| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary sclerosing cholangitis (PSC) |
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| E.1.1.1 | Medical condition in easily understood language |
| Primary sclerosing cholangitis (PSC) |
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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 |
| To assess the safety and tolerability of PLN 74809 in participants with PSC and suspected liver fibrosis |
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| E.2.2 | Secondary objectives of the trial |
To assess the pharmacokinetics (PK) of PLN-74809 in participants with PSC and suspected liver fibrosis
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
General and Administrative
1. Aged 18 to 75 years, inclusive.
2. Female participants of childbearing potential must use a contraceptive method with a failure rate of <1% per year or remain abstinent (refrain from heterosexual intercourse) during the treatment period and for 1 month after the last dose of study drug.
Male participants with female partners of childbearing potential must agree to use contraceptive measures or remain abstinent (refrain from heterosexual intercourse) during screening and the treatment period and for at least 3 months after the last dose of study drug.
3. Female participants of nonchildbearing potential must be surgically sterile or postmenopausal.
4. Participants must agree to abstain from sperm or egg donation for the duration of the study, through to 3 months or 1 month, respectively, after administration of the last dose of study drug.
5. Able to understand the purpose and procedures that are involved in the study and willing to sign a written informed consent form.
Primary Sclerosing Cholangitis Diagnosis
6. Established clinical diagnosis of large duct PSC based on an abnormal cholangiography as assessed by magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), and/or percutaneous transhepatic cholangiopancreatography (PTC) in the context of elevated cholestatic liver chemistries.
7. Serum alkaline phosphatase concentration within normal ranges or > 1 × the upper limit of normal (ULN).
8. Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) concentration ≤ 5 × ULN.
9. Serum total bilirubin ≤ 1.5 × ULN, in the absence of hemolysis.
Participants with serum total bilirubin > 1.5 x ULN may be enrolled if they have Gilbert’s Syndrome and a direct bilirubin < 0.6 mg/dL.
10. Suspected liver fibrosis, as defined by any of the following:
- Liver stiffness measurement (LSM) ≥ 8 kPa but ≤ 14.4 kPa, assessed by FibroScan® OR
- Enhanced Liver Fibrosis (ELF) Score ≥ 7.7 at Screening OR
- Historical liver biopsy showing fibrosis without cirrhosis (by any scoring system) OR
- Magnetic resonance elastography (MRE) ≥ 2.4 kPa but ≤ 4.9 kPa
11. Platelet count ≥ 140,000/mm3.
12. Albumin ≥ 3.3 g/dL.
13. International normalized ratio (INR) ≤ 1.3 in the absence of anticoagulant therapy.
14. Serum carbohydrate antigen 19-9 (CA19-9) value ≤ 130 U/mL.
Prior and Concomitant Medications
15. If receiving treatment with UDCA, therapy is at a dose of < 25 mg/kg/day, has been stable for at least 3 months before screening, will remain stable from screening through Day 1 (baseline), and is expected to remain stable for the duration of the study.
16. If receiving allowed concomitant medications for the treatment of IBD, therapy must be stable from screening and expected to remain stable for the duration of the study.
Medical History and Comorbid Conditions
17. Participants with IBD must have had a colonoscopy showing no evidence of dysplasia within no more than 18 months before screening.
18. Participants with IBD must have no evidence of active disease and a partial Mayo score of < 2, with a score of < 1 on the Rectal Bleeding domain, between screening through Day 1.
19. Participants with IBD who are receiving treatment with biologics, including tumor necrosis factor alpha (TNF α) inhibitors and/or vedolizumab, immunosuppressive agents, or corticosteroids must have been receiving a stable dose for at least 3 months before screening, the dose must remain stable from screening through Day 1 (baseline), and expected to remain stable for the duration of the study.
20. Estimated glomerular filtration rate ≥ 60 mL/min, according to the Cockcroft-Gault equation.
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| E.4 | Principal exclusion criteria |
Primary Sclerosing Cholangitis Diagnosis
1. Other causes of liver disease, including secondary sclerosing cholangitis or viral, metabolic, or alcoholic liver disease, as assessed clinically.
2. Known or suspected overlapping clinical and histologic diagnosis of autoimmune hepatitis.
3. Small duct PSC with no evidence of large duct involvement (evidence of PSC on historical liver histology, with normal bile ducts on cholangiography).
Liver Disease Status
4. Presence of a clinically significant dominant stricture based on the combination of radiological, biochemical, and clinical features.
5. Presence of a percutaneous drain or bile duct stent.
6. Serum alkaline phosphatase (ALP) concentration > 10 times ULN.
7. Worsening of liver disease, defined as 2 consecutive ALP, ALT or AST measurements obtained ≥ 2 weeks apart during the screening period that increase by > 30% and represent either a Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 that is associated with new or worsening symptoms or a CTCAE Grade 2 with or without new or worsening symptoms, as defined by CTCAE Version 5.0.
8. Ascending cholangitis within 60 days of screening, as assessed clinically or use of antibiotics for acute cholangitis within 60 days of screening.
9. IgG4-associated cholangitis.
10. Positive anti-mitochondrial antibody.
11. Presence of liver cirrhosis as assessed by historical liver histology, ultrasound based liver stiffness measurement (FibroScan® value > 14.4 kPa), MRE > 4.9 kPa, and/or signs and symptoms of hepatic decompensation (including, but not limited to, jaundice, ascites, variceal hemorrhage, and/or hepatic encephalopathy).
