E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
Ulcerative Colitis, a form of inflammatory bowel disease. |
|
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 | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10045365 |
E.1.2 | Term | Ulcerative colitis |
E.1.2 | System Organ Class | 100000004856 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10045366 |
E.1.2 | Term | Ulcerative colitis, unspecified |
E.1.2 | System Organ Class | 100000004856 |
|
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 |
To assess the efficacy of etrasimod when administered for 12 weeks on clinical remission in subjects with moderately to severely active ulcerative colitis (UC). |
|
E.2.2 | Secondary objectives of the trial |
Secondary:
The secondary objective is to assess the efficacy of etrasimod when administered for 12 weeks on clinical response, symptomatic response and remission, endoscopic changes, and mucosal healing in subjects with moderately to severely active UC.
Safety:
The safety objective is to assess the safety of etrasimod after daily doses of 2 mg for 12 weeks in subjects with moderately to severely active UC.
Other:
Other objectives include evaluation of etrasimod pharmacokinetics (PK) and the effect of etrasimod on health related subject reported outcomes and biomarkers. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Men, women and adolescents 16 to 80 years of age, inclusive, at the
time of assent/consent. Enrollment of subjects < 18 years should be
conducted only if acceptable according to local laws and regulations
2. Ability to provide written informed consent or assent and to be
compliant with the schedule of protocol assessments
3. Diagnosed with UC ≥ 3 months prior to screening confirmed by
endoscopic and histologic evidence
4. Active UC confirmed by endoscopy with ≥ 10 cm rectal involvement.
Subjects with proctitis only at baseline who meet the other eligibility criteria for inclusion, including the endoscopic and rectal bleeding
criteria for moderate to severe disease,will be capped at 15% of the
total subjects enrolled
5. Moderately to severely activeUC defined as MMS of 4 to 9, including
an ES of ≥ 2 and RB score ≥ 1
6. Received a surveillance colonoscopy within 12 months before baseline
to rule out dysplasia in subjects with pancolitis > 8 years duration or
subjects with left-sided colitis > 12 years duration. Subjects without a
surveillance colonoscopy within the prior 12 months will have a
colonoscopy at screening (ie, in place of screening
proctosigmoidoscopy). Any adenomatous polyps must be removed prior
to their first dose of study treatment
7. Demonstrated an inadequate response to, loss of response to, or
intolerance to at least 1 of the following therapies as defined below:
Conventional therapy
a. Corticosteroids
b. Thiopurines
Biologic therapy or JAK inhibitor therapy
a. Antitumor necrosis factor alpha (TNFα) antibodies (eg, infliximab,
adalimumab, golimumab, or biosimilars)
b. Anti-integrin antibodies (eg, vedolizumab)
c. Anti-Interleukin 12/23 antibodies (eg, ustekinumab)
d. JAK inhibitors (eg, tofacitinib)
8. Subjects are permitted to be receiving a therapeutic dose of the
following drugs:
• Oral 5 ASA compounds provided the dose has been stable for ≥ 2
weeks immediately prior to randomization
• Oral corticosteroid therapy (prednisone at a stable dose ≤ 20 mg/day,
budesonide at a stable dose ≤ 9 mg/day, or equivalent steroid) provided
the dose has been stable for the 4 weeks immediately prior to the
screening endoscopy assessment
• Immunosuppressive agents such as oral azathioprine or 6
mercaptopurine must be discontinued ≥ 2 weeks prior to randomization
• Probiotics (eg, Culturelle®, Saccharomyces boulardii) provided the
dose has been stable for the 2 weeks immediately prior to randomization
If oral 5-ASA or corticosteroids have been recently discontinued, they
must have been stopped for at least 2 weeks prior to the endoscopy used
for the baseline MMS.
9. Adequate hematological function defined by white blood cell count ≥
3.5 × 109/L with absolute neutrophil count (ANC) ≥ 1.5 × 109/L,
lymphocyte count ≥ 0.8 × 109/L, platelet count ≥ 100 × 109/L, and
hemoglobin ≥ 8 g/dL
10. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 ×
the upper limit of normal (ULN) range and aspartate aminotransferase
(AST) and alanine aminotransferase (ALT) levels ≤2.0 × ULN. Subjects
with an isolated total bilirubin and normal AST and ALT diagnosed with
Gilbert's syndrome may participate
11. Adequate renal function defined by an estimated glomerular
filtration rate ≥ 30 mL/min/1.73 m2 by the Chronic Kidney Disease
Epidemiology Collaboration equation at screening
12. Females must meet either a or b of the following criteria and males
must meet
criterion c to qualify for the study:
a. A female who is not of childbearing potential must meet 1 of the
following:
Postmenopausal, defined as no menses for 12 months without an
alternative medical cause;
Permanent sterilization procedure, such as hysterectomy, bilateral
salpingectomy, or bilateral oophorectomy.
b. Nonpregnant female of childbearing potential must agree to using a highly
effective contraception method during treatment, and for 30 days
following treatment. The following are considered highly effective birth
control methods include:
- Combined (estrogen and progestogen containing) hormonal
contraception associated with inhibition of ovulation, which may be oral,
intravaginal, or transdermal
- Progestogen only hormonal contraception associated with inhibition of
ovulation, which may be oral, injected, or implanted
- Intrauterine device (IUD)
- Intrauterine hormone-releasing system
- Bilateral tubal occlusion
- Vasectomized partner, provided that partner is the sole sexual partner
of the WOCBP trial subject and that the vasectomized partner has received medical
assessment of the surgical success
- Sexual abstinence (complete sexual abstinence defined as refraining
from heterosexual intercourse for the entire period of risk associated
with study treatments).
c. c. A male subject with a pregnant or nonpregnant female of childbearing
potential partner must agree to using condoms during treatment and for
430 days following treatment. |
|
E.4 | Principal exclusion criteria |
1.Severe extensive colitis as evidenced by:
Physician judgement that the subject is likely to require hospitalization
for medical care or surgical intervention of any kind for UC
(eg,colectomy) within 12w following randomization
Current evidence of fulminant colitis,toxic megacolon or recent history
(within last 6 m) of toxic megacolon,or bowel perforation
Previous total or partial colectomy
2.Diagnosis of Crohn's disease (CD) or indeterminate colitis or the
presence or history of a fistula consistent with CD
3.Diagnosis of microscopic colitis,ischemic colitis,or infectious colitis
4.Hospitalization for exacerbation of UC requiring IV steroids within 12w
of screening
5.Positive assay or stool culture for pathogens or positive test for
Clostridioides difficile toxin at screening
6.Pregnancy,lactation,or a positive serum β-hCG measured during
screening
7.Clinically relevant
neurological,endocrine,metabolic,psychiatric,cognitive
impairment,alcohol/drug abuse/dependence,or other major systemic
disease making implementation of the protocol or interpretation of the
study difficult or would put the subject at risk
8.Have any of the following conditions or receiving treatments that may
affect cardiovascular function:
Myocardial infarction,unstable angina,stroke/transient ischemic
attack,decompensated heart failure requiring hospitalization or Class
III/IV heart failure ≤6 m prior to & during the Screening Period
History or presence of second-degree or third-degree atrioventricular
block,sick sinus syndrome,or periods of asystole for >3seconds without
a funcional pacemaker
History or presence of recurrent symptomatic bradycardia or recurrent
cardiogenic syncope
Screening or W0/D1 prerandomization vital signs with a heart rate
<50bpm OR systolic blood pressure <90mm Hg OR diastolic BP<55mm
Hg & Screening or W0/D1 prerandomization ECG with PR interval
>200ms or Fridericia's corrected QT interval QTcF≥450 ms in men or ≥
470ms in women
Start,stop,change or planned change in dosage of any anti-arrhythmic
drugs (Class I to IV) ≤1w before screening or within 1w b4 or afterrandomization
9.Forced expiratory volume at 1 second (FEV1) or forced vital capacity
(FVC) <70% of predicted values and FEV1/FVC ratio <0.70 at screening
10.Uncontrolled diabetes as determined by hemoglobin A1c
(HbA1c)>9% at screening, or subjects with diabetes with significant
comorbid conditions such as retinopathy
11. History of macular edema or retinopathy
12.History of active TB, history of untreated or inadequately treated
latent TB infection, active or latent TB infection at screening
13.A clinically significant active infection ≤28d prior to randomization
14.Have HIV/acquired immune deficiency syndrome or test positive for
HIV antibodies
15.Have acute or chronic hep B infection or test positive for hep B virus
at screening (detectable HBV DNA, or positive for hep B surface antigen,
or negative for HBsAg & positive for antihepatitis B core antibody in
conjunction with detectable HBV DNA)
16.Have current hep C infection or test positive for hep C virus
17.History of an opportunistic infection or a history of disseminated
herpes simplex or disseminated herpes zoster
18.History of or currently active primary or secondary immunodeficiency
19.History of cancer within the last 5y, including solid tumors and
hematological malignancies (except basal cell &in situ squamous cell
carcinomas of the skin that have been excised and resolved) or colonic
mucosal dysplasia
20.History of lymphoproliferative disorder, lymphoma, leukemia,
myeloproliferative disorder, or multiple myeloma
21.Hypersensitivity to etrasimod or any of the excipients or placebo
compounds
22.Prior treatment with sphingosine 1 phosphate receptor modulators
23.Treatment with a biologic agent ≤8w or a small molecule agent ≤5
elimination half lives and detectable drug level prior to randomization
24.Treatment with an investigational therapy ≤3m prior to
randomization
25.Treatment with ≥3biologic agents or ≥2biologics plus a JAK inhibitor
26.Treatment with topical rectal 5ASA, short chain fatty acid enemas, or
steroids ≤2w prior to &during screening
27.Treatment with topical rectal traditional medicine (eg, Chinese
medicine), herb enemas,or suppositories ≤2w prior to randomization
28.Treatment with methotrexate ≤8w prior to and during screening or
cyclosporine,tacrolimus,sirolimus,or mycophenolate mofetil ≤16w prior
to & during screening
29.Receipt of a live vaccine ≤4w prior to randomization
30.Previous treatment with natalizumab
31.Previous treatment with lymphocyte-depleting therapies
32.Previous treatment with D penicillamine,or thalidomide,dimethyl
fumarate,or pyrimidine synthesis inhibitors
33.Treatment with IV immune globulin or plasmapheresis ≤3m prior to
randomization
34.Chronic use of therapies inhibit/induce cytochrome P450(CYP) 2C8 and 2C9 metabolism and inhibitors of UGT1A7≤4w prior to randomization. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoints will evaluate etrasimod versus placebo
in:
• The proportion of subjects achieving clinical remission at Week 12 |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
The key secondary efficacy endpoints are:
• The proportion of subjects achieving endoscopic improvement at Week
12
• The proportion of subjects achieving symptomatic remission at Week
12
• The proportion of subjects with mucosal healing at Week 12
The other secondary endpoints are:
•The proportion of subjects achieving clinical response at Week 12
• The proportion of subjects achieving endoscopic normalization at Week
12
• The proportion of subjects achieving symptomatic remission at Weeks
2, 4, 8
• The proportion of subjects achieving complete symptomatic remission
at each study visit (Weeks 2, 4, 8, 12)
• The proportion of subjects achieving noninvasive clinical response at
each study visit (Weeks 2, 4, 8, 12)
• The proportion of subjects achieving symptomatic response at each
study visit (Weeks 2, 4, 8, 12) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Weeks 2, 4, 8, and 12 and 2 & 4 weeks follow-up |
|
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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
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 | No |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 253 |
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 |
Bulgaria |
Canada |
Chile |
Colombia |
Croatia |
Czechia |
Denmark |
Egypt |
Estonia |
France |
Georgia |
Germany |
Hungary |
India |
Israel |
Italy |
Japan |
Korea, Republic of |
Latvia |
Lebanon |
Lithuania |
Mexico |
Moldova, Republic of |
Netherlands |
Poland |
Portugal |
Romania |
Russian Federation |
Serbia |
Slovakia |
South Africa |
Spain |
Switzerland |
Thailand |
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
|
|
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 | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |