Clinical trial NCT04378010: A Randomized, Double-blind Study to Assess the Safety and Efficacy of EDP-305 in Subjects With Liver-biopsy Proven NASH
Official title: A Phase 2b Randomized, Double-Blind, Placebo-controlled, Multicenter Study Evaluating Safety and Efficacy of EDP-305 in Subjects With Liver Biopsy Proven Non-alcoholic Steatohepatitis (NASH) (ARGON-2)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Non-Alcoholic Steatohepatitis
Keywords: Fatty Liver, non-alcoholic fatty liver disease, NASH
Lead sponsor: Enanta Pharmaceuticals, Inc
Sponsor class: INDUSTRY
First posted: 2020-05-07
Enrollment: 98
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 and efficacy of EDP-305 in subjects with liver-biopsy proven Non-Alcoholic Steatohepatitis (NASH)

Detailed description: The aim of this Phase 2b study aimed to evaluate safety and efficacy of the investigational novel FXR agonist, EDP-305, in a population of patients with liver biopsy proven NASH.

This Phase 2b study aimed to evaluate the safety and efficacy of two doses of EDP-305 compared to placebo for the treatment of NASH in subjects with liver biopsy proven NASH. As suggested in the FDA guidance, this late stage Phase 2 study explored the effect of EDP-305/placebo treatment on histological endpoints. The patient population selected for inclusion in the study was designed to represent the target population for treatment. Specifically, in patients with liver disease, there is a significant overlap of NASH and various metabolic conditions including obesity and T2DM. In order to be reflective of the NASH population, these patients were not excluded from participation in this study.

Eligibility criteria: Inclusion Criteria:

* Informed consent documentation signed and dated by the participant.
* Male and female participants, of all ethnic origins, between the ages of 18 and 75 years, inclusive.
* Participants of all ethnic origins had to have a Body Mass Index (BMI) \> 25 kg/m2 and ≤ 45 except Asian participants who qualified for the study with BMI \> 23 kg/m2.
* Histological evidence of definite NASH based on NASH Clinical Research Network (CRN) criteria obtained from assessment of a liver biopsy by the central histopathologist. The biopsy may be obtained either 1) during the Screening window or 2) within 26 weeks prior to the Screening visit.
* NAFLD Activity Score (NAS) of 4 or greater with a score of at least 1 in each component of the NAS (steatosis scored 0-3, lobular inflammation scored 0-3, ballooning scored 0-2).
* Fibrosis stage 2 or 3 using the NASH CRN Histologic Scoring System.
* Participants had to have Screening laboratory values for Hepatitis B surface antigen (HBsAg), anti-HCV antibodies and HCV RNA, and Human Immunodeficiency Virus (HIV) 1 and 2 antibodies (Ab) as seronegative. \[Note: participants previously infected by chronic hepatitis C and treated with direct acting antivirals (DAAs) with sustained virologic response (SVR) for at least 3 years were allowed.\]
* A woman of childbearing potential who was sexually active with a male had to agree to use two effective methods of contraception from the date of Screening until 30 days after the last dose of study drug.
* A male participant who had not had a vasectomy and was sexually active with a woman of childbearing potential had to agree to use effective contraception from the date of Screening to 90 days after the last dose of study drug.
* Participant had to be willing and able to adhere to the assessments, visit schedules, prohibitions and restrictions, as described in this protocol.

Exclusion Criteria:

* Laboratory Screening results as indicated below:

  * Total white blood cells (WBC) \<3000 cells/mm3
  * Absolute neutrophil count (ANC) \<1500 cells/mm3
  * Platelet count \<140,000/mm3
  * International Normalized Ratio, INR \>1.2 (unless due to use of anticoagulants)
  * Estimated glomerular filtration rate (eGFR) \< 60 mL/min according to the Modification of Diet in Renal Disease (MDRD) equation
  * AST ≥5× ULN
  * ALT ≥5× ULN
  * ALP ≥2× ULN
  * Total bilirubin \> 1.5 times ULN during Screening. \[Note: Patients with Gilbert's syndrome were allowed following review by the Medical Monitor if they had a known history of Gilbert's syndrome with a normal direct bilirubin value and normal reticulocyte count.\]
* Pregnant or nursing females.
* MELD: Model for End-stage Liver Disease score \>12.
* Clinical or laboratory evidence of known chronic liver disease such as alcoholic liver disease, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis, Wilson disease, iron overload, alpha-1-antitrypsin deficiency, drug-induced liver injury, known or suspected hepatocellular carcinoma (HCC).
* History of acute liver complications due to gallstones (e.g., acute cholecystitis or acute biliary obstruction) unless the participant had a cholecytectomy (more than 3 months prior to screening).
* History of liver transplant, or current placement on a liver transplant list.
* Hepatorenal syndrome (type I or II).
* Prior variceal hemorrhage, uncontrolled encephalopathy, liver cirrhosis Child-Pugh Class A, B, and C, esophageal varices, or refractory ascites within the previous 26 weeks of Screening and/or histological presence of liver cirrhosis.
* Prior or planned ileal resection, or prior or planned bariatric surgery. \[Note: Participants who had undergone gastric surgeries that did not affect drug absorption (e.g., gastric band or gastric sleeve procedures) were allowed if they were stable for at least 1 year prior to Screening. Gastrectomy or Roux-en-Y bypass was allowed if stable for at least 3 years prior to Screening.\]
* Participants with clinically or otherwise documented cardiovascular or cerebrovascular disease including clinically significant anomalies of rhythm or pattern of ECG, that in the judgement of the Principal Investigator (PI) could affect the safety of the participant or their ability to comply with the study requirements.
* HbA1c ≥ 9.5% within 60 days prior to Day 1.
* Use of a new antidiabetic regimen in the months prior to Screening including metformin, glucagon-like peptide (GLP) 1 agonists, sodium glucose cotransporter-2 (SGLT2) inhibitors, sulfonylureas, or dipeptidyl peptidase 4 (DPP4) inhibitors, insulin or peroxisome proliferator-activated receptor (PPAR)γ agonists (e.g., pioglitazone or rosiglitazone). For pre-existing antidiabetic treatment, participants were to be on a stable dose of antidiabetic drugs: (1) for at least 8 weeks (for metformin and/or sulfonylureas), (2) 12 weeks (for SGLT2 or DPP4 inhibitors), or (3) 12 weeks (for GLP-1 receptor agonists and thiazolidinediones) prior to Screening with the intention to keep the regimen stable during the study.
* Use of a new statin regimen or other lipid lowering agents from 12 weeks prior to Screening.
* Use of a new fibrate regimen from 12 weeks prior to Screening.
* Participants with contraindications to MRI imaging, or not being able to have the MRI performed.
* Participant had received any investigational agent (including investigational vaccine) or biological product within 30 days or 5 times the half-life (whichever was longer) prior to the planned first dose of study drug.
* Use of an experimental or approved treatment for NASH within 26 weeks of Screening.
* Prior use of OCA within 26 weeks of Screening and/or concurrent treatment with OCA (or any other FXR agonists).
* Use of systemic immunosuppressant (e.g., corticosteroids) for more than 4 weeks in duration within 1 year prior to Screening with the intention to continue during the study (chronic use of inhaled, topical, ophthalmological, nasal corticosteroids was allowed)
* Use of any prohibited concomitant medications, including systemic CYP3A4 inhibitors and inducers, within 14 days prior to the first dose of study drug and for the duration of the study.
* Clinically significant history of drug sensitivity or drug allergy, as determined by the PI.
* Current or history of significant alcohol consumption defined as: \>14 standard drinks per week and/or ≥4 standard drinks per occasion for males and \>7 standard drinks per week and/or ≥3 standard drinks per occasion for females.
* History of substance (including alcohol) abuse and in the judgement of the PI, the participant was not suitable for participation in the study.
* Any other condition(s) that would compromise the safety of the participant or compromise the quality of the clinical study, as judged by the PI.
* Use of medication for weight loss or appetite reduction (e.g., orlistat, bupropion/naltrexone, phentermine-topiramate, phentermine, lorcaserin, non-prescription supplements) at Screening.
* History of malignancy of any organ system (other than localized and considered cured cutaneous basal or squamous cell carcinoma, or in situ cervical cancer), treated or untreated, within 5 years of Screening.

