| 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, pre-baseline 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 (12 to 17) with a body weight ≥ 45 kg
2. 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.
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. For adolescents, a parent/legal guardian of the adolescent must sign the informed consent form. In addition, adolescent subjects must also agree to participate in the study by signing an assent form. A parent or guardian must be willing to supervise adherence to the protocol requirements. Adolescent subjects who reach the legal age of consent while participating in the study will be asked to sign an ICF themselves to acknowledge their willingness to continue in the study
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 CD treatments: corticosteroids, immunomodulators, biologic therapy (eg, ustekinumab, TNFα antagonists, or vedolizumab)
7. If the subject is taking the following background therapies for CD, a
stable dose must be maintained 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/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. Examples of 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 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 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, ileal-anal 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. 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. Subjects receiving azathioprine, 6-MP, or methotrexate at screening must discontinue treatment with these agents prior to first dose of IP 31. Subject has chronic nonsteroidal anti-inflammatory 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 (eg, cyclosporine, eltrombopag). 34. Subject has received cholestyramine or other drugs interfering with enterohepatic circulation within 3 weeks of screening 35. Subject is receiving treatment with any of the following drugs or interventions within the corresponding timeframe:
- At randomization o CYP2C8 inhibitors and inducers
- Two weeks prior to randomization o Monoamine oxidase inhibitors
Exclusions Related to Laboratory Results: Please see the protocol |
|
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 104 |
| 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 |
| Argentina |
| Australia |
| Belarus |
| Belgium |
| Bosnia and Herzegovina |
| Brazil |
| Bulgaria |
| Canada |
| China |
| Croatia |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Latvia |
| Moldova, Republic of |
| New Zealand |
| Norway |
| Poland |
| Puerto Rico |
| Romania |
| Russian Federation |
| Spain |
| Switzerland |
| Taiwan |
| Turkey |
| Ukraine |
| 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
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| 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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