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

Study Overview
=================
Brief Summary
-----------------
A randomized, double-blind study to assess the safety, tolerability, PK 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)

Conditions
-----------------
Primary Biliary Cholangitis

Intervention / Treatment
-----------------
* Drug: EDP-305 1 mg
* Drug: EDP-305 2.5 mg
* Drug: Placebo


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EDP-305 1 mg<br>Subjects will take 2 tablets once a day orally for 12 weeks | Drug: EDP-305 1 mg<br>* Two tablets daily for 12 weeks<br>|
| Experimental: EDP-305 2.5 mg<br>Subjects will take 2 tablets once a day orally for 12 weeks | Drug: EDP-305 2.5 mg<br>* Two tablets daily for 12 weeks<br>|
| Placebo Comparator: Placebo<br>Subjects will take two tablets once a day orally for 12 weeks | Drug: Placebo<br>* Two tablets daily for 12 weeks<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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: 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 | 
| 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 | 
| 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 | 
| 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 | 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. | Baseline and Week 12 | 
| 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 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | FGF19 was measured in plasma. BA was measured in serum. C4 was measured in serum. | Baseline and Week 12 | 
| 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) | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PBC, Primary Biliary Cholangitis (PBC)