Primary outcomes:
measure: Proportion of Participants Who Achieve ≥1 Stage Improvement in Fibrosis Without Worsening of Steatohepatitis and/or Resolution of Steatohepatitis and no Worsening of Liver Fibrosis as Determined by Liver Biopsy
timeFrame: Week 72
Secondary outcomes:
measure: Change in 5D-itch Scale From Baseline
timeFrame: Baseline, Week 12
measure: Proportion of Participants With Improvement of Fibrosis by at Least 1 Stage and/or Resolution of NASH Without Worsening of Either as Determined by Liver Biopsy
timeFrame: Week 72
measure: Proportion of Participants With no Worsening of Fibrosis Combined With no Worsening of NASH as Determined by Liver Biopsy
timeFrame: Week 72
measure: Proportion of Participants With Resolution of Fibrosis as Determined by Liver Biopsy
timeFrame: Week 72
measure: Proportion of Participants With Improvement in Each Histologic Feature of NASH by at Least 1 Point as Determined by Liver Biopsy
timeFrame: Week 72
measure: Proportion of Participants With Improvement of Fibrosis by ≥ 2 Stages by Liver Biopsy
timeFrame: Week 72
measure: Proportion of Participants With Improvement in NAS by at Least 2 Points With no Worsening of Fibrosis as Determined by Liver Biopsy
timeFrame: Week 72
measure: Proportion of Participants With Improvement of Fibrosis and Resolution of NASH as a Composite Endpoint as Defined by Both Endpoints Being Met in the Same Participant
timeFrame: Baseline, Week 72
measure: Proportion of Participants With Resolution of NASH and no Worsening of Liver Fibrosis
timeFrame: Week 72
measure: Proportion of Participants With Histological Progression to Cirrhosis as Determined by Liver Biopsy
timeFrame: Week 72
measure: Participants With TEAEs Leading to Discontinuation
timeFrame: Day 1 to Week 72
measure: Percentage Change of Fat in the Liver From Baseline
timeFrame: Baseline, Week 12
measure: Change in Liver Stiffness From Baseline
timeFrame: Baseline, Week 12
measure: Change in Triglycerides From Baseline
timeFrame: Baseline, Week 12
measure: Change in Adiponectin From Baseline
timeFrame: Baseline, Week 12
measure: Plasma Concentration of EDP-305
timeFrame: 2-4 hours post dose at Week 12
measure: Change in VAS (Visual Analog Score) From Baseline
timeFrame: Baseline, Week 12
measure: Change in Total Cholesterol From Baseline
timeFrame: Baseline, Week 12
measure: Change in HDL From Baseline
timeFrame: Baseline, Week 12
measure: Change in LDL From Baseline
timeFrame: Baseline, Week 12
Other outcomes:
Locations:
city: Chandler
country: United States
facility: Arizona Liver Health
state: Arizona
city: Glendale
country: United States
facility: The Institute of Liver Health
state: Arizona
city: Phoenix
country: United States
facility: Dignity Health DBA St. Joseph's Hospital and Medical Center
state: Arizona
city: Tucson
country: United States
facility: Del Sol Research Management LLC
state: Arizona
city: Bakersfield
country: United States
facility: Rajeev Krishan, MD, Inc
state: California
city: Chula Vista
country: United States
facility: eStudy Site
state: California
city: Coronado
country: United States
facility: Southern California Research Center
state: California
city: Fullerton
country: United States
facility: St. Jude Hospital Yorba Linda DBA St. Joseph Heritage Healthcare
state: California
city: Garden Grove
country: United States
facility: National Institute of Clinical Research, Inc
state: California
city: La Mesa
country: United States
facility: eStudySite - La Mesa
state: California
city: Lancaster
country: United States
facility: Om Research LLC
state: California
city: Los Angeles
country: United States
facility: Keck Medical Center Of USC
state: California
city: Rialto
country: United States
facility: Inland Empire Liver Foundation
state: California
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: San Clemente
country: United States
facility: Southern California Gastrointestinal and Liver Centers
state: California
city: San Diego
country: United States
facility: Precision Research Institute, Llc
state: California
city: Torrance
country: United States
facility: Paradigm Clinical Research Institute
state: California
city: Doral
country: United States
facility: Universal Axon Clinical Research
state: Florida
city: Fleming Island
country: United States
facility: Fleming Island Center for Clinical Research
state: Florida
city: Homestead
country: United States
facility: Universal Axon- Homestead, LLC
state: Florida
city: Inverness
country: United States
facility: Nature Coast 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 Endoscopy - Southside ; Borland Groover Clinic
state: Florida
city: Jacksonville
country: United States
facility: Encore Borland Groover Clinical Research
state: Florida
city: Lakeland
country: United States
facility: Meridien Research
state: Florida
city: Maitland
country: United States
facility: Meridien Research
state: Florida
city: Miami Lakes
country: United States
facility: San Marcus Research Clinic, Inc.
state: Florida
city: Miami
country: United States
facility: Research Associates of South Florida
state: Florida
city: Miami
country: United States
facility: University of Miami, Miller School of Medicine-Don Soffer Clinical Research Center
state: Florida
city: Miami
country: United States
facility: Well Pharma Medical Research, Corp.
state: Florida
city: Miami
country: United States
facility: Med Research Of Florida, LLC
state: Florida
city: Ocala
country: United States
facility: Ocala GI Research
state: Florida
city: Palmetto Bay
country: United States
facility: IMIC, Inc.
state: Florida
city: Saint Petersburg
country: United States
facility: Meridien Research
state: Florida
city: Tampa
country: United States
facility: Guardian Angel Research
state: Florida
city: Atlanta
country: United States
facility: Agile Clinical Research Trials, LLC
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center - University Cardiovascular Surgeons
state: Illinois
city: South Bend
country: United States
facility: Digestive Research Alliance of Michiana
state: Indiana
city: Iowa City
country: United States
facility: University Of Iowa Hospital & Clinics
state: Iowa
city: New Orleans
country: United States
facility: Ochsner Health System
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Baltimore
country: United States
facility: Mercy Medical Center
state: Maryland
city: Catonsville
country: United States
facility: Digestive Disease Associates, PA
state: Maryland
city: Greenbelt
country: United States
facility: Mid-Atlantic GI Research
state: Maryland
city: Detroit
country: United States
facility: Henry Ford Health Hospital
state: Michigan
city: Jackson
country: United States
facility: Southern Therapy and Advanced Research LLC GI Associates and Endoscopy Center
state: Mississippi
city: Saint Louis
country: United States
facility: St. Louis Univ. School Of Medicine
state: Missouri
city: Egg Harbor Township
country: United States
facility: AGA Clinical Research Associates, LLC
state: New Jersey
city: Fresh Meadows
country: United States
facility: Intercity Gastroenterology
state: New York
city: New York
country: United States
facility: New York University Medical Centre
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center School of Medicine and Dentistry
state: New York
city: Concord
country: United States
facility: Northeast GI Research Division
state: North Carolina
city: Huntersville
country: United States
facility: Carolinas HealthCare System Digestive - Huntersville
state: North Carolina
city: Morehead City
country: United States
facility: Lucas Research
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic - Taussig Cancer Institute
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center - Center for Liver Diseases
state: Pennsylvania
city: Hermitage
country: United States
facility: Digestive Health Research, LLC
state: Tennessee
city: Lebanon
country: United States
facility: Digestive Health Research
state: Tennessee
city: Nashville
country: United States
facility: Quality Medical Research
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: DeSoto
country: United States
facility: Crescent Health Clinical
state: Texas
city: Garland
country: United States
facility: DHAT Research Institute
state: Texas
city: San Antonio
country: United States
facility: American Research Corporation at The Texas Liver Institute
state: Texas
city: San Antonio
country: United States
facility: Clinical Trials of Texas, Inc.
state: Texas
city: Newport News
country: United States
facility: Bon Secours St. Mary's Hospital of Richmond, Inc
state: Virginia
city: Seattle
country: United States
facility: Liver Institute Northwest
state: Washington
city: Buenos Aires
country: Argentina
facility: CINME
state: Caba
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Frankfurt am Main
country: Germany
facility: Klinikum der Johann Wolfgang Goethe-Universitaet Frankfurt
state: Hessen
city: Mainz
country: Germany
facility: Universitaetsmedizin der Johannes Gutenberg Universitaet Mainz KoeR
state: Rheinland-Pfalz
city: San Juan
country: Puerto Rico
facility: Latin Clinical Trial Center
city: Wokingham
country: United Kingdom
facility: MediNova West London Quality Research Site
state: Berkshire
city: Romford
country: United Kingdom
facility: MeDiNova East London Quality Research Site
state: Essex
city: London
country: United Kingdom
facility: King's College Hospital - King's College Hospital NHS Foundation Trust
state: Greater London
city: Sidcup
country: United Kingdom
facility: MeDiNova South London Quality Research Site
state: Kent
city: Corby
country: United Kingdom
facility: MeDiNova Northampton Dedicated research site
state: Northamptonshire
city: Kenilworth
country: United Kingdom
facility: MeDiNova Warwickshire Quality Research Site
state: Warwickshire
city: Shipley
country: United Kingdom
facility: MeDiNova Yorkshire Quality Research Site
state: Yorkshire
city: Middlesex
country: United Kingdom
facility: MeDiNova North London Quality Research Site
Study officials:
affiliation: Enanta Pharmaceuticals, Inc
name: Enanta Pharmaceuticals, Inc
role: STUDY_DIRECTOR
References: