A Randomized, Double-blind Study to Assess the Safety and Efficacy of EDP-305 in Subjects With Liver-biopsy Proven NASH

Non-Alcoholic Steatohepatitis Clinical Trial

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04378010
• Other study ID #: EDP 305-102
• Secondary ID: 2019-003876-38
• Status: Terminated
• Phase: Phase 2
• Start date: January 27, 2020
• Est. completion date: November 30, 2021

Study information

• Verified date: April 2023
• Source: Enanta Pharmaceuticals, Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 98
• Est. completion date: November 30, 2021
• Est. primary completion date: October 4, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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)? 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.

Related Conditions & MeSH terms

• Fatty Liver
• Non-alcoholic Fatty Liver Disease
• Non-Alcoholic Steatohepatitis

Intervention

Drug:
• EDP-305 1.5 mg
Tablet
• EDP-305 2 mg
Tablet
• Placebo
Tablet

Locations

Country	Name	City	State
Argentina	CINME	Buenos Aires	Caba
Canada	University of Calgary	Calgary	Alberta
Germany	Klinikum der Johann Wolfgang Goethe-Universitaet Frankfurt	Frankfurt am Main	Hessen
Germany	Universitaetsmedizin der Johannes Gutenberg Universitaet Mainz KoeR	Mainz	Rheinland-Pfalz
Puerto Rico	Latin Clinical Trial Center	San Juan
United Kingdom	MeDiNova Northampton Dedicated research site	Corby	Northamptonshire
United Kingdom	MeDiNova Warwickshire Quality Research Site	Kenilworth	Warwickshire
United Kingdom	King's College Hospital - King's College Hospital NHS Foundation Trust	London	Greater London
United Kingdom	MeDiNova North London Quality Research Site	Middlesex
United Kingdom	MeDiNova East London Quality Research Site	Romford	Essex
United Kingdom	MeDiNova Yorkshire Quality Research Site	Shipley	Yorkshire
United Kingdom	MeDiNova South London Quality Research Site	Sidcup	Kent
United Kingdom	MediNova West London Quality Research Site	Wokingham	Berkshire
United States	Texas Clinical Research Institute	Arlington	Texas
United States	Agile Clinical Research Trials, LLC	Atlanta	Georgia
United States	Texas Diabetes & Endocrinology	Austin	Texas
United States	Rajeev Krishan, MD, Inc	Bakersfield	California
United States	Mercy Medical Center	Baltimore	Maryland
United States	University of Maryland	Baltimore	Maryland
United States	Digestive Disease Associates, PA	Catonsville	Maryland
United States	Arizona Liver Health	Chandler	Arizona
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center - University Cardiovascular Surgeons	Chicago	Illinois
United States	eStudy Site	Chula Vista	California
United States	Cleveland Clinic - Taussig Cancer Institute	Cleveland	Ohio
United States	Northeast GI Research Division	Concord	North Carolina
United States	Southern California Research Center	Coronado	California
United States	Crescent Health Clinical	DeSoto	Texas
United States	Henry Ford Health Hospital	Detroit	Michigan
United States	Universal Axon Clinical Research	Doral	Florida
United States	AGA Clinical Research Associates, LLC	Egg Harbor Township	New Jersey
United States	Fleming Island Center for Clinical Research	Fleming Island	Florida
United States	Intercity Gastroenterology	Fresh Meadows	New York
United States	St. Jude Hospital Yorba Linda DBA St. Joseph Heritage Healthcare	Fullerton	California