12. Presence of hepatic impairment, end-stage liver disease, and/or a model for end stage liver disease (MELD) score ≥ 15.
13. Prior or planned liver transplantation during the study.
Medical History and Comorbid Conditions
14. Presence of end-stage renal disease that requires dialysis.
15. History, current clinical or radiological suspicion, or diagnosis of cholangiocarcinoma, other hepatobiliary malignancy, colorectal cancer, or other abdominal malignancy at any time.
16. Human immunodeficiency virus (HIV), hepatitis A virus, hepatitis B virus, and/or hepatitis C virus infection, with the exception of those who have been successfully treated for hepatitis C infection and have achieved sustained virologic response for ≥ 1 year
17. History of malignancy within the past 5 years or ongoing malignancy other than basal cell carcinoma, resected noninvasive cutaneous squamous cell carcinoma, or treated cervical carcinoma in situ.
18. Clinical evidence of active bacterial, viral, or fungal infection within 30 days before screening.
19. History of unstable or deteriorating cardiac disease within the previous 6 months, including, but not limited to:
a. Unstable angina pectoris or myocardial infarction
b. Congestive heart failure requiring hospitalization
c. Uncontrolled clinically significant arrhythmias
d. Clinically significant electrocardiogram (ECG) abnormalities, including but not limited to, QT interval corrected for heart rate using Fridericia's formula (QTcF) > 450 msec for males or > 460 msec for females at Screening Visit 1 or prior to administration of the initial dose of study drug.
20. Surgery within the 4 weeks before administration of study drug.
Prior and Concomitant Medications
21. Currently receiving and expected to remain on treatment during the study with: potent (i.e., strong) inhibitors or inducers of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) (e.g., itraconazole), breast cancer resistance protein (BCRP) or organic anion transporting polypeptide (OATP) 1B1/1B3 transporters.
22. Current treatment or anticipated need for treatment with immunomodulating agents (such as interleukins and interferons), radiation therapy, or cytotoxic or chemotherapeutic agents.
23. Hypersensitivity to PLN-74809 or to any of the excipients, or placebo.
Screening Assessments
24. Pregnancy or breastfeeding or male participant whose female partner is pregnant.
25. History of weekly alcohol consumption > 21 units for male participants or > 14 units for female participants (1 unit = 1 oz/30 mL of alcohol contained in 12 oz/360 mL of beer, 4 oz/120 mL of wine, or 1 oz/30 mL of 40% proof alcohol).
26. Positive urine drug screen at screening unless the positive result is due to a medical treatment for a comorbid condition.
27. Any other clinically significant disorders or prior therapy that, in the opinion of the Investigator, would make the participant unsuitable for the study or unable to comply with the dosing and protocol requirements.
28. Prior use of an investigational drug within 5 half-lives or 30 days before screening, whichever time is longer, or the use of an investigational device within 30 days before screening.
29. Participation in an earlier part of the current study (ie, Part 1 or 2) within 6 months of dosing for a subsequent part (ie, Part 2 or 3). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is the nature and proportion of AEs between PLN-74809 and placebo groups (descriptive).
Safety data from all participants who received at least one dose of study drug will be incorporated into the final safety analysis. Treatment-emergent adverse events (TEAEs) are defined as AEs that emerged or worsened in severity after the first administration of study drug.
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®). All AEs will be graded for severity per the CTCAE grading scale and listed by participant and summarized by last treatment taken at onset of AE. All AEs will be listed by participant and summarized by last treatment taken at onset of AE.
The incidence of AEs, the incidence of TEAEs, the incidence of treatment-related AEs, and the severity of AEs will be summarized by system organ class, preferred term, and maximum severity. In cases where a participant reports multiple occurrences of the same event (preferred term), the greatest severity will be included in the summary. The number and percentage of participants with SAEs and treatment-related SAEs and participants who withdraw prematurely due to an AE will be tabulated by study treatment and dose.
Clinical laboratory test parameters will be graded using the CTCAE grading scale for individual participants and values outside the reference ranges will be flagged. The incidence of treatment-emergent laboratory abnormalities will be summarized by severity and treatment group. For each parameter, summary statistics will be calculated for each measure and summarized by treatment and dose.
Individual ECG results will be listed for each participant. Summaries of ECGs by treatment and dose will include changes from baseline for each parameter.
Vital sign measurements, other laboratory tests, concomitant medications, medical history and changes in physical examinations at each time point will be listed by participant. The number and percentage of participants with abnormal ECGs will be summarized by treatment and dose.
Concomitant medications will be coded using the most current World Health Organization drug dictionary available. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| AEs will be collected from the time the participant signs the ICF until the last study visit. |
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| E.5.2 | Secondary end point(s) |
Plasma PLN-74809 concentrations (total and unbound concentrations) at each sampling timepoint will be presented in listings and descriptive summary statistics by dose and visit. The data will also be presented graphically.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At each sampling timepoint until EOS/ET, inclusive. |
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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 | No |
| 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 | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| 3-Part. Part 3 will initiate after DSMB review of Part 2 clinical data of 80/160mg dosis |
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| 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 | 5 |
| 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 | 22 |
| 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 |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| France |
| Germany |
| Netherlands |
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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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 21 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 19 |
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