A Trial of Setanaxib in Patients With Primary Biliary Cholangitis (PBC) and Liver Stiffness (TRANSFORM)
Primary Biliary Cholangitis, Liver Stiffness
About this trial
This is an interventional treatment trial for Primary Biliary Cholangitis focused on measuring Setanaxib, Primary Biliary Cholangitis, Elevated Liver Stiffness
Eligibility Criteria
Inclusion Criteria:
- Male or female participant aged ≥18 years, inclusive at the time of informed consent.
- Willing and able to give written informed consent and to comply with the requirements of the study.
Definite or probable primary biliary cholangitis (PBC) diagnosis as demonstrated by the presence of ≥2 of the following 3 diagnostic factors:
- Documented history of elevated alkaline phsopatase (ALP) levels ≥1.67×upper limit of normal (ULN) of the local reference range.
- Documented history of positive antimitochondrial antibodies (AMA) titer or positive PBC-specific antibodies (anti-GP210 or anti-SP100 or antibodies against the major M2 components [PDC-E2, 2-oxo-glutaric acid dehydrogenase complex]).
- Historical liver biopsy consistent with PBC.
- Serum ALP ≥1.67×ULN at Screening.
- Liver stiffness measured by transient elastography (FibroScan®) of ≥8.8 kilopascals (kPa) and an interquartile range over median ratio (IQR/med) of ≤30% at Screening, are taken with the results expressed in kilopascals).
- Ursodeoxycholic acid (UDCA) prescriptional dose use for the past 6 months (at a stable dose for >3 months prior to Screening) OR intolerant to UDCA (last dose of UDCA >3 months prior to Screening). Intolerance to UDCA is defined as participants unable to tolerate the full-labelled dose of UDCA in PBC (13-15 mg/kg) due to frequently reported gastrointestinal symptoms such as diarrhea and abdominal pain.
- For participants receiving obeticholic acid (OCA), fenofibrate, or bezafibrate treatment for at least 6 months and stable dose for >3 months prior to Screening.
- For participants intolerant to OCA, OCA must have been discontinued >3 months prior to Screening.
- For participants previously treated with bezafibrate or fenofibrate, and these agents were discontinued prior to screening, they must have been discontinued >3 months prior to Screening.
Female participants of childbearing potential must use a highly effective method of contraception to prevent pregnancy for ≥4 weeks before Randomization and must agree to continue strict contraception up to 90 days after the last dose of investigational medicinal product (IMP).
- For the purposes of this trial, women of childbearing potential are defined as "Fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy."
- Postmenopausal state is defined as no menses for 12 months without an alternative medical cause. In female participants who are not using hormonal contraception or hormonal replacement therapy but with suspected menopause and less than 12 months of amenorrhea, a high follicle stimulating hormone (FSH) level in the postmenopausal range will be required at Screening to confirm a postmenopausal state. Confirmation with more than one FSH measurement is required.
Highly effective contraception is defined as methods that can achieve a failure rate of less than 1% per year when used consistently and correctly. These methods are:
- Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal)
- Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable)
- Intrauterine device
- Intrauterine hormone-releasing system
- Bilateral tubal occlusion
- Vasectomized partner
- Sexual abstinence (refraining from heterosexual intercourse during the entire period of risk associate with the study treatments). The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of contraception. Female condom and male condom should not be used together.
- Female participants of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline/Randomization before dosing.
- Male participants with female partners of childbearing potential must be willing to use a condom and require their partner to use a highly effective contraceptive method. This requirement begins at the time of informed consent and ends 90 days after receiving the last dose of IMP.
- Male participants must be willing not to donate sperm, and female study participants must be willing not to donate eggs, from Baseline until 90 days after the last dose of IMP.
Exclusion Criteria:
- A positive pregnancy test or breastfeeding for female participants.
- Any historical or current hepatic decompensation event defined as variceal/portal hypertension bleed and/or hepatic encephalopathy, spontaneous bacterial peritonitis, ascites requiring treatment, or liver transplantation list inclusion.
- History of liver transplantation, current placement on a liver transplant list or current model for end stage liver disease (MELD) score of ≥12 unless the participant is on anticoagulant therapy, or a Child-Pugh Score of ≥6.
- Cirrhosis with complications, including history or presence of hepatocellular carcinoma.
- Total bilirubin >2×ULN. In case of total bilirubin elevation >ULN the Screening serum albumin must be within the reference range.
- Plasma alanine aminotransferase (ALT) >3×ULN and/or aspartate aminotransferase (AST) >3×ULN.
- International normalized ratio (INR) >1.2 unless participant is on anticoagulant therapy. One repeat blood sampling (with analysis by the central laboratory) can be performed at the discretion of the Investigator at Screening Visit 2 for participants who meet this exclusion criterion at Screening Visit 1. If this exclusion criterion is not met at Screening Visit 2, the participant may be eligible for the study.
- Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m^2, as calculated by the central laboratory using the chronic kidney disease-epidemiology collaboration (CKD- EPI) equation.
- Thyroid-stimulating hormone >ULN at Screening. One repeat blood sampling (with analysis by the central laboratory) can be performed at the discretion of the Investigator at Screening Visit 2 for participants who meet this exclusion criterion at Screening Visit 1. If this exclusion criterion is not met at Screening Visit 2, the participant may be eligible for the study.
- Competing etiology for liver disease (eg, hepatitis C [unless effectively cured of hepatitis C, with a sustained virologic response for at least 6 months prior to Screening], active hepatitis B [HBsAg positive], nonalcoholic steatohepatitis [NASH], alcoholic liver disease, autoimmune hepatitis, autoimmune hepatitis-PBC overlap syndrome, primary sclerosing cholangitis, Gilbert's Syndrome).
- Medical conditions that could cause nonhepatic increases in ALP (eg, Paget's disease).
- Known history of human immunodeficiency virus (HIV) infection.
- Surgery (eg, stomach bypass) or medical condition that might significantly affect absorption of medicines (as judged by the Investigator).
- Positive urine drug screen (if not due to prescriptional use of a concomitant medication, as confirmed by the Investigator) at Screening. Participants on stable methadone or buprenorphine maintenance treatment for at least 6 months prior to Screening Visit 1 may be included in the study. Medicinal cannabis and cannabidiol products are not exclusionary and may be allowed if the prescription and diagnosis are reviewed and approved by the Investigator.
- Participants receiving prohibited medications within 3 months of Screening Visit 1.
- Treatment with any investigational agent within 12 weeks of Screening Visit 1 or 5 half-lives of the IMP (if known) (whichever is longer) or current enrollment in an interventional clinical trial.
- Evidence of any of the following cardiac conduction abnormalities: A QTc Fridericia interval >450 milliseconds for males or >470 milliseconds for females, as calculated by the central reader. Participants with a second- or third-degree atrioventricular block are to be excluded.
- For participants in the US, in participants treated with or for planned treatment with a pacemaker, implanted cardioverter-difibrillator, or other implanted electronic device, FibroScan® assessments will be prohibited.
History of a malignancy within 5 years of Screening with the following exceptions:
- Adequately treated carcinoma in situ of the cervix
- Adequately treated basal or squamous cell cancer or other localized nonmelanoma skin cancer.
- The occurrence of any acute infection requiring systemic antibiotic therapy within the 2 weeks prior to Screening Visit 1.
- A history of bone marrow disorder including aplastic anemia, or any current marked anemia defined as hemoglobin <10.0 g/dL.
- Prior treatment with setanaxib or participation in a previous setanaxib clinical trial.
- Unstable cardiovascular disease.
- Presence of any laboratory abnormality or condition that, in the opinion of the Investigator, could interfere with or compromise a participant's treatment, assessment, or compliance with the protocol and/or study procedures.
- Any other condition which, in the opinion of the Investigator, constitutes a risk or contraindication for the participation of the participant in the study, or that could interfere with the study objectives, conduct, or evaluation.
- Hypersensitivity or intolerance to setanaxib or to any of its excipients or placebo compounds.
Sites / Locations
- UA Thomas D. Boyer Liver InstituteRecruiting
- Cedars-Sinai Medical CenterRecruiting
- California Liver Research InstituteRecruiting
- University of California Davis Medical CenterRecruiting
- Gastroenterology Associates - Crystal RiverRecruiting
- University of Miami Leonard M. Miller School of MedicineRecruiting
- AdventHealth Transplant InstituteRecruiting
- Advanced Research Institute, Inc.Recruiting
- Tampa General HospitalRecruiting
- Northwestern UniversityRecruiting
- Springfield ClinicRecruiting
- Kansas Medical Clinic - GastroenterologyRecruiting
- Tulane Medical CenterRecruiting
- A. Alfred Taubman Health Care CenterRecruiting
- Henry Ford HospitalRecruiting
- Summit - Southern Therapy and Advanced Research
- Northwell Health
- New York University Hepatology AssociatesRecruiting
- Icahn School of Medicine at Mount SinaiRecruiting
- Wake Forest University Baptist Medical CenterRecruiting
- University of CincinnatiRecruiting
- Einstein Medical CenterRecruiting
- Rapid City Medical CenterRecruiting
- Vanderbilt Digestive Disease CenterRecruiting
- Liver Specialists of TexasRecruiting
- Pioneer Research SolutionsRecruiting
- University of Utah HospitalRecruiting
- Froedtert and Medical College of WisconsinRecruiting
- Royal Prince Alfred HospitalRecruiting
- John Hunter HospitalRecruiting
- Mater Misericordiae - Hospital BrisbaneRecruiting
- Flinders Medical CentreRecruiting
- Eastern Health - AustraliaRecruiting
- Monash Medical CentreRecruiting
- Fiona Stanley HospitalRecruiting
- Nepean HospitalRecruiting
- Liverpool HospitalRecruiting
- The Alfred HospitalRecruiting
- Ordensklinikum Linz GmbH Barmherzige SchwesternRecruiting
- Klinikum Wels-GrieskirchenRecruiting
- Universitaetsklinikum Graz - Universitätsklinik für Innere MedizinRecruiting
- Medizinische Universität InnsbruckRecruiting
- Hôpital ErasmeRecruiting
- Centre Hospitalier Universitaire Brugmann - Site Victor HortaRecruiting
- Universitair Ziekenhuis Leuven - Campus GasthuisbergRecruiting
- Universitair Ziekenhuis GentRecruiting
- University of CalgaryRecruiting
- Queen Elizabeth II Health Sciences Centre - Victoria GeneralRecruiting
- St. Joseph's Healthcare Hamilton - Charlton CampusRecruiting
- Centricity Research (LMC Manna Research) - LondonRecruiting
- Office Of Stephane M. GauthierRecruiting
- University Health NetworkRecruiting
- Toronto Liver CenterRecruiting
- Centre Hospitalier de l'Université de Montréal (CHUM)Recruiting
- William Osler Health System - Brampton Civic HospitalRecruiting
- Ústřední Vojenská Nemocnice PrahaRecruiting
- Hepato-Gastroenterologie HKRecruiting
- Hôpital Claude HuriezRecruiting
- Hôpitaux Universitaires Henri MondorRecruiting
- Centre Hospitalier Universitaire Grenoble AlpesRecruiting
- Hopital DupuytrenRecruiting
- Hôpitaux de BraboisRecruiting
- Hôpital RangueilRecruiting
- Clinique Pasteur - ToulouseRecruiting
- Centre Hosptitalier Universitaire d'AngersRecruiting
- Centre Hospitalier Universitaire Amiens-Picardie - Site SudRecruiting
- Hôpital de la Croix RousseRecruiting
- Hôpital Claude HuriezRecruiting
- Hôpital Saint Joseph MarseilleRecruiting
- Hôpital l'ArchetRecruiting
- Hôpital Saint-AntoineRecruiting
- Klinikum rechts der Isar der Technischen Universität MünchenRecruiting
- Universitätsklinikum FrankfurtRecruiting
- St. Josefs-Hospital WiesbadenRecruiting
- Medizinische Hochschule HannoverRecruiting
- EugastroRecruiting
- Universitätsklinikum des SaarlandesRecruiting
- University General Hospital of Heraklion (PAGNI)Recruiting
- University General Hospital of LarissaRecruiting
