A Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of EDP-305 in Subjects With Primary Biliary Cholangitis

Phase 2

Completed

Conditions: Primary Biliary Cholangitis

Interventions: Drug: EDP-305 1 mg
Drug: EDP-305 2.5 mg
Drug: Placebo

Registration Number: NCT03394924

Lead Sponsor: Enanta Pharmaceuticals, Inc

Brief Summary: A randomized, double-blind study to assess the safety, tolerability, PK and efficacy of EDP-305 in subjects with primary biliary cholangitis

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 68

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
EDP-305 1 mg	EDP-305 1 mg	Subjects will take 2 tablets once a day orally for 12 weeks
EDP-305 2.5 mg	EDP-305 2.5 mg	Subjects will take 2 tablets once a day orally for 12 weeks
Placebo	Placebo	Subjects will take two tablets once a day orally for 12 weeks

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With At Least a 20% Reduction in Alkaline Phosphatase (ALP) or Normalization of ALP at Week 12 Compared to Baseline	Baseline and Week 12	Percent change was calculated as \[(ALP at Week 12 - ALP at Baseline)/ALP at Baseline\] \*100. The participant was considered to have successfully achieved a 20% reduction in ALP if the result was ≤-20. The participant was considered to have successfully achieved ALP normalization if ALP was abnormal at Baseline and normal at Week 12.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline to Week 12 in Noninvasive Liver Fibrosis Markers: AST to Platelet Ratio Index (APRI) Score	Baseline and Week 12	APRI was calculated as (\[AST level/AST upper limit of normal\]/\[Platelet count 1\^09/L\])×100. AST is aspartate aminotransferase. The aspartate transaminase to platelet ratio index (APRI) is used to assess liver fibrosis in participants with chronic liver disease. Scores range from 0 to ≥ 2.0, with scores \< 0.5 predictive of no liver fibrosis; scores \>1.5 significant fibrosis; and scores \> 2.0 indicative of cirrhosis. A negative change from baseline indicates a decrease in fibrosis.
Change From Baseline to Week 12 in Fibrinogen and C Reactive Protein (CRP) Levels	Baseline and Week 12
Change From Baseline to Week 12 in Interleukin (IL) and Tumor Necrosis Factor (TNF) Levels	Baseline and Week 12	For IL, both IL6 and IL1β variants were analysed. For TNF, both TNF α and TNF β (also known as lymphotoxin alpha) variants were analyzed.
Change From Baseline to Week 12 in Haptoglobin and Alpha2 Macroglobulin Levels	Baseline and Week 12
Change From Baseline to Week 12 in Triglycerides (TG), Total Cholesterol (TC), High Density Lipoprotein Cholesterol (HDL-C), Low Density Lipoprotein Cholesterol (LDL-C)	Baseline and Week 12
Change From Baseline to Week 12 in Total, Conjugated and Unconjugated Bilirubin	Baseline and Week 12	The data presented below was measured using least square mean change from baseline.
Percentage of Participants With a Treatment-Emergent Adverse Event (TEAE) During On-Treatment Period	Up to approximately Week 12	An adverse event (AE) was defined as any event, side effect, or untoward medical occurrence in a subject enrolled in a clinical trial whether or not it is considered to have a causal relationship to the study drug. A TEAE was an AE that first occurred or began previous to and worsened on or after the first dose date and before the last dose date +7 days.
Percentage of Participants With a Treatment-Emergent Serious Adverse Event (SAE) During On-Treatment Period	Up to approximately Week 12	A SAE is any untoward medical occurrence at any dose that results in death, is a life-threatening event, requires inpatient hospitalization or prolonged hospitalization of an existing hospitalization, results in permanent or prolonged disability or incapacity, is a congenital anomaly or birth defect in the offspring of a study subjects, or is a medically important event.
Percentage of Participants Who Stopped Study Treatment Due to a Treatment-Emergent Adverse Event (TEAE) During On-Treatment Period	Up to approximately Week 12	An adverse event (AE) was defined as any event, side effect, or untoward medical occurrence in a subject enrolled in a clinical trial whether or not it is considered to have a causal relationship to the study drug. A TEAE was an AE that first occurred or began previous to and worsened on or after the first dose date and before the last dose date +7 days.
