Clinical trial NCT05014672: A Trial of Setanaxib in Patients With Primary Biliary Cholangitis (PBC) and Liver Stiffness
Official title: TRANSFORM: A 24-week, Randomized, Placebo-controlled, Double-blind, Phase 2b Trial of Setanaxib in Patients With Primary Biliary Cholangitis (PBC) and Elevated Liver Stiffness
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Primary Biliary Cholangitis
Liver Stiffness
Keywords: Setanaxib
Primary Biliary Cholangitis
Elevated Liver Stiffness
Lead sponsor: Calliditas Therapeutics AB
Sponsor class: INDUSTRY
First posted: 2021-08-20
Enrollment: 76
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Placebo-controlled 1:1:1 in double blind treatment period.
Primary purpose: TREATMENT

Brief summary: The primary objective of this study is to evaluate the effect of setanaxib on alkaline phosphatase (ALP) at Week 24 in participants with PBC and with elevated liver stiffness and intolerance or inadequate response to ursodeoxycholic acid (UDCA).


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 PBC diagnosis as demonstrated by the presence of ≥2 of the following 3 diagnostic factors:

  * Documented history of elevated ALP levels ≥1.67×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.
* 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.

Primary outcomes:
measure: Change in ALP at Week 24 Compared to Baseline
timeFrame: Baseline (Day 1) and Week 24
Secondary outcomes:
measure: Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the PROMIS Short Form-Fatigue 7b Daily
timeFrame: Baseline (Day 1) and Week 24
measure: Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the Patient's Global Impression of Severity (PGIS) Fatigue
timeFrame: Baseline (Day 1) and Week 24
measure: Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the Patient's Global Impression of Change (PGIC) Fatigue
timeFrame: Week 24
measure: Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the PBC-40 Questionnaire (PBC 40) Fatigue Domain
timeFrame: Baseline (Day 1) and Week 24
measure: Change in Liver Stiffness at Week 24 Compared to Screening
timeFrame: Screening (Day -28) and Week 24
measure: Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the Worst Itch Numerical Rating Scale (WI-NRS)
timeFrame: Baseline (Day 1) and Week 24
measure: Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the PBC-40 Itch Domain
timeFrame: Baseline (Day 1) and Week 24
measure: Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the PGIS Pruritus
timeFrame: Baseline (Day 1) and Week 24
measure: Change in Pruritus at Week 24 Compared to Baseline, as Assessed by the PGIC Pruritus
timeFrame: Week 24
measure: Changes in Markers of Cholestasis at Week 24
timeFrame: Baseline (Day 1) and Week 24
measure: Change in ALP at Week 24 Compared to Baseline, Where Setanaxib Doses Are Combined
timeFrame: Baseline (Day 1) and Week 24
measure: Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the PROMIS Short Form-Fatigue 7b Daily, Where Setanaxib Doses Are Combined
timeFrame: Baseline (Day 1) and Week 24
measure: Change in Fatigue at Week 24 Compared to Baseline, as Assessed by the PBC-40 Questionnaire (PBC 40) Fatigue Domain, Where Setanaxib Doses Are Combined
timeFrame: Baseline (Day 1) and Week 24
measure: Change in Liver Stiffness at Week 24 Compared to Screening, Where Setanaxib Doses Are Combined
timeFrame: Screening (Day -28) and Week 24
Other outcomes:
Locations:
city: Tucson
country: United States
facility: UA Thomas D. Boyer Liver Institute
state: Arizona
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Pasadena
country: United States
facility: California Liver Research Institute
state: California
city: Sacramento
country: United States
facility: University of California Davis Medical Center
state: California
city: Inverness
country: United States
facility: Gastroenterology Associates - Crystal River
state: Florida
city: Miami
country: United States
facility: University of Miami Leonard M. Miller School of Medicine
state: Florida
city: Orlando
country: United States
facility: AdventHealth Transplant Institute
state: Florida
city: Orlando
country: United States
facility: Advanced Research Institute, Inc.
