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

Primary Biliary Cholangitis Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03394924
• Other study ID #: EDP 305-201
• Status: Completed
• Phase: Phase 2
• Start date: December 27, 2017
• Est. completion date: January 16, 2020

Study information

• Verified date: June 2020
• Source: Enanta Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 68
• Est. completion date: January 16, 2020
• Est. primary completion date: December 19, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Cholangitis
• Liver Cirrhosis, Biliary
• Primary Biliary Cholangitis

Intervention

Drug:
• EDP-305 1 mg
Two tablets daily for 12 weeks
• EDP-305 2.5 mg
Two tablets daily for 12 weeks
• Placebo
Two tablets daily for 12 weeks

Locations

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

Sponsors (3)

Lead Sponsor	Collaborator
Enanta Pharmaceuticals	Pharmaceutical Research Associates, Triangle Biostatistics

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  France,  Germany,  Netherlands,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With At Least a 20% Reduction in Alkaline Phosphatase (ALP) or Normalization of ALP at Week 12 Compared to Baseline	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.	Baseline and Week 12
Secondary	Percentage of Participants With a Treatment-Emergent Adverse Event (TEAE) During On-Treatment Period	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.	Up to approximately Week 12
Secondary	Percentage of Participants With a Treatment-Emergent Serious Adverse Event (SAE) During On-Treatment Period	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.	Up to approximately Week 12
Secondary	Percentage of Participants Who Stopped Study Treatment Due to a Treatment-Emergent Adverse Event (TEAE) During On-Treatment Period	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.	Up to approximately Week 12
Secondary	Change From Baseline to Week 12 in Total, Conjugated and Unconjugated Bilirubin	The data presented below was measured using least square mean change from baseline.	Baseline and Week 12
Secondary	Change From Baseline to Week 12 in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), and Gamma Glutamyl Transferase (GGT)		Baseline and Week 12
Secondary	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)	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.	Baseline and Week 12
Secondary	Change From Baseline to Week 12 in Noninvasive Liver Fibrosis Markers: AST to Platelet Ratio Index (APRI) Score	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.	Baseline and Week 12
Secondary	Change From Baseline to Week 12 in Noninvasive Liver Fibrosis Markers: Fibrosis-4 (FIB-4) Score	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.	Baseline and Week 12
Secondary	Change From Baseline to Week 12 in Fibrinogen and C Reactive Protein (CRP) Levels		Baseline and Week 12
Secondary	Change From Baseline to Week 12 in Interleukin (IL) and Tumor Necrosis Factor (TNF) Levels	For IL, both IL6 and IL1ß variants were analysed. For TNF, both TNF a and TNF ß (also known as lymphotoxin alpha) variants were analyzed.	Baseline and Week 12
Secondary	Change From Baseline to Week 12 in Haptoglobin and Alpha2 Macroglobulin Levels		Baseline and Week 12
Secondary	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
Secondary	Change From Baseline to Week 12 in Domain and Total Scores on the 5D-Itch Scale	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.	Baseline and Week 12
Secondary	Change From Baseline to Week 12 in Visual Analog Score (VAS) for Itching	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.	Baseline to Week 12
Secondary	Change From Baseline to Week 12 in Domain Scores on the Primary Biliary Cholangitis-40 (PBC-40) Quality of Life (QoL) Assessment	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.	Baseline and Week 12
Secondary	Maximum Plasma Concentration (Cmax) of EDP-305 and Its Metabolites	Metabolites of EDP-305 are EP-022571, EP-022572, and EP-022679.	Day 1 and Week 12: Pre-dose and 2, 6 and 8 hours post-dose
Secondary	Time to Maximum Plasma Concentration (Tmax) of EDP-305 and Its Metabolites	Metabolites of EDP-305 are EP-022571, EP-022572, and EP-022679.	Day 1 and Week 12: Pre-dose and 2, 6 and 8 hours post-dose
Secondary	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	Metabolites of EDP-305 are EP-022571, EP-022572, and EP-022679.	Day 1 and Week 12: Pre-dose and 2, 6 and 8 hours post-dose
Secondary	Percentage Change From Baseline to Week 12 in Fibroblast Growth Factor 19 (FGF19), 7a-OH-4-cholesten-3-one (C4) and Bile Acid (BA) Concentrations	FGF19 was measured in plasma. BA was measured in serum. C4 was measured in serum.	Baseline and Week 12
Secondary	Percentage Change From Baseline to Week 12 in AUC0-8 and AUC2-8 of Fibroblast Growth Factor 19 (FGF19), 7a-OH-4-cholesten-3-one (C4) and Bile Acid (BA)	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.	Day 1 and Week 12: Pre-dose and 2, 6 and 8 hours post-dose