Clinical trial NCT03394924: A Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of EDP-305 in Subjects With Primary Biliary Cholangitis
Official title: A Phase 2 Dose Ranging, Randomized, Double Blind, Placebo-Controlled Study Evaluating the Safety, Tolerability, Pharmacokinetics and Efficacy of EDP-305 in Subjects With Primary Biliary Cholangitis (PBC) With or Without an Inadequate Response to Ursodeoxycholic Acid (UDCA)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Primary Biliary Cholangitis
Keywords: PBC
Primary Biliary Cholangitis (PBC)
Lead sponsor: Enanta Pharmaceuticals, Inc
Sponsor class: INDUSTRY
Collaborators: name: Pharmaceutical Research Associates
name: Triangle Biostatistics, LLC
First posted: 2018-01-09
Enrollment: 68
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 primary biliary cholangitis


Eligibility criteria: Inclusion Criteria:

* An informed consent document 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 a diagnosis of PBC by at least two of the following criteria:

  * History of ALP above ULN for at least six months
  * Positive Anti-Mitochondrial Antibodies (AMA) titers (\>1/40 on immunofluorescence or M2 positive by enzyme linked immunosorbent assay (ELISA) or positive PBC-specific antinuclear antibodies)
* For subjects with no documented liver biopsy performed within 2 years, subjects must undergo a transient elastography (Fibroscan) showing liver stiffness \< 14.0 kPA
* Must be on a stable dose of UDCA12-20 mg/kg/day for at least 6 months prior to Screening or intolerant of UDCA in the opinion of the Investigator (no UDCA for at least 12 weeks prior to Screening)
* Alkaline Phosphatase (ALP) ≥ 1.67 × ULN and/or total bilirubin \>ULN but \< 2×ULN (\<2.4 mg/dL)
* Subjects must have Screening laboratory values for Hepatitis B surface antigen (HBsAg), anti-HCV antibodies and HCV RNA negative and Human Immunodeficiency Virus (HIV) 1 and 2 antibodies (Ab) as seronegative. Note: subjects previously infected by chronic hepatitis C and treated with direct acting antivirals (DAAs) with sustained virologic response (SVR) for at least 3 years will be allowed.
* 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.
* All male participants who have not had a vasectomy must use effective contraception from Day -1 to 90 days after their last dose of study drug.
* Male subjects must agree to refrain from sperm donation from the date of Screening until 90 days after their last dose of study drug
* Screening body mass index (BMI) of ≥18 kg/m2
* Subject must be willing and able to adhere to the assessments, visit schedule, prohibitions and restrictions, as described in this protocol

Exclusion Criteria:

* Laboratory Screening Results:

  * AST \>5 x ULN
  * ALT \>5 x ULN
  * Patients with Gilbert's syndrome will not be allowed due to interpretability of bilirubin levels
  * Total white blood cells (WBC) \<3000 cells/mm3
  * Absolute neutrophil count (ANC) \<1500 cells/mm3
  * Platelet count \<140,000/mm3
  * Prothrombin time (international normalized ratio, INR) \>1.2
  * Serum creatinine \>2 mg/dL or creatinine clearance \<60 mL/min (based on Cockroft-Gault Method)
* Suspected to have relevant nonalcoholic fatty liver disease (NAFLD) as based on the judgment of the Investigator at Screening
* Use of immunosuppressants known to have an effect on the liver of patients with PBC (eg, colchicine, methotrexate, azathioprine, or systemic steroids) in the three months preceding screening
* Current use of fibrates, including fenofibrates. Note: Subjects who discontinued fibrates for at least 3 months before Screening can participate
* Use of an experimental treatment for PBC within the past 6 months
* Co-existing liver or biliary diseases, such as primary sclerosing cholangitis, choledocholithiasis, acute or chronic hepatitis, autoimmune hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis (NASH), acute infection of bile duct system or gall bladder, history of gastrointestinal bleeding (secondary to portal hypertension), cirrhosis, cholangiocarcinoma diagnosed or suspected liver cancers
* Cirrhosis with or without complications, including history or presence of: spontaneous bacterial peritonitis, hepatocellular carcinoma
* 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)
* Medical conditions that may cause nonhepatic increases in ALP (e.g., Paget's disease)
* Use of a new statin regimen from Screening and throughout study duration. NOTE: Subjects on a stable dose of statins for at least 3 months prior to Screening are allowed. No dose modification during the study will be allowed.
* Use of immunosuppressants (eg, systemic corticosteroids) for more than 2 consecutive weeks in duration within 1 year prior to Screening.

Primary outcomes:
measure: Percentage of Participants With At Least a 20% Reduction in Alkaline Phosphatase (ALP) or Normalization of ALP at Week 12 Compared to Baseline
timeFrame: Baseline and Week 12
Secondary outcomes:
measure: Percentage of Participants With a Treatment-Emergent Adverse Event (TEAE) During On-Treatment Period
timeFrame: Up to approximately Week 12
measure: Percentage of Participants With a Treatment-Emergent Serious Adverse Event (SAE) During On-Treatment Period
timeFrame: Up to approximately Week 12
measure: Percentage of Participants Who Stopped Study Treatment Due to a Treatment-Emergent Adverse Event (TEAE) During On-Treatment Period
timeFrame: Up to approximately Week 12
measure: Change From Baseline to Week 12 in Total, Conjugated and Unconjugated Bilirubin
timeFrame: Baseline and Week 12
measure: Change From Baseline to Week 12 in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), and Gamma Glutamyl Transferase (GGT)
timeFrame: Baseline and Week 12
measure: Change From Baseline to Week 12 in Noninvasive Liver Fibrosis Markers: Enhanced Liver Fibrosis (ELF) Panel and N-terminal Type III Collagen Propeptide (PRO C3)
timeFrame: Baseline and Week 12
measure: Change From Baseline to Week 12 in Noninvasive Liver Fibrosis Markers: AST to Platelet Ratio Index (APRI) Score
timeFrame: Baseline and Week 12
measure: Change From Baseline to Week 12 in Noninvasive Liver Fibrosis Markers: Fibrosis-4 (FIB-4) Score
timeFrame: Baseline and Week 12
measure: Change From Baseline to Week 12 in Fibrinogen and C Reactive Protein (CRP) Levels
timeFrame: Baseline and Week 12
measure: Change From Baseline to Week 12 in Interleukin (IL) and Tumor Necrosis Factor (TNF) Levels
timeFrame: Baseline and Week 12
measure: Change From Baseline to Week 12 in Haptoglobin and Alpha2 Macroglobulin Levels
timeFrame: Baseline and Week 12
measure: Change From Baseline to Week 12 in Triglycerides (TG), Total Cholesterol (TC), High Density Lipoprotein Cholesterol (HDL-C), Low Density Lipoprotein Cholesterol (LDL-C)
timeFrame: Baseline and Week 12
measure: Change From Baseline to Week 12 in Domain and Total Scores on the 5D-Itch Scale
timeFrame: Baseline and Week 12
measure: Change From Baseline to Week 12 in Visual Analog Score (VAS) for Itching
timeFrame: Baseline to Week 12
measure: Change From Baseline to Week 12 in Domain Scores on the Primary Biliary Cholangitis-40 (PBC-40) Quality of Life (QoL) Assessment
timeFrame: Baseline and Week 12
measure: Maximum Plasma Concentration (Cmax) of EDP-305 and Its Metabolites
timeFrame: Day 1 and Week 12: Pre-dose and 2, 6 and 8 hours post-dose
measure: Time to Maximum Plasma Concentration (Tmax) of EDP-305 and Its Metabolites
timeFrame: Day 1 and Week 12: Pre-dose and 2, 6 and 8 hours post-dose
measure: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of EDP-305 and Its Metabolites
timeFrame: Day 1 and Week 12: Pre-dose and 2, 6 and 8 hours post-dose
measure: Percentage Change From Baseline to Week 12 in Fibroblast Growth Factor 19 (FGF19), 7α-OH-4-cholesten-3-one (C4) and Bile Acid (BA) Concentrations
timeFrame: Baseline and Week 12
measure: Percentage Change From Baseline to Week 12 in AUC0-8 and AUC2-8 of Fibroblast Growth Factor 19 (FGF19), 7α-OH-4-cholesten-3-one (C4) and Bile Acid (BA)
timeFrame: Day 1 and Week 12: Pre-dose and 2, 6 and 8 hours post-dose
Other outcomes:
Locations:
city: Dothan
country: United States
facility: Digestive Health Specialists of the Southeast
state: Alabama
city: Little Rock
country: United States
facility: Arkansas Diagnostic Center
state: Arkansas
city: Little Rock
country: United States
facility: Texas Clinical Research Institute
state: Arkansas
city: Coronado
country: United States
facility: Southern California Research Center
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Pasadena
country: United States
facility: California Liver Research Institue
state: California
city: Pasadena
country: United States
facility: Pasadena Liver Center
state: California
city: Rialto
country: United States
facility: Inland Empire Liver Foundation
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: Englewood
country: United States
facility: South Denver Gastroenterology - Swedish Medical Center Office
state: Colorado
city: New Haven
country: United States
facility: Yale School of Medicine
state: Connecticut
city: Clearwater
country: United States
facility: Gastroenterology Consultants of Clearwater
state: Florida
city: Inverness
country: United States
facility: Nature Coast Clinical Research
state: Florida
city: Miami
country: United States
facility: University of Miami Leonard M. Miller School of Medicine
state: Florida
city: Atlanta
country: United States
facility: Consultative Gastroenterology
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Shreveport
country: United States
facility: Louisiana Research Center
state: Louisiana
city: Baltimore
country: United States
facility: Mercy Medical Center-McAuley Plaza
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Catonsville
country: United States
facility: Digestive Disease Associates
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Omaha
country: United States
facility: CHI Health
state: Nebraska
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: Bronx
country: United States
facility: Montefiore Medical Center - Bronx
state: New York
city: Manhasset
country: United States
facility: Northwell Health
state: New York
city: New York
country: United States
facility: Concorde Medical Group
state: New York
city: New York
country: United States
facility: Mount Sinai Beth Isreal
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center - Center for Liver Disease
state: Pennsylvania
city: Dallas
country: United States
facility: The Liver Institute at Methodist Dallas Medical Center
state: Texas
city: Dallas
country: United States
facility: Liver Consultants of Texas
state: Texas
city: Houston
country: United States
facility: Baylor Saint Luke's Medical Center
state: Texas
city: San Antonio
country: United States
facility: American Research Corporation at the Texas Liver Institute
state: Texas
city: Richmond
country: United States
facility: Liver Institute of Virginia-Bremo
state: Virginia
city: Seattle
country: United States
facility: Swedish First Hill Campus
state: Washington
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Kingswood
country: Australia
facility: Nepean Hospital
state: New South Wales
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Perth
country: Australia
facility: Linear Clinical Research
state: Western Australia
city: Klagenfurt am Wörthersee
country: Austria
facility: Klinikum Klagenfurt Am Wörthersee
state: Carinthia
city: Innsbruck
country: Austria
facility: Medizinische Universität Innsbruck
state: Tyrol
city: Wels
country: Austria
facility: Klinikum Wels-Grieskirchen
state: Upper Austria
city: Liège
country: Belgium
facility: CHU de Liège, Cardiology Dept.
state: Liege
city: Genk
country: Belgium
facility: Ziekenhuis Oost-Limburg
state: Limburg
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
state: Oost-vlaanderen
city: London
country: Canada
facility: London Health Sciences Centre University Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto Liver Center
state: Ontario
city: Strasbourg cedex
country: France
facility: Nouvel Hôpital Civil
state: Alsace
city: Pessac
country: France
facility: Hôpital Haut-Lévêque
state: Aquitaine
city: Paris Cedex 12
country: France
facility: Hôpital Saint-Antoine
state: Ile-de-france
city: Villejuif Cedex
country: France
facility: Hôpital Paul Brousse
state: Ile-de-france
city: Montpellier cedex 5
country: France
facility: Hôpital Saint-Eloi
state: Languedoc-roussillon
city: Lille
country: France
facility: Centre Hospitalier Régional Universitaire de Lille
state: NORD Pas-de-calais
city: Amiens Cedex 1
country: France
facility: Centre Hospitalier Universitaire Amines-Picardie Hôpital Sud
state: Picardie
city: Lyon Cedex 04
country: France
facility: Hôpital de la Croix Rousse
state: Rhone-alpes
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
state: Bayern
city: Frankfurt am Main
country: Germany
facility: Universitätsklinikum Frankfurt
state: Hessen
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
state: Nordrhein-westfalen
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
state: Nordrhein-westfalen
city: Mainz
country: Germany
facility: Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz
state: Rheinland-pfalz
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
state: Sachsen
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin
city: Amsterdam
country: Netherlands
facility: Vrije Universiteit Medisch Centrum
state: Noord-holland
city: Leiden
country: Netherlands
facility: Leiden Universitair Medisch Centrum
state: Zuid-holland
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: San Sebastian
country: Spain
facility: Hospital Universitario Donostia
state: Guipuzcoa
city: El Palmar
country: Spain
facility: Hospital Universitario Virgen de la Arrixaca
state: Murcia
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebrón
city: Madrid
country: Spain
facility: Hospital Universitario Ramón Y Cajal
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe de Valencia
city: Valladolid
country: Spain
facility: Universidad de Valladolid - Hospital Universitario Rio Hortega
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust
state: England
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
state: England
city: Leeds
country: United Kingdom
facility: The Leeds Teaching Hospitals NHS Trust
state: England
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
state: England
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospitals NHS Foundation Trust
state: England
city: Nottingham
country: United Kingdom
facility: Queen's Medical Centre - Nottingham
state: England
city: Portsmouth
country: United Kingdom
facility: Portsmouth Hospitals NHS Trust
state: England
city: Edinburgh
country: United Kingdom
facility: NHS Lothian
state: Scotland
Study officials:
References: