Clinical trial NCT03421431: A Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of EDP-305 in Subjects With Non-Alcoholic Steatohepatitis
Official title: A Phase 2 Dose Ranging, Randomized, Double Blind, and Placebo-Controlled Study Evaluating the Safety, Tolerability, Pharmacokinetics and Efficacy of EDP-305 in Subjects With Non-Alcoholic Steatohepatitis (NASH)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non-Alcoholic Steatohepatitis
Keywords: NASH
Non-Alcoholic Steatohepatitis (NASH)
Lead sponsor: Enanta Pharmaceuticals, Inc
Sponsor class: INDUSTRY
Collaborators: name: ICON Clinical Research
name: Triangle Biostatistics, LLC
First posted: 2018-02-05
Enrollment: 134
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A randomized, double-blind study to assess the safety, tolerability, PK and efficacy of EDP-305 in subjects with Non-Alcoholic Steatohepatitis


Eligibility criteria: Inclusion Criteria:

* An informed consent document must be signed and dated by the subject
* Male and female subjects of any ethnic origin between the ages of 18 and 75 years, inclusive
* Male or female with presence of NASH by:

  * Histologic evidence on a historical liver biopsy within 24 months of Screening consistent with NASH with fibrosis (no cirrhosis), and elevated ALT at Screening AND Screening MRI PDFF with \>8 % steatosis OR
  * Phenotypic diagnosis of NASH based on elevated ALT and diagnosis of T2DM or pre-diabetes AND Screening MRI PDFF with \>8 % steatosis
* Body mass index (BMI) \>25 kg/m2; for Asian-Americans, BMI \>23 kg/m2
* Female subjects of childbearing potential must agree to use two effective methods of contraception from the date of Screening until 90 days after the last dose of EDP-305.
* Subject must be willing and able to adhere to the assessments, visit schedules, prohibitions and restrictions, as described in this protocol

Exclusion Criteria:

* Laboratory Screening Results:

  * Total bilirubin \> ULN (normal range 0.2-1.2 mg/dL)
  * Total white blood cells (WBC) \<3,000 cells/mm3
  * Absolute neutrophil count (ANC) \<1,500 cells/mm3
  * Platelet count \<140,000/mm3
  * Prothrombin time (international normalized ratio, INR) \> 1.2
  * Creatine kinase above the upper limit of normal (ULN) except when in relation with intense exercise
  * Serum creatinine \>2 mg/dL or creatinine clearance \<60 ml/min (based on Cockroft Gault method)
* Known history of alpha-1-antitrypsin deficiency
* Use of an experimental treatment for NASH within the past 6 months
* Use of immunosuppressant (eg, corticosteroids) for more than 2 weeks in duration within 1 year prior to Screening and during the course of the study
* Use of experimental or unapproved drugs within a year of Screening
* Any other condition(s) (including cardiovascular diseases) that would compromise the safety of the subject or compromise the quality of the clinical study, as judged by the Principal Investigator (PI)
* Pregnant or nursing females
* Recipients of liver or other organ transplantation or anticipated need for orthotropic organ transplantation in one year as determined by a Model for End-Stage Liver Disease (MELD) Score ≥ 15
* Clinical suspicion of advanced liver disease or cirrhosis
* Coexisting liver or biliary diseases, such as primary sclerosing cholangitis (PSC), choledocholithiasis, acute or chronic hepatitis, autoimmune hepatitis, alcoholic liver disease, acute infection of bile duct system or gall bladder, history of gastrointestinal bleeding (secondary to portal hypertension), cirrhosis
* Suspicion of cancer (eg, liver cancer) with the exception of basal cell carcinoma that has been resected
* Cirrhosis with or without complications, including history or presence of: spontaneous bacterial peritonitis, hepatocellular carcinoma, bilirubin \> 2xULN
* Hepatorenal syndrome (type I or II) or Screening serum creatinine \> 2 mg/dL (178 μmol/L)
* Prior variceal hemorrhage, uncontrolled encephalopathy, Child-Pugh Class A, B, and C, esophageal varices, or refractory ascites within the previous 6 months of Screening (defined as date informed consent signed)
* Any condition possibly affecting drug absorption (eg, gastrectomy \<3 years prior to Screening)
* Subject has received an investigational agent or vaccine within 30 days, or a biological product within 3 months or 5 elimination half-lives (whichever is longer) prior to the planned intake of study drug. NOTE: Flu vaccine will be allowed upon Medical Monitor's approval
* Use of a new statin regimen from Screening and throughout study duration. NOTE: Subjects on a stable dose of statins for at least three months prior to Screening are allowed. No dose modification during the study will be allowed.
* Current use of fibrates. Note: Subjects who discontinued fibrates for at least 3 months before Screening can participate
* Clinically significant history of drug sensitivity or allergy, as determined by the PI
* Uncontrolled diabetes mellitus (ie, HbA1c ≥9% or higher) 60 days prior to Day 1
* Subjects with contraindications to MRI imaging, or not being able to have the MRI performed

