| 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 maintenance of clinical remission and endoscopic response |
|
| E.2.2 | Secondary objectives of the trial |
- Demonstrate the efficacy of ozanimod compared to placebo on maintenance of clinical response
- Demonstrate the efficacy of ozanimod compared to placebo on maintenance of endoscopic remission and mucosal healing
- Demonstrate the efficacy of ozanimod, compared to placebo, in achieving corticosteroid-free remission among subjects receiving corticosteroids at entry into the Maintenance Study
- Demonstrate the efficacy of ozanimod, compared to placebo, on maintenance of clinical remission in adolescent subjects with active CD
- Characterize the population pharmacokinetics (PK) and PK/pharmacodynamics (PD) relationship of ozanimod
- Demonstrate the efficacy of ozanimod, compared to placebo, on healthcare resource utilization (HRU), subject-reported outcomes, and quality of life
- Demonstrate the safety and tolerability of ozanimod as maintenance therapy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject fulfilled the inclusion criteria at time of entry into the Induction Study (RPC01 3201 or RPC01-3202) and has completed the Week 12 efficacy assessments of the Induction Study.
2. Subject must provide written informed consent prior to any study-related procedures and have the ability to comply with the Table of Events. For adolescent subjects, the parent/legal guardian of the adolescent must sign an informed consent form (ICF). In addition, adolescent patients must also agree to participate in the study by signing an assent. 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 is in clinical response (a reduction from baseline in CDAI of ≥ 100 points or CDAI score of < 150 points) and/or clinical remission (CDAI score of < 150 points) and/or has an average daily stool frequency score ≤ 3 and an average abdominal pain score ≤ 1 with abdominal pain and stool frequency no worse than baseline at Week 12 of the Induction Study.
4. Female subjects of childbearing potential:
Note: For the purposes of this study, a female subject 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. Examples of acceptable methods of birth control in the study are the following:
• combined hormonal (containing oestrogen and progestogen) contraception, which may be oral, intravaginal, or transdermal
• progestogen-only hormonal contraception associated with inhibition of ovulation, which may be oral, injectable, or implantable
• placement of an intrauterine device (IUD)
• placement of an intrauterine hormone-releasing system (IUS)
• bilateral tubal occlusion
• vasectomised partner
• complete sexual abstinence
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 Day 1, as appropriate. The subject will be re-educated every time her contraceptive measures/methods or ability to become pregnant changes. The female subject’s chosen form of contraception must be effective by the time the female subject is randomized into the study (for example, hormonal contraception should be initiated at least 28 days before randomization). |
|
| E.4 | Principal exclusion criteria |
Exclusions Related to General Health:
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 pregnant, lactating, or has a positive urine beta human chorionic gonadotropin (β-hCG) measured prior to randomization.
3. Subject has suspected or diagnosed intra-abdominal or perianal abscess that has not been appropriately treated.
4. Subject has undergone a colectomy (partial or total), small bowel resection, or an ostomy (ie, temporary colostomy, permanent colostomy, ileostomy, or other enterostomy) since Day 1 of the Induction Studies or has developed symptomatic fistula (enterocutaneous or entero enteral).
5. Subject has had cancer within 5 years including solid tumors and hematological malignancies (except basal cell and in situ squamous cell carcinomas of the skin or cervical dysplasia/cancer that have been excised and resolved); or colonic dysplasia that has not been completely removed.
Exclusions Related to Medications:
6. Hypersensitivity to active ingredients or excipients of ozanimod or placebo
7. Subject has received any of the following therapies during the Induction Study:
a. rectal steroid therapy (ie, steroids administered to the rectum or sigmoid via foam or enema)
b. post-baseline initiation of, or increase in, corticosteroids to treat worsening CD to a dose greater than the maximum daily dose taken between the screening and baseline visits
c. rectal 5- aminosalicylates (ASA) (ie, 5-ASA administered to the rectum)
d. parenteral corticosteroids
e. total parenteral nutrition therapy
f. antibiotics for the treatment of CD
g. immunomodulatory agents (6-MP, AZA, including but not limited to cyclosporine, mycophenolate mofetil, tacrolimus, and sirolimus)
h. immunomodulatory biologic agents as well as other treatments for CD such as etrasimod, filgotinib, and upadacitinib
i. investigational agents
j. apheresis
8. Subject has current or planned treatment with immunomodulatory agents (eg, AZA, 6-MP, or MTX) during the Maintenance Study.
9. Subject has chronic nonsteroidal anti-inflammatory drug (NSAID) use (note: occasional use of NSAIDs and acetaminophen [eg, headache, arthritis, myalgias, or menstrual cramps] and aspirin up to 325 mg/day is permitted).
10. Subject has received treatment with Class Ia or Class III anti-arrhythmic drugs or treatment with 2 or more agents in combination known to prolong PR interval.