United States	National Institute of Clinical Research, Inc	Garden Grove	California
United States	DHAT Research Institute	Garland	Texas
United States	The Institute of Liver Health	Glendale	Arizona
United States	Mid-Atlantic GI Research	Greenbelt	Maryland
United States	Digestive Health Research, LLC	Hermitage	Tennessee
United States	Universal Axon- Homestead, LLC	Homestead	Florida
United States	Carolinas HealthCare System Digestive - Huntersville	Huntersville	North Carolina
United States	Nature Coast Clinical Research	Inverness	Florida
United States	University Of Iowa Hospital & Clinics	Iowa City	Iowa
United States	Southern Therapy and Advanced Research LLC GI Associates and Endoscopy Center	Jackson	Mississippi
United States	Encore Borland Groover Clinical Research	Jacksonville	Florida
United States	Jacksonville Center for Endoscopy - Southside ; Borland Groover Clinic	Jacksonville	Florida
United States	Westside Center for Clinical Research	Jacksonville	Florida
United States	eStudySite - La Mesa	La Mesa	California
United States	Meridien Research	Lakeland	Florida
United States	Om Research LLC	Lancaster	California
United States	Digestive Health Research	Lebanon	Tennessee
United States	Keck Medical Center Of USC	Los Angeles	California
United States	Meridien Research	Maitland	Florida
United States	Med Research Of Florida, LLC	Miami	Florida
United States	Research Associates of South Florida	Miami	Florida
United States	University of Miami, Miller School of Medicine-Don Soffer Clinical Research Center	Miami	Florida
United States	Well Pharma Medical Research, Corp.	Miami	Florida
United States	San Marcus Research Clinic, Inc.	Miami Lakes	Florida
United States	Lucas Research	Morehead City	North Carolina
United States	Quality Medical Research	Nashville	Tennessee
United States	Ochsner Health System	New Orleans	Louisiana
United States	New York University Medical Centre	New York	New York
United States	Bon Secours St. Mary's Hospital of Richmond, Inc	Newport News	Virginia
United States	Ocala GI Research	Ocala	Florida
United States	IMIC, Inc.	Palmetto Bay	Florida
United States	Dignity Health DBA St. Joseph's Hospital and Medical Center	Phoenix	Arizona
United States	University of Pittsburgh Medical Center - Center for Liver Diseases	Pittsburgh	Pennsylvania
United States	Inland Empire Liver Foundation	Rialto	California
United States	University of Rochester Medical Center School of Medicine and Dentistry	Rochester	New York
United States	UC Davis Medical Center	Sacramento	California
United States	St. Louis Univ. School Of Medicine	Saint Louis	Missouri
United States	Meridien Research	Saint Petersburg	Florida
United States	American Research Corporation at The Texas Liver Institute	San Antonio	Texas
United States	Clinical Trials of Texas, Inc.	San Antonio	Texas
United States	Southern California Gastrointestinal and Liver Centers	San Clemente	California
United States	Precision Research Institute, Llc	San Diego	California
United States	Liver Institute Northwest	Seattle	Washington
United States	Digestive Research Alliance of Michiana	South Bend	Indiana
United States	Guardian Angel Research	Tampa	Florida
United States	Paradigm Clinical Research Institute	Torrance	California
United States	Del Sol Research Management LLC	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Enanta Pharmaceuticals, Inc

Countries where clinical trial is conducted

United States,  Argentina,  Canada,  Germany,  Puerto Rico,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.	Week 72
Secondary	Change in 5D-itch Scale From Baseline	5D-itch scale, change from baseline at Week 12. Change from baseline for 5D-itch scale was analyzed using a restricted maximum likelihood-based mixed model repeated measures (MMRM) technique. The model included treatment, visit, treatment-by-visit interaction as fixed effects along with baseline NAS score and baseline score for 5D-itch scale as covariate.; A multidimensional 5D-itch scale developed by Elman (Elman et al., 2010) indicated sum of 0-2 = score of 1, sum of 3-5 = score of 2, sum of 6-10 = score of 3, sum of 11-13 = score of 4, and sum of 14-16 = score of 5. The total 5D score was obtained by summing up the five domain scores and ranges between 5 (no pruritus) and 25 (most severe pruritus).	Baseline, Week 12
Secondary	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	Description of endpoint is 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.	Week 72
Secondary	Proportion of Participants With no Worsening of Fibrosis Combined With no Worsening of NASH as Determined by Liver Biopsy	Proportion of participants with no worsening of fibrosis combined with no worsening of NASH as determined by liver biopsy.	Week 72
Secondary	Proportion of Participants With Resolution of Fibrosis as Determined by Liver Biopsy	Proportion of participants with resolution of fibrosis as determined by liver biopsy at Week 72.	Week 72
Secondary	Proportion of Participants With Improvement in Each Histologic Feature of NASH by at Least 1 Point as Determined by Liver Biopsy	Proportion of participants with improvement in each histologic feature of NASH by at least 1 point as determined by liver biopsy at Week 72.	Week 72
Secondary	Proportion of Participants With Improvement of Fibrosis by = 2 Stages by Liver Biopsy	Proportion of participants with improvement of fibrosis by = 2 stages by liver biopsy.	Week 72
Secondary	Proportion of Participants With Improvement in NAS by at Least 2 Points With no Worsening of Fibrosis as Determined by Liver Biopsy	Proportion of participants with improvement in NAS by at least 2 points with no worsening of fibrosis as determined by liver biopsy at Week 72.	Week 72
Secondary	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	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 at week 72.	Baseline, Week 72
Secondary	Proportion of Participants With Resolution of NASH and no Worsening of Liver Fibrosis	Proportion of participants with resolution of NASH and no worsening of liver fibrosis at Week 72.	Week 72
Secondary	Proportion of Participants With Histological Progression to Cirrhosis as Determined by Liver Biopsy	Proportion of participants with histological progression to cirrhosis as determined by liver biopsy at Week 72.	Week 72
Secondary	Participants With TEAEs Leading to Discontinuation	Treatment emergent adverse events (TEAEs) were defined as AEs occurring or worsening on or after the first dose of study drug until the last dose of study drug. TEAEs were regarded as leading to discontinuation if they led to discontinuation of the study drug.	Day 1 to Week 72
Secondary	Percentage Change of Fat in the Liver From Baseline	Percentage change of fat in the liver as assessed by magnetic resonance imaging proton density fat fraction (MRI PDFF) from Baseline to Week 12.	Baseline, Week 12
Secondary	Change in Liver Stiffness From Baseline	Change in liver stiffness by magnetic resonance elastography (MRE) in kilopascal (kPa) from Baseline at Week 12.	Baseline, Week 12
Secondary	Change in Triglycerides From Baseline	Change in Triglycerides from Baseline at Week 12.	Baseline, Week 12
Secondary	Change in Adiponectin From Baseline	Change in adiponectin from Baseline at Week 12.	Baseline, Week 12
Secondary	Plasma Concentration of EDP-305	Plasma concentration at second post dose (2-4 hours post dose) at Week 12.	2-4 hours post dose at Week 12
Secondary	Change in VAS (Visual Analog Score) From Baseline	Change in VAS from Baseline at Week 12. Change from baseline was analyzed using a restricted maximum likelihood-based MMRM technique. Two separate scales were used to assess pruritus. An itch VAS was used to record the intensity of the pruritus by Furue (Furue et al., 2013). Scale referred to no pruritus (0 point) and the end of the scale to the most severe pruritus (10 points).; If the VAS score was greater than zero (i.e. itch), a multidimensional 5D-itch scale developed by Elman (Elman et al., 2010) indicated sum of 0-2 = score of 1, sum of 3-5 = score of 2, sum of 6-10 = score of 3, sum of 11-13 = score of 4, and sum of 14-16 = score of 5. It was used to assess five different dimensions of pruritus within the last two weeks. The five dimensions assessed were duration, degree, direction, disability, and distribution. The total 5D itch score was obtained by summing up the five domain scores and ranges between 5 (no pruritus) and 25 (most severe pruritus).	Baseline, Week 12
Secondary	Change in Total Cholesterol From Baseline	Change in Total Cholesterol from Baseline to Week 12 versus placebo.	Baseline, Week 12
Secondary	Change in HDL From Baseline	Change in HDL from Baseline at week 12.	Baseline, Week 12
Secondary	Change in LDL From Baseline	Change in LDL From Baseline to Week 12.	Baseline, Week 12