Main objective:*To evaluate the dose-response relationship of 2 doses of etrasimod versus placebo as induction therapy in subjects with moderately to severely active Crohn's disease (CD).*To select an oral etrasimod dose, based on efficacy and…
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Proportion of subjects who achieve endoscopic response at Week 14
Secondary outcome
* Proportion of subjects who achieve clinical remission APSF at Week 14
* Proportion of subjects who achieve CDAI < 150 by visit up to Week 14
* Proportion of subjects who achieve clinical response CDAI by visit up to Week
14
* Proportion of subjects who achieve clinical response APSF by visit up to Week
14
* Proportion of subjects who achieve clinical response CDAI-70 by visit up to
Week 14
* Proportion of subjects who achieve clinical response APSF-30 by visit up to
Week 14
* Change from baseline in CDAI score by visit up to Week 14
* Change from baseline in SES-CD at Week 14
* Proportion of subjects with clinical response by PRO2 at Week 14
* Proportion of subjects with endoscopic response and clinical remission by
PRO2 at Week 14
* Change and percentage change from baseline in absolute lymphocyte count by
visit up to Week 14
* Change and percentage change from baseline in FCP concentration at Weeks 2,
4, 6, 10, and 14
* Change and percentage change from baseline in CRP concentration at Weeks 2,
4, 6, 10, and 14
* Proportion of subjects who achieve endoscopic remission at Week 14 Extension
Period:
endpoints for the induction period will be assessed at scheduled visits up to
Week 66.
Background summary
CD is a chronic, relapsing and remitting, immune-mediated inflammatory
condition that may affect the entire gastrointestinal tract and is associated
with an increased risk for colon cancer. The transmural tissue damage observed
with CD can result in intestinal infections and abscesses, intestinal
perforation, strictures, and fistula formation.
Treatment for patients with CD is generally focused on symptomatic care and
mucosal healing with overall goals of inducing and sustaining clinical
remission, improving quality of life, and preventing more severe disease
manifestations and complications that require hospitalization and surgical
intervention. Treatment of CD includes several major classes of medications:
corticosteroids, immunosuppressants (such as thiopurines [azathioprine and
mercaptopurine] and methotrexate), biologics (anti-tumor necrosis factor alpha
[TNF*] [infliximab, adalimumab, and certolizumab pegol], interleukin-12 and -23
antagonist [ustekinumab], integrin receptor antagonists [vedolizumab]), and
antibiotics. Janus kinase (JAK) inhibitors are being explored for use in CD
(tofacitinib and filgotinib). Though used in the treatment of IBD more broadly,
the anti-inflammatory drug 5-aminosalicylic acid (5-ASA) demonstrates a low
efficacy preoperatively and at prevention of CD recurrence in the postoperative
setting.
CD is considered neither medically nor surgically *curable,* with clinical,
endoscopic, and surgical recurrence reported in 50%, 80%, and 30% of patients,
respectively. The surgical burden in CD remains high. There remains a great
unmet clinical need for new efficacious and safe treatments for CD, as current
therapies often provide only transient or marginal symptomatic relief. The
complex and heterogenous nature of the disease further underscores the need for
a range of therapies for CD.
Given that immune system dysregulation is a pathophysiological feature of many
immune-mediated inflammatory disorders, synthetic small molecule sphingosine
1-phosphate (S1P) modulators have the potential to act across a wide range of
such diseases. S1P modulators have been shown to reduce inflammation and induce
clinical remission in multiple sclerosis (fingolimod, ponesimod, siponimod,
ozanimod), psoriasis (ponesimod), and ulcerative colitis (ozanimod, etrasimod).
Therefore, S1P modulators may also reduce inflammation in CD and induce
clinical remission.
