| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with Cholestatic Pruritus Due to Primary Biliary Cholangitis or Primary Sclerosing Cholangitis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Subjects with itch (pruritus) due to the reduction or stoppage of bile flow. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 24.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064190 |
| E.1.2 | Term | Cholestatic pruritus |
| E.1.2 | System Organ Class | 10040785 - Skin and subcutaneous tissue disorders |
|
| 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 assess the efficacy of EP547 compared to placebo on pruritus as assessed by the Worst Itch Numeric Rating Scale (WI-NRS) |
|
| E.2.2 | Secondary objectives of the trial |
•To assess the efficacy of EP547 compared to placebo on the following:
− Pruritus-related quality of life using the 5-D Itch Scale
− Pruritus severity using the Patient Global Impression of Severity (PGI-S)
− Overall pruritus response to therapy using the Patient Global Impression of Change (PGI-C)
•To assess the safety and tolerability of EP547
•To assess the pharmacokinetics (PK) of EP547
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age 18 to 80 years, inclusive
2. Has experienced self-reported daily or near-daily moderate to severe pruritus before Screening
3. Has a mean daily WI-NRS score indicative of moderate to severe pruritus (score ≥4) as recorded using a study-issued electronic device or application (app) during Screening (Day -7 through Day -1); data from at least 4 of the 7 days are required to be considered an acceptable profile
4. If currently taking medications to treat the cholestatic disorder (obeticholic acid [OCA]), must be on a stable dose for >12 weeks before Screening and plans to maintain the regimen throughout the study
5. If currently taking a fibrate, must be on a stable dose for >12 weeks before Screening and plans to maintain the regimen throughout the study
6. Either is not treated with or has been on a stable regimen with any medications to treat pruritus for >4 weeks before Screening and plans to maintain the regimen throughout the study
7. If female, must be willing to not donate eggs from Screening until 30 days after the last dose of study drug
8. If male and is not surgically sterile for at least 3 months, must be willing to not donate sperm and must agree to use a barrier method of contraception (eg, condom) during intercourse and at least 1 other acceptable contraceptive measure (eg, hormonal contraceptives, intrauterine device, female surgical sterilization, or abstinence) from Screening through 30 days after the last dose of study drug
9. Must be able to communicate well with the Investigator, understand and comply with the requirements of the study, and understand and provide written consent
10. For subjects with concomitant inflammatory bowel disease (IBD):
a. Colonoscopy (if subject has a colon) or other appropriate endoscopic procedure within 18 months of Day 1 confirming no dysplasia or colorectal cancer
b. Subjects with Crohn’s disease (CD) must be in remission as defined by a Crohn’s Disease Activity Index (CDAI) <150 at Screening
c. Subjects with ulcerative colitis (UC) must have a Partial Mayo Scoring Index score≤3 with no individual sub-score exceeding 1 point at Screening
11. Documented history of PBC that is consistent with the American Association for the Study of Liver Diseases (AASLD) Practice Guidelines (Lindor 2019), defined as having ≥2 of the following 3 factors upon diagnosis:
a. History of elevated alkaline phosphatase (ALP) levels
b. Historic positive antimitochondrial antibody (AMA) or AMA-M2 by immunofluorescence, enzyme linked immunosorbent assay (ELISA), or immunoblot or if AMA is negative, positive for PBC-specific antibodies (anti-GP210 and/or anti-SP100)
c. Liver histology at any point in time consistent with PBC
12. If currently taking ursodeoxycholic acid (UDCA), must be treated for ≥1 year, and must be on a stable dose of not more than 20 mg/kg/day for ≥12 weeks. If not currently taking UDCA, must not be treated with UDCA within 12 weeks before Screening or plan to be treated with UDCA during the study
13. Documented history of PSC based on either cholangiography (ie, magnetic resonance cholangiopancreatography, endoscopic retrograde cholangiopancreatography, or percutaneous transhepatic cholangiogram) or if small duct PSC, confirmed by typical histologic evidence of PSC for ≥1 year
14. If currently taking UDCA, must be treated for ≥1 year, and must be on a stable dose of not more than 23 mg/kg/day for ≥12 weeks. If not currently taking UDCA, must not be treated with UDCA within 12 weeks before Screening or plan to be treated with UDCA during the study. |
|
| E.4 | Principal exclusion criteria |
1.Pruritus is attributed mainly to any disease unrelated to PBC or PSC
2.Prior liver transplant or presently listed for transplantation
3.Is receiving ongoing ultraviolet B (UVB) treatment or plasmapheresis or anticipates receiving such treatments during the study
4.Evidence of compensated or decompensated cirrhosis based on ANY of the following: Historical liver biopsy demonstrating cirrhosis
b. Liver stiffness as assessed by a FibroScan® score of ≥16.9 kPa for subjects with PBC or ≥14.4 kPa for subjects with PSC within 6 months of Screening
c. History or presence of portal hypertension with complications, including known gastric or esophageal varices, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, history of variceal bleeds, or related therapeutic or prophylactic interventions
