| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Active Skin Extra-Intestinal Manifestations in Inflammatory Bowel Disease. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Skin Conditions associated with Inflammatory Bowel Disease. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| 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 |
The objectives will be to determine the:
a) Effect of Etrasimod (APD334) in Inflammatory Bowel Disease patients on the clinical improvement of active skin extraintestinal manifestation.
b) Safety and tolerability profile of Etrasimod (APD334).
|
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Men or women of age 18 to 80 years, inclusive.
2. Able to give signed informed consent and willing and able to comply with the study requirements.
3. Considered to be in stable health in the opinion of the investigator as determined by:
a.) A pre-study physical examination with no clinically significant abnormalities unrelated to IBD.
b.) Vital signs (VS) at screening: pulse rate ≥ 55 bpm, systolic blood pressure (SBP) ≥ 90, and diastolic blood pressure (DBP) ≥ 55 mmHg.
c.) Liver function tests (ALT/AST, bilirubin and alkaline phosphatase) < 2x the upper limit of normal [ULN].
d.) All other pre-study clinical laboratory findings within normal range, or if outside of the normal range are not deemed clinically significant in the opinion of the investigator.
e.) 12-lead electrocardiogram (ECG) showing no clinically significant abnormalities in the opinion of the investigator (for confirmation please refer to exclusion criteria # 22).
f.) A chest x- ray showing no evidence of active pulmonary disease (a chest x-ray taken within the previous 12 months from the screening visit may also be used).
g.) Ophthalmology evaluation (by an ophthalmologist) without evidence of macular edema, supported with OCT where available (dependent on site capability) no later than 3 months prior to screening.
4. Patients receiving stable treatment for IBD and EIM as defined in section 6.12 of protocol.
5. Diagnosis of active psoriasis, erythema nodosum or pyoderma gangrenosum by Investigator assessments. After the enrollment of 10 patients with active EIM, patients with active psoriasis due to anti TNF-alpha therapy can also be included.
6. Diagnosis of ulcerative colitis (UC) or Crohn’s disease (CD) established prior to screening by clinical and endoscopic evidence.
7. Eligible female patients must be:
a.) non-pregnant, evidenced by a negative serum human chorionic gonadotropin (hCG) pregnancy test at screening and a urine dipstick pregnancy test at Day 1.
b.) non-lactating.
c.) sexually abstinent (if this is the preferred and usual lifestyle of the individual). Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), and lactational amenorrhoea method are not acceptable methods of contraception.
d.) surgically sterile or postmenopausal or agree to continue to use an accepted method of birth control during and for at least 30 days after last study medication administration. Acceptable methods of birth control are:
- combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation)
o oral
o intravaginal
o transdermal
- progestogen-only hormonal contraception associated with inhibition of ovulation
o oral
o injectable
o implantable
- intrauterine device (IUD)
- intrauterine hormone-releasing system (IUS) patients should be consistently taking the hormonal contraceptive for at least 3 months [90 days] prior to screening);
- surgical sterility for at least 6 months prior to screening for tubal ligation performed laparoscopically, hysterectomy and/or bilateral oophorectomy; and/or postmenopausal (defined as at least 2 years without menses).
Contraceptive measures, such as Plan B (used after unprotected sex), are not acceptable methods of contraception for this study.
8. Eligible male patients will either be:
- surgically sterile (i.e., vasectomy), for at least 3 months (90 days) prior to screening
or
- when sexually active with a female partner, the partner must be either surgically sterile, postmenopausal, or agree to continue to use an
accepted method of birth control during and for at least 30 days after last study medication administration as defined in 7 above. Please note that
the use of condoms is an acceptable method of contraception for this study.
9. Eligible male and female patients must agree not to participate in a conception process (i.e. active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization) for 30 days after the last dose of study drug. |
|
| E.4 | Principal exclusion criteria |
1. Evidence of abdominal abscess or toxic megacolon at the screening visit.
2. Patients with history of extensive colitis or pancolitis of > 8 years duration or left-sided colitis of > 12 years duration must have documented evidence that a surveillance colonoscopy was performed within 12 months of the initial screening visit (if not, the patient should undergo a colonoscopy in lieu of a flexible proctosigmoidoscopy during screening).
3. Previous extensive colonic resection (subtotal or total colectomy).
4. Current evidence of adenomatous colonic polyps that have not been removed.
5. Current evidence of colonic mucosal dysplasia.
6. Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine or stoma.
7. Clinical significant infection as judged by the investigator in the previous 6 weeks before enrollment.
8. Evidence of or treatment for C. difficile infection within 60 days or other intestinal pathogen within 30 days prior to
randomization.
9. Within 5 half-lives prior to randomization exposure to natalizumab or rituximab.
10. Within 30 days prior to randomization, treatment of underlying disease other than those specifically listed in Section 6.12.
11. Within 30 days or 5 half-lives (whichever is longer) prior to randomization receipt of any investigational agent.
12. Currently require or are anticipated to require surgical intervention for IBD during the study.
13. FEV1 or FVC < 80% of predicted values (i.e., abnormal).
14. Infection with the Hepatitis B or C virus.
15. Active or latent tuberculosis, regardless of treatment history, as evidenced by any of the following:
a. History of tuberculosis (that has not been successfully treated)
b. A positive diagnostic tuberculosis (TB) test within one month of randomization defined as a positive
QuantiFERON® test or 2 successive indeterminate
QuantiFERON tests
c. Chest X-ray within 12 months of randomization in which active or latent pulmonary tuberculosis cannot be excluded.
16. Any known history of congenital or acquired immunodeficiency (e.g., common variable immunodeficiency, human
immunodeficiency virus [HIV] infection [ELISA and Western blot] test result, organ transplantation).
17. Clinically significant extra-intestinal infection (e.g., pneumonia, pyelonephritis) within 30 days prior to randomization.
18. Recent history (within 6 months of screening visit) of cardio or cerebrovascular disease, ACS, MI, unstable angina, CVA, TIA
at screening.
19. Any surgical procedure requiring general anesthesia within 30 days prior to randomization or plans to undergo major surgery
during the study period.
20. History of retinal macular edema.
21. History of or signs and symptoms of progressive multifocal leukoencephalopathy (PML) as assessed by the PML checklist.
22. History of cardiac arrhythmia, conduction system disease (including AV node dysfunction, 2nd or 3rd degree heart block,
and sick sinus syndrome), or use of Class Ia and Class III antiarrhythmic agents, or baseline QTc ≥ 500 msec.
23. Infection requiring hospitalization or intravenous antimicrobial therapy, or opportunistic infection within 4 weeks of screening.
24. History of more than one episode of herpes zoster or any episode of disseminated zoster.
25. Without documented positive varicella zoster virus (VZV) IgG antibody status or who have completed VZV vaccination within
30 days prior to randomization.
26. Receipt of live vaccine within 4 weeks prior to screening.
27. History of lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative disorder, or multiple myeloma.
28. History of malignancy except for adequately treated basal cell skin cancer.
29. History of severe allergic or anaphylactic reactions requiring medical attention.
30. Current or recent history (within one year prior to randomization) of alcohol dependence or illicit drug use.
31. History of clinically significant leukopenia or lymphopenia at screening.
32. Active psychiatric problems that, in the investigator’s opinion, may interfere with compliance with the study procedures.
33. History of any clinically significant medical condition that, in the investigator's opinion, would preclude participation in the
study.
34. Use of moderate to strong inhibitors of CYP2C9.
35. History of severe renal or hepatic impairment.
36. Inability to attend all the study visits or comply with study procedures.
37. Prior exposure of etrasimod.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
As this is a proof-of-concept study, all endpoints are exploratory.
- UC endpoint: Change from baseline in stool frequency, rectal bleeding, PGA (Physicians Global Assessments) at weeks 1, 2, 4, 8 and 12.
- CD endpoint: Change from baseline in disease activity score at week 1, 2, 4, 8 and 12.
- Change from baseline in endoscopic improvement/histologic healing using endoscopy or flexible proctosigmoidoscopy (only if there are signs of inflammation at screening another
evaluation will be performed at week 12).
- Change from baseline in level of fecal calprotectin at week 4, 8 and 12.
- Change from baseline in Physician Global Assessments for active skin extra-intestinal manifestations (PG, EN and psoriasis) at week 1, 2, 4, 8 and 12.
- Change from baseline in Patients Global Assessments for active skin extra-intestinal manifestations (PG, EN and psoriasis) at week 1, 2, 4, 8 and 12.
- Change from baseline in the Dermatology Life Quality Index (DLQI) score at week 1, 2, 4, 8 and 12.
- Psoriasis endpoint only (all other endpoints are for all skin manifestations): Change from baseline in Psoriasis Area and Severity Index (PASI) score at week 1, 2, 4, 8 and 12.
- Change from baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) score at week 2, 4, 8 and 12.
- Skin punch biopsies (from healthy skin and from target lesion) will be collected before treatment and at week 8 or 12. Immunohistochemistry and other analyzing methods such as RT-PCR will be performed to evaluate immune cell infiltration, cytokine expression in the skin and other inflammatory parameters.
- Change from baseline in C - reactive protein (CRP) at Weeks 1, 2, 4, 8 and 12.
- Chang from baseline in leucocyte characterization.
- Change from baseline in lymphocyte counts at Weeks 1, 2, 4, 8 and 12. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Endpoints will be evaluated during visits at weeks 1, 2, 4, 8 and 12 |
|
| E.5.2 | Secondary end point(s) |
|
| 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 | No |
| 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 | 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| 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 |
| Belgium |
| Germany |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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