Primary objective:- Demonstrate the efficacy of ozanimod compared to placebo on the induction of clinical remissionSecondary objectives:- Demonstrate the efficacy of ozanimod compared to placebo on induction of clinical response, clinical remission…
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint:
- Proportion of subjects with a CDAI score < 150 at Week 12
Secondary outcome
Major Secondary Endpoints:
* Proportion of subjects with average daily abdominal pain score <= 1 point, and
average daily stool frequency score <= 3 points and a stool frequency score 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
Other Secondary Endpoints:
- Proportion of subjects with CDAI score <150 at Week 12 and SES-CD decrease
from baseline of >= 50% at Week 12
- Histologic Improvement: based on the significant differences between
ozanimod and placebo in histologic disease activity scores (ie, Global
Histologic Disease Activity Score changes (Geboes, 2000) at Week 12
- Proportion of subjects with CDAI reduction from baseline of >= 70 points at
Week 12
- Proportion of subjects with absence of ulcers >= 0.5 cm with no segment with
any ulcerated surface >= 10% at Week 12
- Proportion of subjects with a Crohn*s Disease Endoscopic Index of Severity
(CDEIS) decrease from baseline of >= 50% at Week 12
Other Resource Utilization and Subject-Reported Outcome Endpoints:
- Improvement in Inflammatory Bowel Disease Questionnaire (IBDQ) scores
- Improvement in 36-Item Short Form-36 Survey (SF-36) scores
- Improvement in Work Productivity and Activity Impairment questionnaire for
Crohn*s disease (WPAI-CD) scores
- Improvement in EuroQol 5 dimensions questionnaire (EQ-5D) scores
- Differences in CD-related hospitalizations and surgery
Exploratory Endpoints:
- Proportion of subjects with resolution of extraintestinal manifestations
(EIM) of Inflammatory Bowel Disease (IBD) among those who had them at baseline
- Improvement in fecal calprotectin
- Improvement in C-reactive protein
- Proportion of subjects with SES-CD decrease from baseline of >= 25%
- Proportion of subjects with SES-CD <= 4 points and a SES-CD decrease >= 2
- Proportion of subjects with absence of ulcers (ulcerated surface score = 0
in all explored segments)
- Proportion of subjects with SES-CD = 0
- Change from baseline in SES-CD components
- Change from baseline in CDAI
- Improvement in Bristol Stool Scale
- Proportion of subjects with CDAI reduction from baseline of >= 100 points or
CDAI score < 150 and SES-CD decrease from baseline of >= 50%
- Proportion of subjects with CDAI score < 150 and SES-CD <= 4 points and a
SES-CD decrease >=2 points
- Proportion of subjects with average daily abdominal pain score <= 1 point and
average daily stool frequency score <= 3 points and a stool frequency no worse
than baseline and a SES-CD decrease from baseline of >= 50%
- Proportion of subjects with average daily abdominal pain score <= 1 point and
average daily stool frequency score <= 3 points and a stool frequency score no
worse than baseline and SES-CD <= 4 points and a SES-CD decrease >= 2 points
- Improvement in subject overall well-being based on the change in the visual
analogue scale (VAS) from the EQ-5D
- Histologic improvement based on the significant differences between ozanimod
and placebo in histologic disease activity score (Robarts Histologic Index)
- Proportion of subjects with CDAI score < 150 in subjects who had previously
received biologic treatment
- Proportion of subjects with CDAI reduction from baseline of >= 100 points or
CDAI score < 150 in subjects who had previously received biologic treatment
Biomarker Endpoints:
- Efficacy in subjects (clinical response, clinical remission, mucosal
improvement, and histologic improvement at Week 12) as a function of baseline
- Circulating lymphocyte concentration, such as plasmablasts
- Gene expression, such as interferon signature in blood and/or colon biopsy
- Protein biomarker concentration, such as high-density lipoprotein,
C-reactive protein, fecal calprotectin, immunoglobulin A (IgA)
- Pharmacogenetics, such as at the interferon regulatory factor (IRF) 5 locus
Background summary
Crohn*s disease (CD) is an immune-mediated inflammatory disease of the
gastrointestinal (GI) tract. Annual incidence varies geographically, with
estimates ranging from 3.1 to 14.6 per 100,000 people in the United States and
from 0.1 to 16 per 100,000 worldwide (Lakatos, 2006). Subjects with CD suffer
from diarrhea, rectal bleeding, weight loss, abdominal pain, and fever. Crohn*s
disease is characterized by a lifelong chronic course of remissions and
exacerbations. The pathology of this disease is characterized by transmural
infiltration of lymphocytes and macrophages, granulomas, fissuring ulceration,
and submucosal fibrosis. The transmural inflammatory process of CD predisposes
subjects to the formation of fistulas and it has been estimated that
approximately 35% of subjects will have at least 1 fistula during the course of
their disease (Schwartz, 2002). In a recent study, within 10 years of
diagnosis, 50% of adults with CD had undergone bowel surgery (Peyrin-Biroulet,
2010).
The current standard of medical care for patients with moderately to severely
active CD consists of anti-inflammatory approaches, such as corticosteroids,
azathioprine (AZA)/6-mercaptopurine (6-MP), methotrexate (MTX), and biologics
such as anti-tumor necrosis factor (TNF)α, anti-IL-12/IL-23, or anti-integrins.
Immunomodulators aid in corticosteroid withdrawal and in preventing relapse,
but also are associated with considerable side effects. Infliximab, an
anti-TNFα-therapy, is able to reduce signs and symptoms and induce and maintain
remission in the majority of subjects for which it is indicated.
Therefore, there remains considerable unmet medical need for safe, effective,
and oral treatments for adult subjects with CD, and the identification of
biomarkers that predict response to therapy in a CD patient population with
significant genotypic and phenotypic diversity.
Study objective
Primary objective:
- Demonstrate the efficacy of ozanimod compared to placebo on the induction of
clinical remission
Secondary objectives:
- Demonstrate the efficacy of ozanimod compared to placebo on induction of
clinical response, clinical remission, endoscopic response, endoscopic
remission, and histologic improvement
- Demonstrate 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)
- Characterize the population pharmacokinetics (PK) and PK/pharmacodynamics
(PD) relationship of ozanimod
- Demonstrate the safety and tolerability of ozanimod as induction therapy
Study design
This is a Phase 3, randomized, double-blind, placebo-controlled study to
determine the effect of oral ozanimod as an induction treatment for subjects
with moderately to severely active CD, defined as a CDAI score >= 220 to <= 450.
Subjects who complete the Induction Study are anticipated to receive 12 weeks
of treatment (12-week Induction Study). Subjects not entering the Maintenance
Study or Open-label Extension Study will have a Safety Follow-Up Visit (30 to
45 days after the last dose of investigational product [IP]).
The end of study (Induction Study RPC01-3202) 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.
Intervention
Subjects will receive a single 0.92 mg (equivalent to ozanimod HCl 1 mg) oral
dose of ozanimod or matching placebo administered daily, starting with a 7-day
dose escalation regimen of ozanimod 0.23 mg (equivalent to ozanimod HCl 0.25
mg) or matching placebo daily on Days 1 through 4 and ozanimod 0.46 mg daily
(equivalent to ozanimod HCl 0.5 mg; administered as two 0.23 mg capsules) or
two matching placebo capsules on Days 5 through 7, and reaching the final dose
level, 0.92 mg, or matching placebo on Day 8. Subjects will then receive
ozanimod 0.92 mg/day (or matched placebo) through Week 12.
Study burden and risks
Patients may experience drug-related side effects. For full list of side
effects please refer to Appendix E of the main patient information sheet and
infomed consent from. In addition to side effects patients may experience
discomforts and risks associated with the study procedures such as blood
drawing, endoscopies, colonic biopsies.
Route de Perreux 1 1
Boudry 2017
CH
Route de Perreux 1 1
Boudry 2017
CH
Listed location countries
Age
Inclusion criteria
1. Male or female subjects aged 18 to 75 years (at Screening).
2. Subject should not have any constraints under local regulations and, must
provide written informed consent prior to any study-related procedures, and
must 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 (see Appendix B for
additional details):
* - 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 beginning from the
screening period 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 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 FCBP. 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. Subject 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.
Exclusion criteria
Exclusions Related to General Health:
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. Any other modality used in addition to
the colonoscopy to assess this criterion must be discussed with the Medical
Monitor.
4. Subject has current stoma, ileal-anal pouch anastomosis, symptomatic
fistula, 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 a positive test for toxin producing Clostridium
difficile (C. difficile), or polymerase chain reaction (PCR) examination of the
stool on their most recent test, which must have been done in the past 60 days.
If positive, subjects may be treated and retested no earlier than 7 days after
completion of treatment.
8. Subject has documentation of positive examination for pathogens (ova and
parasites, and bacteria), which must have been done in the past 60 days. If
positive, subjects may be treated and retested.
9. Subject is pregnant, lactating, or has a positive serum β-hCG test measured
during Screening.
10. Subject has clinically relevant cardiovascular conditions, making
implementation of the protocol or interpretation of the study difficult or that
would put the subject at risk by participating in the study, including history
or presence of the following:
- Recent (within the last 6 months) occurrence of myocardial infarction,
unstable angina, stroke, transient ischemic attack, decompensated heart failure
requiring hospitalization, Class III/IV heart failure, sick sinus syndrome, or
severe untreated sleep apnea
*- Second degree atrioventricular (AV) Block (eg, Mobitz II), third degree
heart block unless subjects have a pacemaker in place
* - Prolonged QTcF interval (QTcF > 450 ms males, > 470 ms females)
* - Resting heart rate (HR) <55 bpm when taking vitals as part of a physical
examination at Screening
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 macular edema.
13. Subject has a 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 major episode of infection that either
required hospitalization, treatment with intravenous (IV) antibiotics within 30
days of Screening, or treatment with oral antibiotics within 14 days of
Screening. • Note: In the case of a known 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 subject at a higher risk of receiving investigational
treatment. SARS-CoV 2 testing may be conducted prior to randomization if
required by and in accordance with national, local or institutional guidelines.
See App C for more details.
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 active 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.
16. Subject has a history of alcohol or drug abuse within 1 year prior to
initiation of Screening. Please see the protocol for Exclusions Related to
Laboratory Results and Exclusions related to Medications
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-004293-33-NL |
| ClinicalTrials.gov | NCT03440385 |
| CCMO | NL64984.028.18 |