Primary outcomes:
measure: Mean Change From Baseline (Average) in Alanine Aminotransferase (ALT) at Week 12
timeFrame: Baseline and Week 12
Secondary outcomes:
measure: Mean Change From Baseline in Percentage of Fat in the Liver as Assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) at Week 12
timeFrame: Baseline and Week 12
measure: Mean Change From Baseline in Aspartate Aminotransferase to Platelet Ratio Index (APRI) at Week 12
timeFrame: Baseline and Week 12
measure: Mean Change From Baseline in Triglycerides (TG) at Week 12
timeFrame: Baseline and Week 12
measure: Mean Change From Baseline in Total Cholesterol at Week 12
timeFrame: Baseline and Week 12
measure: Mean Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 12
timeFrame: Baseline and Week 12
measure: Mean Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12
timeFrame: Baseline and Week 12
measure: Mean Change From Baseline in Adiponectin at Week 12
timeFrame: Baseline and Week 12
measure: Mean Change From Baseline in Apolipoproteins A1 (ApoA-1) at Week 12
timeFrame: Baseline and Week 12
measure: Mean Change From Baseline in Apolipoproteins B (ApoB) at Week 12
timeFrame: Baseline and Week 12
measure: Mean Change From Baseline in Apolipoproteins C3 (ApoC3) at Week 12
timeFrame: Baseline and Week 12
measure: Mean Change From Baseline in Fasting Blood Glucose at Week 12
timeFrame: Baseline and Week 12
measure: Mean Change From Baseline in Fasting Insulin at Week 12
timeFrame: Baseline and Week 12
measure: Mean Change From Baseline in Homeostasis Model Assessment (HOMA) Index for Nondiabetic Participants at Week 12
timeFrame: Baseline and Week 12
measure: Mean Change From Baseline in HOMA Index for Diabetic Participants at Week 12
timeFrame: Baseline and Week 12
measure: Mean Change From Baseline in Glycated Hemoglobin (HbA1c) in Participants With T2DM at Week 12
timeFrame: Baseline and Week 12
measure: Maximum Plasma Concentration (Cmax) of EDP-305 on Day 1 and Week 12
timeFrame: Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12)
measure: Time to Reach Maximum Plasma Concentration (Tmax) of EDP-305 on Day 1 and at Week 12
timeFrame: Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12)
measure: Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Time of the Last Quantifiable Concentration (AUC[Last]) of EDP-305 on Day 1 and at Week 12
timeFrame: Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12)
measure: Cmax of EP-022571 on Day 1 and at Week 12
timeFrame: Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12)
measure: Tmax of EP-022571 on Day 1 and at Week 12
timeFrame: Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12)
measure: AUC(Last) of EP-022571 on Day 1 and at Week 12
timeFrame: Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12)
measure: Cmax of EP-022572 on Day 1 and at Week 12
timeFrame: Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12)
measure: Tmax of EP-022572 on Day 1 and at Week 12
timeFrame: Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12)
measure: AUC(Last) of EP-022572 on Day 1 and at Week 12
timeFrame: Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12)
measure: Cmax of EP-022679 on Day 1 and at Week 12
timeFrame: Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12)
measure: Tmax of EP-022679 on Day 1 and at Week 12
timeFrame: Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12)
measure: AUC(Last) of EP-022679 on Day 1 and at Week 12
timeFrame: Predose and 2, 6, and 8 hours postdose on Day 1 and on Day 84 (Week 12)
measure: Mean Change From Baseline in Body Weight at Week 12
timeFrame: Baseline and Week 12
measure: Mean Change From Baseline in Waist to Hip (WTH) Ratio at Week 12
timeFrame: Baseline and Week 12
measure: Mean Change From Baseline in Fibroblast Growth Factor 19 (FGF19) by Nominal Timepoint (Intensive Pharmacodynamic [PD] Samples) at Week 12
timeFrame: Predose and 2, 6, and 8 hours postdose on Day 1 and Day 84 (Week 12)
measure: Mean Change From Baseline in FGF19 by Bin Timepoint (Sparse PD Samples) at Week 12
timeFrame: Predose and two samples postdose (first sample between 1 to 3 hours postdose and second sample 1 hour later than fist sample) on Day 1 and Day 84 (Week 12)
measure: Mean Change From Baseline in 7a-Hydroxy-4-Cholestene-3-One (C4) by Nominal Timepoint (Intensive PD Samples) at Week 12
timeFrame: Predose and 2, 6, and 8 hours postdose on Day 1 and Day 84 (Week 12)
measure: Mean Change From Baseline in C4 by Bin Timepoint (Sparse PD Samples) at Week 12
