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    Summary
    EudraCT Number:2020-001428-33
    Sponsor's Protocol Code Number:PLN-74809-PSC-203
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2020-06-22
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2020-001428-33
    A.3Full title of the trial
    A randomized, double-blind, dose-ranging, placebo-controlled, Phase 2a evaluation of the safety, tolerability, and pharmacokinetics of PLN-74809 in participants with primary sclerosing cholangitis (PSC) and suspected liver fibrosis (INTEGRIS-PSC)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to assess efficacy, safety and pharmacokinetics of PLN-74809 in participants with primary sclerosing cholangitis and suspected liver fibrosis)
    A.4.1Sponsor's protocol code numberPLN-74809-PSC-203
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPliant Therapeutics, Inc
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPliant Therapeutics, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPliant Therapeutics Inc.
    B.5.2Functional name of contact pointMonica Sandberg
    B.5.3 Address:
    B.5.3.1Street Address260 Littlefield Avenue
    B.5.3.2Town/ citySouth San Francisco, CA
    B.5.3.3Post code94080
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1650481 6931
    B.5.5Fax number+1650481 6776
    B.5.6E-mailMsandberg@pliantrx.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePLN-74809
    D.3.2Product code PLN-74809
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot yet established
    D.3.9.1CAS number 2376257-44-0
    D.3.9.2Current sponsor codePLN-74809-000
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Primary sclerosing cholangitis (PSC)
    E.1.1.1Medical condition in easily understood language
    Primary sclerosing cholangitis (PSC)
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10036732
    E.1.2Term Primary sclerosing cholangitis
    E.1.2System Organ Class 100000004871
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the safety and tolerability of PLN-74809 following daily administration for up to 12 weeks in participants with PSC
    E.2.2Secondary objectives of the trial
    To assess the pharmacokinetics (PK) of PLN-74809 in participants with PSC.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    General and Administrative
    1. Aged 18 to 75 years, inclusive.
    2. Female participants of childbearing potential (ovulating or premenopausal and not surgically sterile) and male participants with sexual partners of childbearing potential must agree to use highly effective methods of birth control during their participation in the study and for 30 days for female participants and 90 days for male participants and female partners of male
    participants after the last administration of study drug. Highly effective methods of birth control
    are defined as those with 99% or greater efficacy.
    3. Female participants of nonchildbearing potential must be either surgically sterile (defined as hysterectomy, bilateral tubal ligation, salpingectomy and/or bilateral oophorectomy at least 6 months prior to screening) or postmenopausal (defined as spontaneous amenorrhea for at least 2 years with a follicle-stimulating hormone [FSH] level in the postmenopausal range at
    screening).
    4. Participants must agree to abstain from sperm or egg donation through 90 or 30 days, 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 cholestatic liver chemistry.
    7. Serum alkaline phosphatase concentration >1.5 times 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 Gilbert's syndrome or hemolysis.
    10. Suspected liver fibrosis, as defined by liver stiffness measurement (LSM) ≥8 kPa but ≤14.4 kPa, assessed by ultrasound-based transient elastography (TE, FibroScan®).
    Note: participants with LSM <8 kPa and documented evidence of liver fibrosis by histology (any severity except cirrhosis; any staging system) may be eligible, pending consultation with the Medical Monitor.
    11. Platelet count ≥150,000/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 (maximum corticosteroid dose, 10 mg/day of prednisone or equivalent), 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.
    E.4Principal 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 (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 vary by >30%.
    8. Ascending cholangitis within 60 days of screening, as assessed clinically.
    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), 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. Active infection that required antibiotic or antifungal therapy 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 the Screening visit (including Day -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 and concomitant inhibitors or inducers of CYP3A4, 2C9 and 2C19 (i.e., simultaneous inhibition or induction of all 3 CYP isoforms); potent inhibitors or inducers of P-gp, BCRP or OATP1B1/1B3 transporters; digoxin (a P-gp substrate with a narrow therapeutic window).
    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.
    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, including, but not limited to, suspected infection with COVID-19.

    Administrative
    28. Participation in a clinical trial with an investigational agent for any indication within 30 days before screening.
    E.5 End points
    E.5.1Primary 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. AEs will be collected from the time the participant signs the ICF until the last study visit. 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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 16
    E.5.2Secondary 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.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 16
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Part 1-Part 2.Part 2 to initiate after favorable opinion of clinical data to support dose escalation
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    E.8.3 The trial involves single site in the Member State concerned Information not present in EudraCT
    E.8.4 The trial involves multiple sites in the Member State concerned Information not present in EudraCT
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA31
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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
    Norway
    United Kingdom
    United States
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days7
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days7
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 42
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 42
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 43
    F.4.2.2In the whole clinical trial 84
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Subsequent treatments of the study subject will be at the discretion of the investigator in accordance to standard care
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-07-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-11-05
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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