11. Subject has received a live or live attenuated vaccine within 4 weeks prior to first dose of IP.
12. Subject has received previous treatment with lymphocyte-depleting therapies (eg, Campath™, anti-CD4, cladribine, rituximab, ocrelizumab, cyclophosphamide, mitoxantrone, total body irradiation, bone marrow transplantation, alemtuzumab, or daclizumab).
13. Subject has received previous treatment with D-penicillamine, leflunomide or thalidomide.
14. Subject has received previous treatment with natalizumab, fingolimod, or other S1P modulators.
15. Subject has received previous treatment with cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil within 16 weeks of first dose of IP.
16. Subject has a history of treatment with intravenous immunoglobulin (IVIg) or plasmapheresis, within 3 months prior to first dose of IP.
17. Subject is receiving treatment with breast cancer resistance protein (BCRP) inhibitors (eg, cyclosporine, eltrombopag)
18. Subjects is receiving treatment with any of the following drugs or interventions
a. CYP2C8 inhibitors (eg, gemfibrozil or clopidogrel) and inducers (eg, rifampicin)
b. Monoamine oxidase inhibitors (eg, selegiline, phenelzine)
19. Subjects who have met the discontinuation criteria in the Induction Period
Exclusions Related to Laboratory Results:
20. Subject has any clinically significant abnormality which, in the opinion of the investigator, may put the patient at risk. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Proportion of subjects with a CDAI score of < 150 at Week 52
- Proportion of subjects with a Simple Endoscopic Score for Crohn’s Disease (SESCD) decrease from baseline of ≥ 50% at Week 52 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- The first primary endpoint is CDAI clinical remission at Week 52. Subjects will be deemed responders with respect to this endpoint if they meet the definition, CDAI score of < 150 at Week 52.
- The second primary endpoint is endoscopic response (50%) at Week 52. Subjects will be deemed responders with respect to this endpoint if they meet the definition, SES-CD decrease from baseline of ≥ 50% at Week 52. |
|
| 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 ≤ 3 points with abdominal pain and stool frequency no worse than baseline at Week 52
- Proportion of subjects with CDAI reduction from baseline of ≥ 100 points or CDAI score of < 150 at Week 52
- Proportion of subjects with a CDAI score of < 150 at both pre-randomization (Day 1) and Week 52
- Proportion of subjects with a CDAI score of < 150 at Week 52 in subjects with a CDAI score < 150 at pre-randomization
- Proportion of subjects with a CDAI score < 150 in subjects off corticosteroids at Week 52
- Proportion of subjects with absence of ulcers ≥ 0.5 cm with no segment with any ulcerated surface ≥10% at Week 52
- Histologic improvement based on differences between ozanimod and placebo in histologic disease activity scores (ie, Global Histologic Disease Activity Score (GHAS) changes at Week 52
- 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 AND an SES-CD decrease from baseline of ≥ 50% at Week 52
Additional Secondary Endpoints:
- Proportion of subjects with CDAI score of < 150 and SES-CD decrease from baseline of ≥ 50% at Week 52
- 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 and an SES-CD ≤ 4 points and a SES-CD decrease ≥2 points at
Week 52
- 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 52
- Proportion of subjects with CDAI score < 150 at Week 12 and SES-CD decrease from baseline of ≥ 50% at Week 52
- Proportion of subjects with CDAI reduction from baseline of ≥ 70 points at Week 52
- Proportion of subjects with mucosal healing (SES-CD ≤ 4 points and a SES-CD decrease ≥ 2 points) and histologic improvement by GHAS or Robarts Histologic Index (RHI) at Week 52
- Time to relapse (an increase in the CDAI score from Maintenance Day 1 of ≥ 100 points and a CDAI score > 220, SES-CD score ≥ 6 [or ≥ 4 if isolated ileal disease]), and exclusion of other causes of an increase in disease activity unrelated to underlying CD (eg, infections, change in medication)
- Proportion of subjects with a Crohn’s Disease Endoscopic Index of Severity (CDEIS) decrease from baseline of ≥ 50% at Week 52
Additional Secondary Endpoints (Adolescent Subjects):
- Proportion of adolescent subjects with Pediatric Crohn’s Disease Activity Index (PCDAI) ≤ 10 points at Week 52
- Proportion of adolescent subjects with decrease from baseline in PCDAI score ≥15 points at Week 52 |
|
| 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 | 3 |
| 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 | 19 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 213 |
| 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 |
| Austria |
| Belarus |
| Belgium |
| Bosnia and Herzegovina |
| Brazil |
| Bulgaria |
| Canada |
| China |
| Croatia |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Georgia |
| Germany |
| Greece |
| Hong Kong |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Latvia |
| Lithuania |
| Mexico |
| Moldova, Republic of |
| Netherlands |
| New Zealand |
| Norway |
| Poland |
| Portugal |
| Puerto Rico |
| Romania |
| Russian Federation |
| Saudi Arabia |
| Serbia |
| Singapore |
| Slovakia |
| Slovenia |
| South Africa |
| Spain |
| Sweden |
| 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 (Maintenance Study RPC01-3203) 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 data point 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 12 |
| 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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