timeFrame: Predose and two samples postdose (first sample between 1 to 3 hours postdose and second sample 1 hour later than fist sample) on Day 1 and Day 84 (Week 12)
measure: Mean Change From Baseline in Bile Acid (BA) by Nominal Timepoint (Intensive PD Samples) at Week 12
timeFrame: Predose and 2, 6, and 8 hours postdose on Day 1 and Day 84 (Week 12)
measure: Mean Change From Baseline in BA by Bin Timepoint (Sparse PD Samples) at Week 12
timeFrame: Predose and two samples postdose (first sample between 1 to 3 hours postdose and second sample 1 hour later than fist sample) on Day 1 and Day 84 (Week 12)
Other outcomes:
Locations:
city: Chandler
country: United States
facility: Radiant Research Incorporated
state: Arizona
city: Mesa
country: United States
facility: Central Arizona Medical Associates
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic Specialty Building
state: Arizona
city: Anaheim
country: United States
facility: Anaheim Clinical Trials
state: California
city: Chula Vista
country: United States
facility: estudy site - Chula Vista
state: California
city: Coronado
country: United States
facility: Southern California Research Center
state: California
city: Fresno
country: United States
facility: Fresno Clinical Research Center (FCRC)
state: California
city: La Jolla
country: United States
facility: UCSD Altman Clinical and Translational Research Institute
state: California
city: Lincoln
country: United States
facility: Clinical Trials Research
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Los Angeles
country: United States
facility: National Research Institute
state: California
city: Montclair
country: United States
facility: Catalina Research Institute, LLC
state: California
city: Rialto
country: United States
facility: Inland Empire Liver Foundation
state: California
city: San Clemente
country: United States
facility: Southern California Transplantation Institute Research Foundation
state: California
city: San Diego
country: United States
facility: Precision Research Institute
state: California
city: Colorado Springs
country: United States
facility: Peak Gastroenterology Associates
state: Colorado
city: Colorado Springs
country: United States
facility: Clinical Research Advantage, Inc. / Colorado Springs Family Practice
state: Colorado
city: Englewood
country: United States
facility: South Denver Gastroenterology,P.C.
state: Colorado
city: DeLand
country: United States
facility: Avail Clinical Research, LLC
state: Florida
city: Fleming Island
country: United States
facility: Fleming Island Center for Clinical Research
state: Florida
city: Jacksonville
country: United States
facility: Westside Center for Clinical Research
state: Florida
city: Jacksonville
country: United States
facility: Jacksonville Center for Clinical Research
state: Florida
city: Jacksonville
country: United States
facility: Jacksonville Center for Endoscopy - Southside ; Borland Groover Clinic
state: Florida
city: Lauderdale Lakes
country: United States
facility: Precision Clinical Research, LLC.
state: Florida
city: Miami Springs
country: United States
facility: Ocean Blue Medical Research Center, Inc
state: Florida
city: Miami
country: United States
facility: Homestead Medical Research
state: Florida
city: Miami
country: United States
facility: Research Associates of South Florida, LLC
state: Florida
city: Miami
country: United States
facility: Florida Advanced Medical Research, Inc.
state: Florida
city: Orlando
country: United States
facility: Clinical Neuroscience Solutions Inc.
state: Florida
city: Palm Harbor
country: United States
facility: Advanced Gastroenterology Associates, LLC
state: Florida
city: Atlanta
country: United States
facility: Piedmont Atlanta Hospital
state: Georgia
city: Marietta
country: United States
facility: Gastrointestinal Specialists Of Georgia
state: Georgia
city: Chicago
country: United States
facility: Feinberg School of Medicine Northwestern University
state: Illinois
city: Indianapolis
country: United States
facility: Midwest Institute For Clinical Research
state: Indiana
city: Shawnee Mission
country: United States
facility: WestGlen Gastrointestinal Consultants, PA
state: Kansas
city: New Orleans
country: United States
facility: Oshsner Clinic Foundation
state: Louisiana
city: Baltimore
country: United States
facility: Mercy Medical Center
state: Maryland
city: Catonsville
country: United States
facility: Digestive Disease Associates, PA
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan Health System
state: Michigan
city: Kansas City
country: United States
facility: Kansas City Research Institute
state: Missouri
city: Saint Louis
country: United States
facility: Saint Louis University
state: Missouri
city: Egg Harbor Township
country: United States
facility: AGA Clinical Research Associates, LLC
state: New Jersey
city: Manhasset
country: United States
facility: Northwell Health Inc.
state: New York
city: New York
country: United States
facility: NYU Langone Medical Center - The Center for Musculoskeletal Care (CMC)
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Charlotte
country: United States
facility: Carolinas Medical Center Transplant Center/Center for Liver Disease
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Huntersville
country: United States
facility: Carolinas Center for Liver Disease / Carolinas Health Care System
state: North Carolina
city: Cincinnati
country: United States
facility: Sterling Research Group, Ltd.
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center - Center for Liver Diseases
state: Pennsylvania
city: Memphis
country: United States
facility: University Of Tennessee Health Science Center
state: Tennessee
city: Nashville
country: United States
facility: Quality Medical Research, PLLC
state: Tennessee
city: Arlington
country: United States
facility: Texas Clinical Research Institute
state: Texas
city: Austin
country: United States
facility: Texas Diabetes & Endocrinology
state: Texas
city: Dallas
country: United States
facility: Dallas Diabetes Research Center
state: Texas
city: Garland
country: United States
facility: DHAT Research Institute
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine - Advanced Liver Therapies
state: Texas
city: San Antonio
country: United States
facility: Texas Liver Institute
state: Texas
city: San Antonio
country: United States
facility: Clinical Trials of Texas, Inc.
state: Texas
city: San Antonio
country: United States
facility: Radiant Research, Inc.
state: Texas
city: Layton
country: United States
facility: Wasatch Peak Family Practice/Radiant Research, Inc
state: Utah
city: Murray
country: United States
facility: Radiant Research, Inc.
state: Utah
city: Gainesville
country: United States
facility: Gastroenterology Associates, PC
state: Virginia
city: Newport News
country: United States
facility: Bon Secours St. Mary's Hospital of Richmond, Inc
state: Virginia
city: Reston
country: United States
facility: The Gastroenterology Group, PC
state: Virginia
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
city: Seattle
country: United States
facility: Swedish Medical Center-Swedish Organ Transplant and Liver Center
state: Washington
city: Seattle
country: United States
facility: University of Washington / Harborview Medical Center
state: Washington
city: La Crosse
country: United States
facility: Mayo Clinic Health System - Franciscan Healthcare
state: Wisconsin
city: Brampton
country: Canada
facility: Aggarwal and Associates Limited
state: Ontario
city: Toronto
country: Canada
facility: Toronto Liver Centre
state: Ontario
city: Montreal
country: Canada
facility: Clinique de recherche Medpharmgene
state: Quebec
city: Montreal
country: Canada
facility: Chronic Viral Illness Service McGill University Health Center/Royal Victoria
state: Quebec
city: Paris
country: France
facility: Hopital Pitie Salpetriere
city: Pessac
country: France
facility: CHU de Bordeaux - GH Sud - Hoital Haut Leveque
city: Strasbourg
country: France
facility: CHU de Strasbourg - Nouvel Hôspital Civil
city: Auckland
country: New Zealand
facility: Auckland Clinical Studies Limited
city: San Juan
country: Puerto Rico
facility: Latin Clinical Trial Center
city: Cambridge
country: United Kingdom
facility: Addenbrookes Hospital (AH)-Cambridge University Hospitals NHS Foundation Trust
state: Cambridgeshire
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation
state: Greater London
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
state: Nottinghamshire
Study officials:
affiliation: Enanta Pharmaceuticals, Inc
name: Nathalie Adda, MD
role: STUDY_DIRECTOR
References:
citation: Ratziu V, Rinella ME, Neuschwander-Tetri BA, Lawitz E, Denham D, Kayali Z, Sheikh A, Kowdley KV, Desta T, Elkhashab M, DeGrauw J, Goodwin B, Ahmad A, Adda N. EDP-305 in patients with NASH: A phase II double-blind placebo-controlled dose-ranging study. J Hepatol. 2022 Mar;76(3):506-517. doi: 10.1016/j.jhep.2021.10.018. Epub 2021 Nov 3.