- Semmelweis Egyetem - I. Sz. Sebészeti és Intervenciós Gasztroenterológiai KlinikaRecruiting
- Carmel Medical CenterRecruiting
- Western Galilee Hospital-NahariyaRecruiting
- Soroka Medical CenterRecruiting
- Rabin Medical Center - Beilinson HospitalRecruiting
- Rambam Health Care CampusRecruiting
- Hadassah University Hospital Ein KeremRecruiting
- Tel Aviv Sourasky Medical CenterRecruiting
- Ospedale San GiuseppeRecruiting
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) - Istituto Clinico HumanitasRecruiting
- Azienda Socio Sanitaria Territoriale Monza - Ospedale San GerardoRecruiting
- Azienda Ospedaliero Universitaria Ospedali Riuniti di AnconaRecruiting
- Azienda Ospedaliera Universitaria Policlinico Gaetano MartinoRecruiting
- Fondazione IRCCS Ca' Granda Ospedale Maggiore PoliclinicoRecruiting
- Università degli Studi di Napoli Federico IIRecruiting
- Azienda Ospedaliero-Universitaria Maggiore della Carità di NovaraRecruiting
- Auckland City HospitalRecruiting
- Wellington Regional HospitalRecruiting
- Dunedin HospitalRecruiting
- Waikato HospitalRecruiting
- Szpital Specjalistyczny Nr 1 w BytomiuRecruiting
- ID ClinicRecruiting
- Centrum Badań Klinicznych Piotr Napora Lekarze Sp. p.Recruiting
- Hospital Germans Trias i PujolRecruiting
- Hospital de SabadellRecruiting
- Hospital Universitario de CanariasRecruiting
- Hospital General Universitari d'AlicanteRecruiting
- Complejo Hospitalario TorrecárdenasRecruiting
- Hospital del Mar - Parc de Salut MarRecruiting
- Hospital Clínic de BarcelonaRecruiting
- Hospital Universitario Reina SofíaRecruiting
- Hospital Universitario de La PrincesaRecruiting
- Hospital General Universitario Gregorio MarañónRecruiting
- Hospital Universitario La PazRecruiting
- Hospital Universitario Virgen de la VictoriaRecruiting
- Hospital Clínico Universitario de SantiagoRecruiting
- Hospital Universitario Virgen del RocíoRecruiting
- Consorci Hospital General Universitari de ValènciaRecruiting
- Hospital Universitario Miguel ServetRecruiting
- Akademiska Sjukhuset - UppsalaRecruiting
- Fondazione Epatocentro TicinoRecruiting
- Kantonsspital Sankt GallenRecruiting
- Gloucestershire Hospitals NHS Foundation TrustRecruiting
- King's College Hospital NHS Foundation TrustRecruiting
- The Newcastle Upon Tyne Hospitals NHS Foundation TrustRecruiting
- Nottingham University Hospitals NHS TrustRecruiting
- Sheffield Teaching Hospitals NHS Foundation TrustRecruiting
- University Hospital Southampton NHS Foundation TrustRecruiting
- NHS Greater Glasgow and ClydeRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Experimental
Experimental
Placebo Comparator
Setanaxib 1200 mg/day
Setanaxib 1600 mg/day
Placebo
Participants will be administered setanaxib at a dose of 1200 mg/day for the 52-week double-blind treatment period and the 52-week extension period. The interim analysis outcome will determine if the setanaxib dose level for participants receiving 1200 mg/day will be escalated to 1600 mg/day for the continued extension period.
Participants will be administered setanaxib at a dose of 1600 mg/day for the 52-week double-blind treatment period and the 52-week extension period. The interim analysis outcome will determine if the setanaxib dose level for participants receiving 1600 mg/day will be reduced to 1200 mg/day for the continued extension period.
Participants will be administered a placebo for the 52-week double-blind treatment period. During the 52-week extension period, participants will switch from placebo to setanaxib at a dose of either 1200 or 1600 mg/day depending on interim analysis outcome.