state: Florida
city: Tampa
country: United States
facility: Tampa General Hospital
state: Florida
city: Evanston
country: United States
facility: Northwestern University
state: Illinois
city: Springfield
country: United States
facility: Springfield Clinic
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Topeka
country: United States
facility: Kansas Medical Clinic - Gastroenterology
state: Kansas
city: New Orleans
country: United States
facility: Tulane Medical Center
state: Louisiana
city: Ann Arbor
country: United States
facility: A. Alfred Taubman Health Care Center
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Jackson
country: United States
facility: Summit - Southern Therapy and Advanced Research
state: Mississippi
city: Manhasset
country: United States
facility: Northwell Health
state: New York
city: New York
country: United States
facility: New York University Hepatology Associates
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest University Baptist Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Philadelphia
country: United States
facility: Einstein Medical Center
state: Pennsylvania
city: Rapid City
country: United States
facility: Rapid City Medical Center
state: South Dakota
city: Nashville
country: United States
facility: Vanderbilt Digestive Disease Center
state: Tennessee
city: Houston
country: United States
facility: Liver Specialists of Texas
state: Texas
city: Houston
country: United States
facility: Pioneer Research Solutions
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Hospital
state: Utah
city: Milwaukee
country: United States
facility: Froedtert and Medical College of Wisconsin
state: Wisconsin
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: New Lambton Heights
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: South Brisbane
country: Australia
facility: Mater Misericordiae - Hospital Brisbane
state: Queensland
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Box Hill
country: Australia
facility: Eastern Health - Australia
state: Victoria
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Kingswood
country: Australia
facility: Nepean Hospital
city: Liverpool
country: Australia
facility: Liverpool Hospital
city: Melbourne
country: Australia
facility: The Alfred Hospital
city: Linz
country: Austria
facility: Ordensklinikum Linz GmbH Barmherzige Schwestern
state: Oberösterreich
city: Wels
country: Austria
facility: Klinikum Wels-Grieskirchen
state: Oberösterreich
city: Graz
country: Austria
facility: Universitaetsklinikum Graz - Universitätsklinik für Innere Medizin
state: Styria
city: Innsbruck
country: Austria
facility: Medizinische Universität Innsbruck
state: Tyrol
city: Bruxelles
country: Belgium
facility: Hôpital Erasme
state: Brussels
city: Laeken
country: Belgium
facility: Centre Hospitalier Universitaire Brugmann - Site Victor Horta
state: Brussels
city: Leuven
country: Belgium
facility: Universitair Ziekenhuis Leuven - Campus Gasthuisberg
state: Flemish Brabant
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
state: Oost-Vlaanderen
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Centre - Victoria General
state: Nova Scotia
city: Hamilton
country: Canada
facility: St. Joseph's Healthcare Hamilton - Charlton Campus
state: Ontario
city: London
country: Canada
facility: Centricity Research (LMC Manna Research) - London
state: Ontario
city: North Bay
country: Canada
facility: Office Of Stephane M. Gauthier
state: Ontario
city: Toronto
country: Canada
facility: Toronto Liver Center
state: Ontario
city: Montréal
country: Canada
facility: Centre Hospitalier de l'Université de Montréal (CHUM)
state: Quebec
city: Brampton
country: Canada
facility: William Osler Health System - Brampton Civic Hospital
city: Praha
country: Czechia
facility: Ústřední Vojenská Nemocnice Praha
state: Prague
city: Hradec Králové
country: Czechia
facility: Hepato-Gastroenterologie HK
city: Lille
country: France
facility: Hôpital Claude Huriez
state: Hauts-de-France
city: Créteil
country: France
facility: Hôpitaux Universitaires Henri Mondor
state: Ile-de-France
city: Grenoble
country: France
facility: Centre Hospitalier Universitaire Grenoble Alpes
state: Isère
city: Limoges
country: France
facility: Hopital Dupuytren
state: Limousin
city: Vandœuvre-lès-Nancy
country: France
facility: Hôpitaux de Brabois
state: Lorraine
city: Toulouse
country: France
facility: Hôpital Rangueil
state: Occitanie
city: Toulouse
country: France
facility: Clinique Pasteur - Toulouse
state: Occitanie
city: Angers
country: France
facility: Centre Hosptitalier Universitaire d'Angers
state: Pays De La Loire
city: Amiens
country: France
facility: Centre Hospitalier Universitaire Amiens-Picardie - Site Sud
state: Picardie
city: Lyon
country: France
facility: Hôpital de la Croix Rousse
state: Rhone-alpes