Etrasimod (APD334) is an orally administered, selective, synthetic S1P receptor
1, 4, 5 modulator that is being developed to treat immune-mediated inflammatory
disorders. A Phase 2 study with etrasimod in adult subjects with moderately to
severely active UC demonstrated consistent and clinically meaningful
improvements in endpoint measures reflecting cardinal symptoms of UC and
objective endoscopic and histologic evidence of colorectal mucosal healing.
Study objective
Main objective:
*To evaluate the dose-response relationship of 2 doses of etrasimod versus
placebo as induction therapy in subjects with moderately to severely active
Crohn's disease (CD).
*To select an oral etrasimod dose, based on efficacy and safety, for continued
development.
Secondary objective:
*To evaluate the long-term safety, tolerability, and efficacy of etrasimod in
subjects with moderately to severely active Crohn's disease (CD).
Study design
This Phase 2b, multicentered, randomized, double-blind, placebo-controlled,
parallel-group,
dose-ranging study will evaluate the efficacy, safety, and tolerability of 2
doses of etrasimod versus placebo as induction therapy in subjects with
moderately to severely active CD who are refractory or intolerant to at least 1
of the current therapies for CD (ie, corticosteroids, immunosuppressants, or
biologics).
The study will start with a screening period of up to 28 days (28-Day Screening
Period) to determine subject eligibility. Eligible subjects will be randomized
in a double-blinded fashion to etrasimod 3 mg, etrasimod 2 mg, or matching
placebo in a 14-week induction treatment period (Induction Period). All
subjects who complete the Induction Period can enter a subsequent 52-week
extension period (Extension Period), where they will be assigned to etrasimod
2mg or 3 mg. All subjects will have follow-up visits at 2 and 4 weeks after the
last dose of study treatment during the 4-Week Follow-Up Period after Week 66
or the Early Termination (ET) Visit. This gives a total study duration of up to
74 weeks.
Intervention
Eligible subjects will be randomized in a double-blinded fashion (1:1:1 ratio)
to etrasimod 3 mg, etrasimod 2 mg, or matching placebo in the Induction Period.
In the Extension Period the subjects will be assigned to receive etrasimod 2 mg
or 3 mg according to their Induction Period treatment and clinical response at
Week 14.
Study burden and risks
To date, etrasimod has been found to be safe and well-tolerated in
approximately 281 adult subjects treated at various doses. The safety and
tolerability of etrasimod has been evaluated in Phase 1 studies with healthy
adult subjects at single doses up to 5 mg and repeated doses up to 4 mg once
daily (qd). In a Phase 2 dose-ranging study in UC patients (APD334-003),
treatment with 2 mg etrasimod qd for 12 weeks led to clinically meaningful and
statistically significant endoscopic and symptomatic improvements versus
placebo. Sustained beneficial effects of etrasimod were observed for up to 46
weeks in the subsequent open-label extension study (APD334-005). Although UC
and CD have different pathophysiology including extent and location of disease,
they are both antigen- and immune-mediated inflammatory bowel diseases and
there is evidence that drugs that are effective for the treatment of UC may
also be efficacious for the management of CD. Therefore, it is reasonable to
hypothesize that etrasimod may offer similar clinical benefits to CD patients
with active disease as UC patients, and this clinical investigation is
necessary to affirm or reject this hypothesis.
There have been no clinically significant safety concerns in clinical studies
with etrasimod. In APD334-003, the most frequently reported treatment emergent
adverse events (TEAEs), reported by > 2 subjects treated with 1 mg or 2 mg
etrasimod were ulcerative colitis (worsening), upper respiratory tract
infection, anemia, and headache. However, rare adverse events (AEs) such as
macular edema, liver enzyme elevations, and dyspnea have been reported with
fingolimod, one of the currently licensed S1P receptor modulators. It is
believed that the non-selectivity (ie, activity at all 5 S1P receptors) of this
first-generation S1P receptor modulator contributes to many of these AEs.
Etrasimod selectively modulates
S1P receptor subtypes 1, 4, and 5, which is expected to mitigate off-target
effects for an improved safety profile.
Based on its mechanism of action, etrasimod is expected to dose-dependently
reduce lymphocyte counts. This reduction is reversible, with lymphocyte counts
returning to baseline levels within 7 days of study drug discontinuation.
Furthermore, S1P receptor modulators are associated with an expected, on-target
dose-dependent effect of reducing heart rate (HR) upon first dosing with HR
recovery to pre-dose baseline thereafter, but there have been no reported cases
of symptomatic bradycardia on first dose and rare first- or second-degree
atrioventricular (AV) block found on ECG has been asymptomatic and transient
(ie, spontaneous resolution) with etrasimod.
Based on the preclinical and clinical data that have been generated from
etrasimod studies and the precautions outlined above, the favorable
benefit/risk assessment justifies the further clinical development of etrasimod
in subjects with moderately to severely active CD in this current Phase 2,
multicenter, randomized, double-blind induction, placebo-controlled study.
Nancy Ridge Drive 6154
San Diego - CA 92121
US
Nancy Ridge Drive 6154
San Diego - CA 92121
US
Listed location countries
Age
Inclusion criteria
1. Men or women 18 to 80 years of age,
2. Ability to provide written informed consent and to be compliant with the
schedule of protocol assessments
3. Diagnosed with CD * 3 months
4.Have moderately to severely active CD at Screening
5.Demonstrated inadequate response, loss of response to, or intolerance to * 1
of the following therapies for the treatment of CD:
a.Oral corticosteroids (eg, prednisone or its equivalent, budesonide)
b.Immunosuppressants (eg, azathioprine [AZA], 6 mercaptopurine [6 MP], or
methotrexate [MTX])
c.Tumor necrosis factor alpha (TNF*) antagonists (eg, infliximab, adalimumab,
certolizumab pegol, or biosimilars)
d.Integrin receptor antagonist (eg, vedolizumab)
e.Interleukin 12/ 23 antagonist (eg, ustekinumab)
6.Females of childbearing potential must be nonpregnant
7.Females of childbearing potential and males must use contraception
Exclusion criteria
- History of inadequate response (ie, primary non response) to agents from * 2
classes of biologics marketed for the treatment of CD (ie, TNF* antagonists,
interleukin 12/ 23 antagonist, and integrin receptor antagonist).
- Have ulcerative colitis, indeterminate colitis, microscopic colitis, ischemic
colitis, radiation colitis, diverticular disease associated colitis, toxic
megacolon, or active infectious colitis or test positive for Clostridium
difficile toxin at Screening.
- Have functional or post operative short bowel syndrome or any associated
complications that may require surgery or interfere with efficacy assessments
- Had surgical treatment for intra abdominal abscesses * 8 weeks prior to
randomization or surgical treatment for perianal abscesses * 4 weeks prior to
randomization.
- Had intestinal resection * 24 weeks prior to randomization or other intra
abdominal surgeries * 12 weeks prior to randomization.
- Have an ileostomy or a colostomy.
- Have a serious infection requiring IV antibiotics/medication(s) * 4 weeks
prior to randomization.
- Have primary or secondary immunodeficiency syndromes, opportunistic
infection, or infection with HIV, HBV, HCV or tuberculosis (active or latent):.
- Have a clinically relevant cardiovascular condition or receiving treatments
that may effect cardiovascular function
- Have active retinopathy or macular oedema.
- Have forced expiratory volume at 1 second or forced vital capacity < 70% of
predicted values at Screening.
- Lactating female who is breastfeeding.
- Any acute illnesses or medical conditions including cognitive impairment and
alcohol/drug abuse/dependence, or signs/symptoms suspicious for a serious
disease that, in the Investigator's opinion, could put the subject at increased
risk for safety event(s) or interfere with
protocol-specified procedures or adherence with study treatment.
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 | EUCTR2019-002895-14-NL |
| ClinicalTrials.gov | NCT04173273 |
| CCMO | NL72428.056.20 |