Principal Investigator: Kathryn Peterson
Keywords: Etrasimod , EoE , Eosinophilic Esophagitis , Arena Department: Gastroenterology
IRB Number: 00142545
Specialty: Gastroenterology, Gastroenterology, Gastroenterology
Sub Specialties: Esophageal Diseases, Endoscopy
Recruitment Status: Not yet recruiting

Contact Information

Amy Holman
amy.holman@hsc.utah.edu
8015859155

Brief Summary

Primary:
• To evaluate the effects of etrasimod on esophageal eosinophilia in adult subjects with active EoE
• To evaluate the dose-response relationship of 2 doses of etrasimod versus placebo in adult subjects with active EoE
• To select an etrasimod dose based on efficacy and safety for continued development

Secondary:
• To evaluate the effect of etrasimod on dysphagia symptoms in adult subjects with active EoE

Exploratory:
• To evaluate the effects of etrasimod on histologic and endoscopic EoE disease activity
• To evaluate the long-term safety and efficacy of etrasimod in adult subjects with active EoE
• To evaluate the pharmacokinetics (PK) of etrasimod in adult subjects with active EoE
• To identify the optimal timepoint for primary and secondary efficacy assessments

Inclusion Criteria

Subjects must meet ALL the following inclusion criteria to be eligible for enrollment into the study.
1. Men or women between 18 to 65 years of age at the time of informed consent (IC)

2. Provide signed IC and willing to comply with all protocol-specified assessments and procedures

3. Have histologically active EoE with an esophageal PEC of ≥ 15 eos/hpf (~60 eos/mm2) from any level (proximal, mid, or distal) of the esophagus at the Screening EGD. Eosinophilia must be isolated to the esophagus.

4. Have dysphagia, defined as solid food going down slowly or getting stuck in the throat with an average frequency of ≥ 2 episodes per week over 2 weeks (as documented using the DSQ during the Screening period)

Eligibility Criteria for the Extension Treatment Period
Inclusion Criteria:
1. Completion of the Week 24 study visit (including EGD) including subjects who discontinued study treatment due to lack of clinical efficacy and started rescue therapy between Weeks 16 and 24. Rescue therapy must be discontinued on the day etrasimod is initiated in the Extension Treatment Period.

2. Compliance with study procedures during the Double-Blind Treatment Period as assessed by the Investigator

3. No notable safety concerns during the Double-Blind Treatment Period, as determined by the Investigator

4. Willing to comply with all study visits and procedures for the Extension Treatment Period

Exclusion Criteria

Subjects will be excluded from study if they meet any of the following exclusion criteria.
Note: A confirmed result means there have been 2 consecutive assessments showing consistent findings meeting exclusionary values. For criteria requiring confirmed results, the 2nd assessment is needed only if the first assessment result was exclusionary.
Exclusion criteria related to medications, therapies, or GI and eosinophilic disease

1. History of any of the following non-EoE conditions or procedures that may interfere with the evaluation of or affect the histologic, endoscopic, or symptom endpoints of the study:
a. Conditions that cause or potentially contribute to esophageal eosinophilia (eg, EG, gastroenteritis, or colitis with esophageal involvement, severe GERD, achalasia and other disorders of esophageal dysmotility, hypereosinophilic syndrome, CD with esophageal involvement, esophageal infection [fungal, viral], connective tissue diseases, hypermobility syndromes, autoimmune disorders and vasculitides, dermatologic conditions with esophageal involvement [ie, pemphigus], drug hypersensitivity reactions, pill esophagitis, graft versus host disease, Mendelian disorders [eg, Marfan syndrome Type II, hyper-IgE syndrome, phosphatase and tensin homolog hamartoma tumor syndrome, Netherton syndrome, severe atopy metabolic wasting syndrome])
b. Conditions that interfere with the evaluation of the esophagus (eg, esophageal varices with risk of spontaneous bleed, high-grade esophageal stenosis where an 8- to 10-mm endoscope could not pass through the stricture without dilation at the time of Screening EGD)
c. Conditions or procedures that cause or potentially contribute to dysphagia (eg, Barrett’s esophagus, erosive esophagitis Los Angeles Grade B or above, significant hiatal hernia [≥ 4 cm], esophageal resection, fundoplication, gastric sleeve surgery)