5.History of malignancy of any organ system, including but not limited to hepatocellular carcinoma, cholangiocarcinoma, and gall bladder carcinoma, treated or untreated, within the past 5 years (localized squamous cell or basal cell carcinoma of the skin that have been excised or resolved is not exclusionary)
6.Alternate causes of liver diseases such as hepatic sarcoidosis, alcoholic liver disease, histology confirmed autoimmune hepatitis, overlap hepatitis, or nonalcoholic steatohepatitis (NASH), or uncontrolled viral hepatitis as defined in Protocol
7.Presence of documented secondary sclerosing cholangitis (eg, ischemic cholangitis, recurrent pancreatitis, intraductal stone disease, severe bacterial cholangitis, surgical or blunt abdominal trauma, recurrent pyogenic cholangitis, choledocholithiasis, toxic sclerosing cholangitis due to chemical agents, or any other cause of secondary sclerosing cholangitis) on prior clinical investigations
8.Immunoglobulin G4 (IgG4) >4× upper limit of normal (ULN) at Screening or evidence of systemic IgG4-related disease
9.Current evidence of clinically significant high-grade strictures or presence of biliary stent at Screening
10.History of recurrent bacterial cholangitis or recent episode within 3 months before Screening
11.Endoscopic interventions with therapeutic intent such as biliary duct dilation within 3 months before Screening or planned during the study
12.History of significant small bowel resection or short bowel syndrome
13.Presence of a concomitant disease or a history of any medical condition that, in the opinion of the Investigator, could pose undue risk to the subject, impede completion of the study procedures, or would compromise the validity of the study measurements
14.Clinically relevant medical history, physical examination, vital sign, standard 12-lead electrocardiogram (ECG), chemistry, hematology, urinalysis, or coagulation results at Screening beyond what is expected for subjects with a cholestatic disorder that would place the subject at undue risk as deemed by the Investigator
15.Has any of the following laboratory results at Screening:
a.Total bilirubin >ULN; total bilirubin >ULN is acceptable for subjects with medically documented Gilbert’s syndrome if direct bilirubin is <0.3 mg/dL
b.Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5× ULN
c.ALP >10× ULN
d.International normalized ratio (INR) >1.3
e.Platelet count <150,000/μL
f.Urine albumin to creatinine ratio ≥30 mg/g
16.Estimated glomerular filtration rate <90 mL/min/1.73 m2 as determined by the Chronic Kidney Disease Epidemiology Collaboration equation at Screening
17.History of human immunodeficiency virus (HIV) or positive for HIV infection at Screening
18.Significant history of abuse of drugs, solvents, or moderate alcohol consumption (≥1 serving or unit/day on average for women and ≥2 servings or units/day on average for men) in the past 2 years before Screening
19.Has received a prohibited medication within 2 weeks or 5 half-lives of Day 1, whichever is longer, as described in Protocol
20.Participation in any clinical study with an investigational or approved drug/device within 30 days before Screening or is planning to participate in another clinical study with an investigational or approved drug/device while enrolled in this study
21.History of known or suspected hypersensitivity to any component of the study drug
22.Female who is pregnant, nursing, or intends to become pregnant during the study
23.Positive SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) test at Screening
24.Is directly affiliated with the study at the study site or is an immediate family member (spouse, parent, child, or sibling; biological or legally adopted) of personnel directly affiliated with the study at the study site
25.Is employed by Escient Pharmaceuticals, Inc., (that is an employee, temporary contract worker, or designee responsible for the conduct of the study) or is an immediate family member of an employee of Escient Pharmaceuticals, Inc.
26.Subject in the opinion of the Investigator, not suitable to participate in the study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the change from baseline in WI-NRS at Week 6. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary analysis will be conducted after the last subject randomized has completed the Double-Blind Treatment Period to determine whether the primary efficacy endpoint of change from baseline in WI-NRS at Week 6 is statistically significant. |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints are:
• Change from baseline in 5-D Itch Scale
• The proportion of subjects with improvement in pruritus as defined by PGI-C
• The proportion of subjects with improvement in pruritus severity from baseline as defined by change in PGI-S
• The proportion of subjects with a reduction in WI-NRS ≥2 from baseline
• The proportion of subjects with a reduction in WI-NRS ≥3 from baseline
• The proportion of subjects with a reduction in WI-NRS ≥4 from baseline
• The proportion of subjects with WI-NRS <4 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The final analysis will be conducted when all randomized subjects have completed the Open-Label Extension Period or are discontinued from the study, and the final database is locked. |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | 2 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| 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 |
| Canada |
| Israel |
| United States |
| France |
| Netherlands |
| Spain |
| Belgium |
| United Kingdom |
|
| 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
|
| The end of the study is defined as the date of the last visit of the last participant in the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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