| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary Sclerosing Cholangitis (PSC) is a chronic cholestatic liver disease that is characterized by diffuse inflammation and fibrosis of the bile ducts. The intra and/or extrahepatic bile ducts can be affected with ongoing ductal destruction leading to cholestasis, advanced fibrosis, and cirrhosis. Disease progression will eventually lead to liver failure with its consequent complications such as portal hypertension and increased risk of malignancy, including HCC and cholangiocarcinoma. |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036732 |
| E.1.2 | Term | Primary sclerosing cholangitis |
| E.1.2 | System Organ Class | 100000004871 |
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| 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 |
| •Evaluate the treatment effect of seladelpar on relative (%) change in AP in subjects with PSC during the study period |
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| E.2.2 | Secondary objectives of the trial |
•Assess the safety and tolerability of seladelpar in subjects with PSC during the study period
•Evaluate the effect of seladelpar on the absolute and/or relative (%) changes of the following:
oAlanine aminotransferase (ALT), AP, aspartate aminotransferase (AST), bilirubin (total, direct), and gamma-glutamyl transpeptidase (GGT)
oTotal cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides
o7-Alpha-hydroxy-4-cholesten-3-one (C4) and serum bile acids
oHigh-sensitivity C-reactive protein (hs-CRP) and fibrinogen
oELF Score (total and individual components) and PRO-C3 levels
•Evaluate changes in pruritus, fatigue, and quality of life (QoL)
•Assess changes in symptoms associated with Inflammatory Bowel Disease (IBD) during the study period
•Evaluate the changes in PSC-related symptoms and adverse events
•Evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of seladelpar in subjects with PSC
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| 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 |
an optional PK sub-study part of this protocol:
A minimum of 6 subjects per treatment arm will participate in an optional PK sub-study to assess a complete 24-hour PK profile after a single dose. Samples will be collected at Baseline (pre-dose) and 0.5, 1, 2, 4, 8, 12 and 24 hours after dosing. Additional blood and urine will be collected at specified time points during this time-period to assess additional PD and PK parameters. Subjects will remain in clinic through the 8-hour timepoint and return to clinic for the 12- and 24-hour sample collections. The window for PK sample collection for the Baseline is within 30 minutes of the pre-dose timepoint, ± 5 minutes for the 0.5-hour through the 8-hour samples, and ± 30 minutes for the 12- and 24-hour samples.
Urine will also be collected over the 24 24-hour period to assess the renal clearance of seladelpar and the primary metabolites.
informed consent for PK sub-study (optional) will be provided to the patient |
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| E.3 | Principal inclusion criteria |
Patients who meet the following criteria may be included in the study:
1.Males and females who are 18 years of age and older and are able to comprehend instructions and follow the study procedures and are willing to sign an Informed Consent Form (ICF)
2.Confirmed diagnosis of PSC based on any two of the following three criteria:
•Historical evidence of an elevated AP > ULN from any prior laboratory result
•Liver biopsy consistent with PSC
•Abnormal cholangiography consistent with PSC as measured by MRCP, ERCP, or PTC
3.Participants must have the following specific additional laboratory parameters measured by the Central Laboratory at Screening:
•AP > 1.5 × ULN but < 8 × ULN
•Total bilirubin ≤ 2 × ULN
•ALT and AST ≤ 5 × ULN
•eGFR > 60 mL/min/1.73 m2 by modification of diet in renal disease (MDRD) calculation
•Platelets ≥ 140 × 103/µL
•INR ≤ 1.3 (in the absence of warfarin or other anticoagulant therapy)
•Albumin > 3.5 g/dL
4.Patients taking UDCA will be allowed to enroll if meeting the following criteria:
•Total daily dose of < 20 mg/kg/day
•A minimum of 24 weeks of stable treatment
•Minimum of 12 weeks off treatment prior to Screening if UDCA is recently discontinued
5.Patients with concomitant IBD may enroll upon meeting the following criteria:
•A colonoscopy performed within 12 to 18 months (as defined by local guidelines) of consent or during the Screening period, with no evidence of dysplasia
•No episode of an IBD flare or IBD flare-related bloody diarrhea within24 weeks of Screening and through Day 1
•Stable regimen of biologic treatments, immunosuppressive, or systemic corticosteroids (≤10 mg/day prednisone or equivalent) for > 12 weeks prior to Screening and through Day 1
6.Participants with FibroScan values ≤14.4 kPa
7.Participants must be able to comply with the instructions for study drug administration and be able to complete the study schedule of procedures
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| E.4 | Principal exclusion criteria |
1.Clinically significant acute or chronic liver disease of an etiology other than PSC
2.Patients with a diagnosis of overlapping AIH and/or small duct PSC
3. Patients with a diagnosis of small-duct PSC
4.Secondary or IgG4 related sclerosing cholangitis
5.Presence of a cholangiocarcinoma on MRCP or MRI at Screening as determined by the central radiologist and the principal investigator (PI) or Medical Monitor