2. Undergone dilation of an esophageal stricture within 12 weeks prior to Screening EGD.

3. Use of corticosteroids for the treatment of EoE within 8 weeks prior to Screening EGD.

4. Discontinue, initiate, or change dosing (dosage/frequency) of the following therapies for EoE within 8 weeks prior to Screening EGD. Subjects on any of the following therapy need to stay on a stable regimen during study participation:
a. Elemental diet
b. EoE food trigger elimination diet
c. PPI therapy

5. Used any immunotherapy/desensitization including oral immunotherapy (OIT) or sublingual immunotherapy (SLIT) within 12 months prior to the Screening EGD Note: Stable (ie, ≥ 6 months prior to the Screening EGD) subcutaneous immunotherapy (SCIT) is permitted. Subjects on SCIT need to stay on a stable treatment during study participation.

6. Used any of the following immunomodulatory therapies within the timeframes prior to Baseline as indicated in Table 1. The Medical Monitor should be consulted with any questions related to prior use of unlisted immunomodulatory therapies.

 

7. Use of moderate or strong inducers or inhibitors of cytochrome P450 (CYP) 2C8 and CYP2C9 or uridine diphosphate glucuronosyltransferase family 1 member A7 (UGT1A7) (Section 6.7.3) within 4 weeks prior to Baseline

8. Use of any investigational agent or device within 12 weeks prior Baseline

9. Have a known hypersensitivity to etrasimod or any of the excipients.

Exclusion criteria related to other medical history
10. Have any of the following conditions or risk factors:
a. Primary or secondary immunodeficiency syndromes (eg, hereditary immunodeficiency syndrome, acquired immunodeficiency syndrome)
b. History of organ transplant (except corneal transplant)
c. History of an opportunistic infection (eg, pneumocystis jirovecii pneumonia, cryptococcal meningitis, progressive multifocal leukoencephalopathy [PML])
d. History of disseminated herpes simplex or disseminated herpes zoster
e. Test positive for human immunodeficiency virus (HIV [positive HIV antibody]), hepatitis B virus (positive hepatitis B surface antigen [HBsAg]), or active hepatitis C (HCV [positive hepatitis C antibody with detectable HCV RNA]) at Screening

Note: If the Investigator suspects false positive hepatitis serology results, such as an antibody pattern indicating acute hepatitis infection, but no corresponding elevated liver enzymes and no signs or symptoms of liver disease, an infectious disease expert may be consulted. If the infectious disease expert finds no evidence of acute or chronic hepatitis infection and considers the serology results false positive and not clinically relevant, the Investigator may document (in source data and in the electronic case report form [eCRF]) that the serology results are considered false positive and may randomize the subject.

11. Have a serious infection that requires hospitalization or treatment with intravenous (IV) medications within 4 weeks prior to Baseline

12. Received a live-attenuated virus vaccine (except for recommended and age-appropriate influenza, measles/mumps/rubella, or varicella vaccine) within 4 weeks prior to Baseline

13. History of malignancy of any organ system (other than localized squamous cell or basal cell carcinoma of the skin that have been excised or resolved), treated or untreated, within the past 5 years regardless of whether there is evidence of local recurrence or metastases

14. Have active epilepsy

15. Have a history of cirrhosis

16. Have any of the following conditions or receiving treatments that may affect cardiovascular function:
a. Myocardial infarction, unstable angina, stroke/transient ischemic attack, decompensated heart failure requiring hospitalization or Class III/IV heart failure within 8 weeks prior to Baseline
b. Second-degree or third-degree AV block, sick sinus syndrome without a functional pacemaker, or periods of asystole for > 3 seconds without an implanted cardiac pacemaker
c. Recurrent symptomatic bradycardia or recurrent cardiogenic syncope
d. Confirmed Screening and Day 1 baseline vital signs (taken in the sitting position) with a HR < 50 bpm OR systolic blood pressure (BP) < 90 mm Hg OR diastolic BP < 55 mm Hg.
e. Confirmed Screening and Day 1 baseline ECG with PR interval ≥ 200 ms or Friderica's corrected QT interval (QTcF) ≥ 450 ms in males or ≥ 470 ms in females.
f. Receiving Class Ia or Class III anti-arrhythmic drugs
g. Start, stop, or change dosage of Class Ib, II, or IV anti-arrhythmic drugs within 1 week prior to Baseline
 

17.Have active diabetic retinopathy, uveitis, retinitis pigmentosum, macular edema, or hadan intraocular surgery within 12 months prior to Baseline. Refer to Appendix 11 formodification in the event that coronavirus disease 2019 (COVID-19) or similar publichealth emergency (PHE)-related restrictions limit the capacity to perform non-essentialophthalmoscopy with OCT.

18.Have a forced expiratory volume at 1 second (FEV1) or forced vital capacity (FVC) of< 70% predicted (prior to the administration of a short-acting bronchodilator) onScreening PFTs. Refer to Appendix 11 for modification in the event that COVID-19 orsimilar PHE-related restrictions limit the capacity to perform non-essential PFTs.

Exclusion criteria related to test or laboratory results (performed by central laboratory)
19.Have confirmed absolute lymphocyte count (ALC) < 0.8 × 109 cells/L at Screening

20.Have confirmed aspartate aminotransferase (AST) or alanine aminotransferase (ALT)>2 × upper limit of normal (ULN) and total bilirubin > 1.5 × ULN (unless consistent with ahistory of Gilbert’s Syndrome) at Screening

21.Have confirmed moderate or severe renal impairment (estimated glomerular filtration rate[eGFR] < 60 mL/min/m2)
General exclusionary criteria

22.Lactating female who is breastfeeding

23.Females who are pregnant, evidenced by a positive serum beta-human chorionicgonadotropin (β-hCG) pregnancy test at Screening and/or urine dipstick pregnancy test atDay 1, or females who do not meet criterion a or agree with criterion b below, or maleswho do not agree with criterion c below
a.A female who is not of child-bearing potential must meet 1 of the following:
−Postmenopausal, defined as no menses for 12 months without an alternativemedical cause and confirmed by follicle-stimulating hormone (FSH) withinpostmenopausal range according to local standards
−Had permanent sterilization procedure, such as hysterectomy, bilateralsalpingectomy, or bilateral oophorectomy
b.A female who is of child-bearing potential must agree to using a highly effectivecontraception method during treatment and for 4 weeks following treatment that canachieve a failure rate of less than 1% per year when used consistently and correctly.The following are considered highly effective birth control methods: Combined(estrogen and progestogen containing) hormonal contraception associated withinhibition 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); intrauterinehormone-releasing system; bilateral tubal occlusion; vasectomized partner; sexualabstinence (complete sexual abstinence defined as refraining from heterosexualintercourse for the entire period of risk associated with study treatments). Thereliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, symptothermal, or post-ovulation methods) is not acceptable
c. A male with pregnant or non-pregnant woman of child-bearing potential (WOCBP) partner must agree to use condoms during treatment and for 4 weeks following the last dose of study treatment

24. Any acute illness or medical condition 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), confound interpretation of study results, or interfere with the subject’s ability to comply with protocol-specified procedures or assessments

If a subject fails ≥ 1 screening laboratory criteria, the assessment(s) may be repeated once at the discretion of the Investigator, and the subject may be enrolled if criteria are then met, provided the assessments are completed within the Screening Period. Any rescreening laboratory assessments beyond 1 time will need to be discussed with the Medical Monitor before proceeding.