| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary Biliary Cholangitis (PBC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| A chronic disease in which the small bile ducts in the liver become injured and inflamed and are eventually destroyed. When there are no bile ducts, bile builds up and causes liver damage. |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036680 |
| E.1.2 | Term | Primary biliary cirrhosis |
| E.1.2 | System Organ Class | 100000004871 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the effect of EDP-305 on alkaline phosphatase (ALP) levels. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of EDP-305
• To evaluate the effect of EDP-305 on bilirubin levels
• To evaluate the effects of EDP-305 on other markers of liver function
• To evaluate the effects of EDP-305 on non-invasive markers of liver fibrosis
• To evaluate the effects of EDP-305 on inflammatory markers
• To evaluate the effects of EDP-305 on lipids
• To evaluate the effects of EDP-305 on pruritus
• To evaluate the effects of EDP-305 on Quality of Life (QoL)
• To evaluate the pharmacokinetics (PK) of EDP-305 and metabolites in plasma
• To evaluate the pharmacodynamics (PD) of EDP-305 |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PK/PD substudy
Additional samples will be collected from subjects at a subset of sites that have the technical capability to collect and process intensive (longer duration) PK samples. At Day 1 and Day 84 (Week 12) PK samples will be collected at predose and 2, 6, and 8 hours postdose. On scheduled visits on Week 2, 4 and 8, PK samples will be collected at three timepoints: predose and at two timepoints postdose; the first samples collected 1 to 3 hours postdose and the second postdose samples collected at least 1 hour later. Where possible, the samples at each visit should be obtained at different times postdose relative to each other. |
|
| E.3 | Principal inclusion criteria |
1. An informed consent document must be signed and dated by the subject
2. Male and female subjects of any ethnic origin between the ages of 18 and 75 years, inclusive
3. Male or female with a diagnosis of PBC by at least two of the following criteria:
• History of ALP above ULN for at least 6 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 [PBC- ANAb])
• Documented liver biopsy result consistent with PBC (with no cirrhosis)
4. For subjects with no documented liver biopsy performed within 2 years, subjects must undergo a transient elastography (Fibroscan) showing liver stiffness <14.0 kPA
5. 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)
6. Alkaline Phosphatase (ALP) ≥1.67 × ULN and/or total bilirubin >ULN but <2 × ULN (<2.4 mg/dL)
7. 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.
8. 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. Effective methods of contraception are defined as:
• a condom for the male partner and at least one of the following for the female participant:
o Intrauterine device
o Oral, injectable, implantable, transdermal, or intravaginal hormonal contraceptive
Note: The above does not apply to female subjects of non-childbearing potential (ie, physiologically incapable of becoming pregnant) defined as:
- has had a complete hysterectomy greater than or equal to 3 months prior to dosing or
- has had a bilateral oophorectomy (ovariectomy) or
- has had a bilateral tubal ligation or fallopian tube inserts or
- is postmenopausal (a demonstration of a total cessation of menses for ≥1 year with an FSH level of >35 mIU/mL).
9. 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. Effective contraception is defined as a condom and spermicide for the male, or condom and at least one of the following for a female partner:
• Intrauterine device
• Oral, injectable, implantable, transdermal, or intravaginal hormonal contraceptive
• Be of non-childbearing potential
10. Male subjects must agree to refrain from sperm donation from the date of Screening until 90 days after their last dose of study drug
11. Screening body mass index (BMI) of ≥18 kg/m2
12. Subject must be willing and able to adhere to the assessments, visit schedule, prohibitions and restrictions, as described in this protocol |
|
| E.4 | Principal exclusion criteria |
1. Laboratory Screening Results:
• AST >5 × ULN
• ALT >5 × 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)
2. Suspected to have relevant nonalcoholic fatty liver disease (NAFLD) as based on the judgment of the Investigator at Screening
3. Known history of alpha-1-Antitrypsin deficiency
4. Use of immunosuppressants known to have an effect on the liver of patients with PBC (eg, colchicine, methotrexate, or azathioprine) in the 3 months preceding Screening.
5. Current use of fibrates, including fenofibrates. NOTE: Subjects who discontinued fibrates for at least 3 months before Screening can participate
6. Use of an experimental treatment for PBC within the past 6 months
7. Prior use and/or concomitant treatment with obeticholic acid (OCA)
8. Use of experimental or unapproved drugs within 1 year of Screening
9. Any other condition(s) that would compromise the safety of the subject or compromise the quality of the clinical study, as judged by the Principal Investigator (PI)
10. Pregnant or nursing females
11. Recipients of liver or other organ transplantation or anticipated need for orthotropic organ transplantation in one year as determined by a Model for End-Stage Liver Disease (MELD) Score ≥15
12. 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
13. Cirrhosis with or without complications, including history or presence of: spontaneous bacterial peritonitis, hepatocellular carcinoma
14. Hepatorenal syndrome (type I or II) or Screening serum creatinine >2 mg/dL (178 μmol/L)
15. 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)
16. Patients with a history of severe pruritus requiring current or prior systemic treatment (e.g., with BAS or rifampicin)
17. Medical conditions that may cause nonhepatic increases in ALP (e.g., Paget's disease)
18. Any condition possibly affecting drug absorption (eg, gastrectomy <3 years prior to Screening. NOTE: Subjects who have undergone gastric surgeries known to not affect drug absorption such as gastric band or gastric sleeve will be allowed if they are stable for at least 1 year prior to Screening.
19. History of regular alcohol consumption exceeding 14 drinks/week for females and 21 drinks/week for males within 6 months of Screening. One drink is defined as 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor)
20. Participation in a clinical trial within 30 days prior to study drug administration
21. Clinically significant electrocardiogram (ECG) abnormalities or QTcF greater than 450 ms for males and 470 ms for females at either Screening or Baseline, or any prior history of QT abnormality
22. Use of CYP3A4 and P-gp inducers and inhibitors within 14 days prior to the first dose of study medication and throughout study duration
23. Clinically significant history of drug sensitivity or allergy, as determined by the PI
24. Subject has received an investigational agent or investigational vaccine within 30 days, or a biological product within 3 months or 5 elimination half-lives (whichever is longer) prior to the planned intake of study drug
25. 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.
26. Use of immunosuppressants (eg, systemic corticosteroids) for more than 2 consecutive weeks in duration within 1 year prior to Screening.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects with at least 20% reduction in ALP from pretreatment value or normalization of ALP at Week 12 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Frequency of adverse events (AEs), serious AEs, and AEs leading to discontinuation through Week 12
• Bilirubin (Total, Conjugated, Unconjugated) decline from Baseline at Week 12
• Change from Baseline in Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST), Gamma-Glutamyl transferase (GGT) at Week 12
• Change from Baseline of noninvasive liver fibrosis markers (Enhanced Liver Fibrosis [ELF] panel, PRO C3, AST to Platelet Ratio Index [APRI] and fibrosis-4 [FIB-4]) at Week 12
• Change from Baseline in fibrinogen, CRP, IL6, IL1β, TNF-α, TNF-β , alpha2 macroglobulin and haptoglobin levels at Week 12
• Change from Baseline in Triglycerides (TG), Total Cholesterol (TC), High Density Lipoprotein Cholesterol (HDL-C), Low Density Lipoprotein Cholesterol (LDL-C) at Week 12
• Change from Baseline in 5D-itch scale and Visual Analog Score (VAS) at Week 12
• Change from Baseline in PBC-40 Quality of Life (QoL) at Week 12
• Pharmacokinetic parameters of EDP-305 (and metabolites): Cmax, Tmax, and AUClast.
• Pharmacodynamic parameters of EDP-305: FGF19, C4 and Bile Acid (BA) at Week 12 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Belgium |
| Canada |
| France |
| Germany |
| Netherlands |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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