Change From Baseline to Week 12 in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), and Gamma Glutamyl Transferase (GGT)	Baseline and Week 12
Change From Baseline to Week 12 in Noninvasive Liver Fibrosis Markers: Fibrosis-4 (FIB-4) Score	Baseline and Week 12	Fibrosis-4 is the ratio of age in years and aminotransferase to platelet count. It is a non-invasive hepatic fibrosis index score that is calculated using formula: FIB-4 = (Age \[years\] x AST \[U/L\]) / (platelets \[10\^9/L\] x (square root of ALT \[U/L\])). A FIB-4 index of \< 1.45 indicates no or moderate fibrosis and an index of \> 3.25 indicates extensive fibrosis/cirrhosis. A positive change from Baseline indicates increased fibrosis.
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)	Baseline and Week 12	The ELF panel included hyaluronic acid (HA), procollagen III amino terminal peptide (PIIINP), and tissue inhibitor of metalloproteinase 1 (TIMP 1). This endpoint also presents PRO C3 results.
Change From Baseline to Week 12 in Domain and Total Scores on the 5D-Itch Scale	Baseline and Week 12	The 5D-Itch scale is a multidimensional questionnaire completed by participants to quantify the magnitude of pruritus, assessed considering the past 2 weeks. Scale range is 1 to 5 covering five dimensions: duration (1=Less than 6 hrs/day to 5=All day), degree (1=Not present to 5=Unbearable), direction (1=Completely resolved to 5=Getting worse), disability (for Sleep rated as 1=Never affects sleep to 5=Delays falling asleep and frequently wakes me up at night; for Leisure/Social, Housework/Errands and Work/School rated as 1=Never affects activity to 5=Always affects activity), and distribution (assess if itching is present in 16 body locations, scored as 1=present at 0-2 locations to 5=present at 14-16 locations). Total scores (including highest disability score obtained from any of the daily activities) ranged between 5 and 25 where higher scores indicated more severe itching. Negative change scores indicate improvement from the baseline score.
Change From Baseline to Week 12 in Visual Analog Score (VAS) for Itching	Baseline to Week 12	An itch VAS (0-100mm) was used to record the intensity of the event. Participants drew a line on a scale corresponding to the maximum intensity of itch. Lines drawn towards the right of the line indicated greater itching and higher scores indicated more severe itching. Negative change from baseline indicates decrease in itching.
Change From Baseline to Week 12 in Domain Scores on the Primary Biliary Cholangitis-40 (PBC-40) Quality of Life (QoL) Assessment	Baseline and Week 12	The PBC-40 is a survey measuring health related quality of life in participants with PBC. The 40 questions from the PBC-40 questionnaire are scored from 1-5, with 5 representing the highest impact and 1 the lowest impact of PBC on the quality of life. Six domains were computed from the 40 questions: symptoms (score range 7-35), itch (0-15), fatigue (11-55), cognition (6-30), social (8-50) and emotional (1-15). Higher scores indicate worse quality of life and negative change scores indicate improvement from the baseline score.
Maximum Plasma Concentration (Cmax) of EDP-305 and Its Metabolites	Day 1 and Week 12: Pre-dose and 2, 6 and 8 hours post-dose	Metabolites of EDP-305 are EP-022571, EP-022572, and EP-022679.
Time to Maximum Plasma Concentration (Tmax) of EDP-305 and Its Metabolites	Day 1 and Week 12: Pre-dose and 2, 6 and 8 hours post-dose	Metabolites of EDP-305 are EP-022571, EP-022572, and EP-022679.
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	Day 1 and Week 12: Pre-dose and 2, 6 and 8 hours post-dose	Metabolites of EDP-305 are EP-022571, EP-022572, and EP-022679.
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	Baseline and Week 12	FGF19 was measured in plasma. BA was measured in serum. C4 was measured in serum.
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)	Day 1 and Week 12: Pre-dose and 2, 6 and 8 hours post-dose	AUC0-8 is area under the biomarker concentration-time curve from time zero to 8 hours. AUC2-8 is area under the biomarker concentration-time curve from 2 hours to 8 hours. FGF19 was measured in plasma. BA was measured in serum. C4 was measured in serum.

Trial Locations

Locations (86): Dartmouth-Hitchcock Medical Center
🇺🇸
Lebanon, New Hampshire, United States
Universitair Ziekenhuis Gent
🇧🇪
Gent, Oost-vlaanderen, Belgium
Vrije Universiteit Medisch Centrum
🇳🇱
Amsterdam, Noord-holland, Netherlands
University Hospitals Birmingham NHS Foundation Trust
🇬🇧
Birmingham, England, United Kingdom
The Leeds Teaching Hospitals NHS Trust
🇬🇧
Leeds, England, United Kingdom
Norfolk and Norwich University Hospitals NHS Foundation Trust
🇬🇧
Norwich, England, United Kingdom
Cedars-Sinai Medical Center
🇺🇸
Los Angeles, California, United States
South Denver Gastroenterology - Swedish Medical Center Office
🇺🇸
Englewood, Colorado, United States
Gastroenterology Consultants of Clearwater
🇺🇸
Clearwater, Florida, United States
Consultative Gastroenterology
🇺🇸
Atlanta, Georgia, United States
Massachusetts General Hospital
🇺🇸
Boston, Massachusetts, United States
Northwell Health
🇺🇸
Manhasset, New York, United States
University of Pittsburgh Medical Center - Center for Liver Disease
🇺🇸
Pittsburgh, Pennsylvania, United States
The Liver Institute at Methodist Dallas Medical Center
🇺🇸
Dallas, Texas, United States
Liver Consultants of Texas
🇺🇸
Dallas, Texas, United States
Toronto General Hospital
🇨🇦
Toronto, Ontario, Canada
King's College Hospital NHS Foundation Trust
🇬🇧
London, England, United Kingdom
Toronto Liver Center
🇨🇦
Toronto, Ontario, Canada
Klinikum Klagenfurt Am Wörthersee
🇦🇹
Klagenfurt am Wörthersee, Carinthia, Austria
Icahn School of Medicine at Mount Sinai
🇺🇸
New York, New York, United States
California Pacific Medical Center
🇺🇸
San Francisco, California, United States
University of Miami Leonard M. Miller School of Medicine
🇺🇸
Miami, Florida, United States
Henry Ford Hospital
🇺🇸
Detroit, Michigan, United States
CHI Health
🇺🇸
Omaha, Nebraska, United States
Baylor Saint Luke's Medical Center
🇺🇸
Houston, Texas, United States
American Research Corporation at the Texas Liver Institute
🇺🇸
San Antonio, Texas, United States
Swedish First Hill Campus
🇺🇸
Seattle, Washington, United States
University of Iowa Hospitals and Clinics
🇺🇸
Iowa City, Iowa, United States
Digestive Health Specialists of the Southeast
🇺🇸
Dothan, Alabama, United States
Texas Clinical Research Institute
🇺🇸
Little Rock, Arkansas, United States
Southern California Research Center
🇺🇸
Coronado, California, United States
Pasadena Liver Center
🇺🇸
Pasadena, California, United States
California Liver Research Institue
🇺🇸
Pasadena, California, United States
Inland Empire Liver Foundation
🇺🇸
Rialto, California, United States
Yale School of Medicine
🇺🇸
New Haven, Connecticut, United States
Nature Coast Clinical Research
🇺🇸
Inverness, Florida, United States
Louisiana Research Center
🇺🇸
Shreveport, Louisiana, United States
Johns Hopkins University
🇺🇸
Baltimore, Maryland, United States
Mercy Medical Center-McAuley Plaza
🇺🇸
Baltimore, Maryland, United States
Digestive Disease Associates
🇺🇸
Catonsville, Maryland, United States
Beth Israel Deaconess Medical Center
🇺🇸
Boston, Massachusetts, United States
Montefiore Medical Center - Bronx
🇺🇸
Bronx, New York, United States
Concorde Medical Group
🇺🇸
New York, New York, United States
Mount Sinai Beth Isreal
🇺🇸
New York, New York, United States
Weill Cornell Medical College
🇺🇸
New York, New York, United States
Liver Institute of Virginia-Bremo
🇺🇸
Richmond, Virginia, United States
University of Washington
🇺🇸
Seattle, Washington, United States
Nepean Hospital
🇦🇺
Kingswood, New South Wales, Australia
Monash Medical Centre
🇦🇺
Clayton, Victoria, Australia
Linear Clinical Research
🇦🇺
Perth, Western Australia, Australia
Medizinische Universität Innsbruck
🇦🇹
Innsbruck, Tyrol, Austria
Klinikum Wels-Grieskirchen
🇦🇹
Wels, Upper Austria, Austria
CHU de Liège, Cardiology Dept.
🇧🇪
Liège, Liege, Belgium
Ziekenhuis Oost-Limburg
🇧🇪
Genk, Limburg, Belgium
London Health Sciences Centre University Hospital
🇨🇦
London, Ontario, Canada
Nouvel Hôpital Civil
🇫🇷
Strasbourg cedex, Alsace, France
Hôpital Saint-Antoine
🇫🇷
Paris Cedex 12, Ile-de-france, France
Hôpital Haut-Lévêque
🇫🇷
Pessac, Aquitaine, France
Hôpital Saint-Eloi
🇫🇷
Montpellier cedex 5, Languedoc-roussillon, France
Hôpital Paul Brousse
🇫🇷
Villejuif Cedex, Ile-de-france, France
Hôpital de la Croix Rousse
🇫🇷
Lyon Cedex 04, Rhone-alpes, France
Centre Hospitalier Régional Universitaire de Lille
🇫🇷
Lille, NORD Pas-de-calais, France
Centre Hospitalier Universitaire Amines-Picardie Hôpital Sud
🇫🇷
Amiens Cedex 1, Picardie, France
Universitätsklinikum Bonn
🇩🇪
Bonn, Nordrhein-westfalen, Germany
Universitaetsklinikum Essen
🇩🇪
Essen, Nordrhein-westfalen, Germany
Universitätsklinikum Würzburg
🇩🇪
Würzburg, Bayern, Germany
Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz
🇩🇪
Mainz, Rheinland-pfalz, Germany
Charité Universitätsmedizin Berlin
🇩🇪
Berlin, Germany
Universitätsklinikum Leipzig
🇩🇪
Leipzig, Sachsen, Germany
Leiden Universitair Medisch Centrum
🇳🇱
Leiden, Zuid-holland, Netherlands
Universitair Medisch Centrum Utrecht
🇳🇱
Utrecht, Netherlands
Hospital Universitario Donostia
🇪🇸
San Sebastian, Guipuzcoa, Spain
Hospital Universitario Virgen de la Arrixaca
🇪🇸
El Palmar, Murcia, Spain
Hospital Universitari Vall d'Hebrón
🇪🇸
Barcelona, Spain
Hospital Universitario Ramón Y Cajal
🇪🇸
Madrid, Spain
Hospital Universitario Marqués de Valdecilla
🇪🇸
Santander, Spain
Hospital Universitario Virgen del Rocio
🇪🇸
Sevilla, Spain
Hospital Universitari i Politecnic La Fe de Valencia
🇪🇸
Valencia, Spain
Cambridge University Hospitals NHS Foundation Trust
🇬🇧
Cambridge, England, United Kingdom
Universidad de Valladolid - Hospital Universitario Rio Hortega
🇪🇸
Valladolid, Spain
Queen's Medical Centre - Nottingham
🇬🇧
Nottingham, England, United Kingdom
Portsmouth Hospitals NHS Trust
🇬🇧
Portsmouth, England, United Kingdom
NHS Lothian
🇬🇧
Edinburgh, Scotland, United Kingdom
Northwestern University
🇺🇸
Chicago, Illinois, United States
Universitätsklinikum Frankfurt
🇩🇪
Frankfurt am Main, Hessen, Germany
Arkansas Diagnostic Center
🇺🇸
Little Rock, Arkansas, United States