational
amenorrhoea method are not acceptable methods of contraception.
Counseling about pregnancy precautions and the potential risks of fetal
exposure must be conducted for female subjects of childbearing
potential. The Investigator will educate all FCBP about the different
options of contraceptive methods or abstinence at Screening and Day 1,
as appropriate. The FCBP's chosen form of contraception must be
effective by the time she is randomized into the study.
10. Subjects must have documentation of positive varicella zoster virus
(VZV) immunoglobulin G (IgG) antibody status or complete VZV
vaccination at least 30 days prior to randomization. |
|
| E.4 | Principal exclusion criteria |
1. Subject has any clinically relevant cardiovascular hepatic,
neurological, pulmonary [severe respiratory disease (pulmonary fibrosis
or chronic obstructive pulmonary disease)], ophthalmological,
endocrine, psychiatric, or other major systemic disease making
implementation of the protocol or interpretation of the study difficult or
that would put the subject at risk by participating in the study. 2.
Subject is likely to require, in the physician's judgment, bowel resection
within 12 weeks of entry into the study. 3. Subject has a diagnosis of UC,
indeterminate colitis, radiation colitis, or ischemic colitis, or has
strictures with prestenotic dilatation 4. Subject has current stoma, ilealanal
pouch anastomosis, fistula that is likely to require, surgical or
medical intervention within 12 weeks of entry into the study or need for
ileostomy or colostomy. 5. Subject has extensive small bowel resection
(> 100 cm) or known diagnosis of short bowel syndrome, or subject
requires total parenteral nutrition. 6. Subject has suspected or
diagnosed intra-abdominal or perianal abscess that has not been
appropriately treated. 7. Subject has documentation of positive test for
toxin producing C. difficile, or PCR examination of the stool. 8. Subject
has documentation of positive examination for pathogens 9. Subject is
pregnant, lactating, or has a positive serum β-hCG measured during
Screening. 10. Subject has any condition that would make
implementation of the protocol or interpretation of the study difficult.
11. Subject has a history of diabetes mellitus type 1, or uncontrolled
diabetes mellitus type 2 with hemoglobin A1c (HbA1c) > 9%, or is a
diabetic subject with significant comorbid conditions such as retinopathy
or nephropathy. 12. Subject has a history of uveitis or clinically
confirmed diagnosis of macular edema. 13. Subject has a known active
bacterial, viral, fungal, mycobacterial infection (including tuberculosis or
atypical mycobacterial disease) or any major episode of infection that
required hospitalization or treatment with IV antibiotics within 30 days
of Screening or oral antibiotics within 14 days of Screening. •In the case
of prior SARS-CoV-2 infection, symptoms must have completely resolved
and based on Investigator assessment in consultation with the Clinical
Trial Physician / Medical Monitor, there are no sequelae that would place
the participant at a higher risk of receiving investigational treatment. 14.
History or known presence of recurrent or chronic infection (eg,
hepatitis B virus (HBV), hepatitis C virus (HCV), human
immunodeficiency virus (HIV); recurrent urinary tract infections are
allowed. 15. Subject has a history of cancer within 5 years, including
solid tumors and hematological malignancies or colonic dysplasia that
has not been completely removed 16. Subject has a history of alcohol or
drug abuse within 1 year prior to initiation of Screening 17.
Hypersensitivity to active ingredients or excipients of ozanimod or
placebo. 18. Prior participation in an ozanimod clinical study 19. Subject
has a history of primary nonresponse to 2 or more approved biologic
agents or has been treated with 4 or more biologics for CD 20. Subject
has been treated with a biologic agent within 8 weeks or 5 elimination
half-lives (whichever is shorter) prior to the first dose of IP 21. Subject
has a history of treatment with an investigational agent within 5
elimination half-lives of that agent prior to the first dose of IP 22.
Subject has received a live or live attenuated vaccine within 4 weeks
prior to the first dose of IP 23. Subject has received previous treatment
with lymphocyte-depleting therapies 24. Subject has received previous
treatment with D-penicillamine, leflunomide, orthalidomide 25. Subject
has received previous treatment with natalizumab or fingolimod or
other S1P receptor modulators 26. Subject has received previous
treatment with oral cyclosporine, tacrolimus, sirolimus, or
mycophenolate mofetil within 16 weeks of initiation of Screening 27.
Subject has a history of treatment with IVIg, or plasmapheresis within 3
months prior to first dose of IP 28. Subject has discontinued oral 5-ASA
or corticosteroids within 2 weeks prior to the screening endoscopy.
29.Subject has received rectal therapy within 2 weeks of screening
endoscopy or has planned concurrent use of any per rectum therapy. 30.
Subject has planned concurrent treatment with immunomodulatory
agents after randomization. 31. Subject has chronic nonsteroidal antiinflammatory
drug (NSAID) use 32. Subject is receiving treatment with
Class Ia or Class III anti-arrhythmic drugs or with 2 or more agents in
combination known to prolong PR interval. 33. Subject receiving
treatment with breast cancer resistance protein (BCRP) inhibitors.
Please see the protocol for Exclusions Related to Laboratory Results and
other Exclusions related to Medications |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects with a CDAI score < 150 at Week 12 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Subjects will be deemed a responder with respect to this endpoint if they meet the definition for CDAI Clinical Remission at Week 12. |
|
| E.5.2 | Secondary end point(s) |
Major Secondary Endpoints:
- Proportion of subjects with average daily abdominal pain score ≤ 1 point, and average daily stool frequency score ≤ 3 points with abdominal pain and stool frequency no worse than baseline at Week 12
- Proportion of subjects with a Simple Endoscopic Score for Crohn’s Disease (SES-CD) score decrease from baseline of ≥ 50% at Week 12
- Proportion of subjects with CDAI reduction from baseline of ≥ 100 points or CDAI score < 150 at Week 12
- Proportion of subjects with CDAI reduction from baseline of ≥ 100 points or CDAI score < 150 and SES-CD decrease from baseline of ≥ 50% at Week 12 |
|
| 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 | 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 | Yes |
| 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 | 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 | Yes |
| 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 | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 109 |
| 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 |
| China |
| Georgia |
| Hong Kong |
| Israel |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Saudi Arabia |
| Serbia |
| Singapore |
| South Africa |
| Turkey |
| Ukraine |
| United States |
| Austria |
| Bulgaria |
| Finland |
| France |
| Germany |
| Greece |
| Hungary |
| Lithuania |
| Netherlands |
| Poland |
| Portugal |
| Slovakia |
| Slovenia |
| Spain |
| Sweden |
|
| 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
|
| The end of study is defined as either the date of the last visit of the last subject to complete the safety follow-up, or the date of receipt of the last datapoint from the last subject that is required for primary or secondary analysis, as prespecified 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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