6.Bile duct stent or percutaneous bile duct drain placement within 12 weeksof Screening
7.Balloon dilation procedure of a stricture within 3 months of Screening
8.History, evidence, or high suspicion of cholangiocarcinoma or other hepatobiliary malignancy based on imaging, screening laboratory values, and/or clinical symptoms
9.Presumptive or diagnosed acute cholangitis within 12 weeks of Screening and through Day 1
10.Evidence of compensated or decompensated cirrhosis based on histology, relevant medical complications, or laboratory parameters:
Historical liver biopsy demonstrating cirrhosis (e.g., Ludwig Stage 4 or Ishak Stage ≥
5)
Current or prior history of decompensated liver disease, including ascites, hepatic
encephalopathy, variceal bleeding or other clinical conditions consistent with
cirrhosis and/or portal hypertension
Liver stiffness > 14.4 kPa by FibroScan®
Combined low platelet count (< 140 × 10
3
/µL) with one or more of the following:
o Albumin < 3.5 g/dL,
o INR > 1.3 (not due to antithrombotic agent use), or
o Total bilirubin > ULN
11. Variability > 40% in any one of the following laboratory parameters: AP, ALT, AST, or total bilirubin values between at least two visits during Screening approximately 4 weeks apart
o If a lab value at Screening Visit 2 is > 40% higher than the lab value at Screening Visit 1, a third sample may be drawn. If the difference between the third sample and the value from Screening Visit 1 is also > 40% higher, the participant is excluded from the study
12.Prior or actively listed for liver transplantation
13. Any contraindication or inability to obtain a MRCP, MRI with contrast, FibroScan®, or colonoscopy (if required)
14.Females who are pregnant or nursing
•Specific criteria for defining child-bearing potential, acceptable methods of birth control and male partner recommendations are outlined in detail in Section 7.5.1 of the protocol
15.ECG with clinically significant abnormalities as determined by the Investigator
16.Positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) RNA, or anti-human immunodeficiency virus (HIV) antibody
17. History of malignancy diagnosed or treated within 2 years
Recent localized treatment of squamous or non-invasive basal cell skin cancers is permitted
Cervical carcinoma in-situ is allowed if appropriately treated prior to Screening
participants under active evaluation for malignancy are not eligible
18.Clinically relevant drug or alcohol abuse within 24 weeks of Screening. A positive drug screen will exclude participants unless it can be explained by a prescribed medication
19.Any prohibited medication as listed in Section 5.2.2 of the study protocol
20.Prior exposure to seladelpar
21.Use of obeticholic acid, vancomycin, minocycline, fibrates or any other experimental or unapproved agent for the treatment of PSC within 12 weeks of Screening and throughout the study period
22.Participation in a study of another investigational agent within 4 weeks of the last study visit for that study or five half-lives of the investigational drug (whichever is longer) prior to Screening
23.History of clinically significant unstable or untreated illness or any other acute or chronic medical condition that may interfere with participants treatment, assessment, or compliance with the protocol
24.Presence of any other conditions (e.g., geographic or social), actual or projected, that the investigator feels would restrict or limit the patient’s participation for the duration of the study
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint, relative change in AP from Baseline to Week 24, will be analyzed using ANCOVA) model with treatment arm, UDCA
stratification group (Yes/No) and total bilirubin stratification group (≤ ULN vs > ULN but ≤ 2 ×ULN) as factors. Baseline AP as a covariate on the observed cases on the FAS population will also be included in the model.. The statistical comparison of each seladelpar treatment arm against the placebo group on the primary endpoint will be made at a two-sided significance level of 0.0166, where the significance level of 0.0166 is the multiplicity-adjusted level using Bonferroni approach. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
The secondary endpoints will be analyzed descriptively. The confidence intervals of differences between each seladelpar treatment arm and the placebo arm will be provided. The ANCOVA and MMRM approaches used for the primary endpoint may also be applied to the secondary endpoints when applicable.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | Yes |
| 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 | 4 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 |
| Canada |
| Germany |
| Israel |
| Poland |
| United Kingdom |
| United States |
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| 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
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| Week 24 will be the End of Treatment (EOT) clinic visit. All participants eligible and willing can be enrolled into a separate 12 month open-label extension (OLE) study starting at Week 24. Participants who do not enrol in the OLE study participant will return to the clinic at Week 28 for an End of Study (EOS) follow-up visit |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 8 |
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