city: Lille
country: France
facility: Hôpital Claude Huriez
city: Marseille
country: France
facility: Hôpital Saint Joseph Marseille
city: Nice
country: France
facility: Hôpital l'Archet
city: Paris
country: France
facility: Hôpital Saint-Antoine
city: Munich
country: Germany
facility: Klinikum rechts der Isar der Technischen Universität München
state: Bayern
city: Frankfurt
country: Germany
facility: Universitätsklinikum Frankfurt
state: Hessen
city: Wiesbaden
country: Germany
facility: St. Josefs-Hospital Wiesbaden
state: Hessen
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
state: Niedersachsen
city: Leipzig
country: Germany
facility: Eugastro
state: Sachsen
city: Homburg
country: Germany
facility: Universitätsklinikum des Saarlandes
city: Heraklion
country: Greece
facility: University General Hospital of Heraklion (PAGNI)
city: Larissa
country: Greece
facility: University General Hospital of Larissa
city: Budapest
country: Hungary
facility: Semmelweis Egyetem - I. Sz. Sebészeti és Intervenciós Gasztroenterológiai Klinika
city: Haifa
country: Israel
facility: Carmel Medical Center
state: Haifa District
city: Nahariya
country: Israel
facility: Western Galilee Hospital-Nahariya
state: Northern District
city: Be'er Sheva
country: Israel
facility: Soroka Medical Center
state: Southern District
city: Petah Tikva
country: Israel
facility: Rabin Medical Center - Beilinson Hospital
state: Tel Aviv
city: Haifa
country: Israel
facility: Rambam Health Care Campus
city: Jerusalem
country: Israel
facility: Hadassah University Hospital Ein Kerem
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Milan
country: Italy
facility: Ospedale San Giuseppe
state: Milano
city: Rozzano
country: Italy
facility: Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) - Istituto Clinico Humanitas
state: Milan
city: Monza
country: Italy
facility: Azienda Socio Sanitaria Territoriale Monza - Ospedale San Gerardo
state: Monza And Brianza
city: Ancona
country: Italy
facility: Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona
city: Messina
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Gaetano Martino
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
city: Napoli
country: Italy
facility: Università degli Studi di Napoli Federico II
city: Novara
country: Italy
facility: Azienda Ospedaliero-Universitaria Maggiore della Carità di Novara
city: Grafton
country: New Zealand
facility: Auckland City Hospital
state: Auckland
city: Crofton Downs
country: New Zealand
facility: Wellington Regional Hospital
state: Wellington
city: Dunedin
country: New Zealand
facility: Dunedin Hospital
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: Bytom
country: Poland
facility: Szpital Specjalistyczny Nr 1 w Bytomiu
city: Myslowice
country: Poland
facility: ID Clinic
city: Wrocław
country: Poland
facility: Centrum Badań Klinicznych Piotr Napora Lekarze Sp. p.
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol
state: Barcelona
city: Sabadell
country: Spain
facility: Hospital de Sabadell
state: Barcelona
city: La Laguna
country: Spain
facility: Hospital Universitario de Canarias
state: Santa Cruz De Tenerife
city: Alicante
country: Spain
facility: Hospital General Universitari d'Alicante
city: Almería
country: Spain
facility: Complejo Hospitalario Torrecárdenas
city: Barcelona
country: Spain
facility: Hospital del Mar - Parc de Salut Mar
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofía
city: Madrid
country: Spain
facility: Hospital Universitario de La Princesa
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Málaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
city: Santiago
country: Spain
facility: Hospital Clínico Universitario de Santiago
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: València
country: Spain
facility: Consorci Hospital General Universitari de València
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
city: Uppsala
country: Sweden
facility: Akademiska Sjukhuset - Uppsala
city: Lugano
country: Switzerland
facility: Fondazione Epatocentro Ticino
state: Ticino
city: Sankt Gallen
country: Switzerland
facility: Kantonsspital Sankt Gallen
city: Gloucester
country: United Kingdom
facility: Gloucestershire Hospitals NHS Foundation Trust
state: England
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
state: England
city: Newcastle upon Tyne
country: United Kingdom
facility: The Newcastle Upon Tyne Hospitals NHS Foundation Trust
state: England
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
state: England
city: Sheffield
country: United Kingdom
facility: Sheffield Teaching Hospitals NHS Foundation Trust
state: England
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust
state: England
city: Glasgow
country: United Kingdom
facility: NHS Greater Glasgow and Clyde
state: Scotland
Study officials:
References: