A Trial of Setanaxib in Patients With Primary Biliary Cholangitis (PBC) and Liver Stiffness

Primary Biliary Cholangitis Clinical Trial

— TRANSFORM  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05014672
• Other study ID #: GSN000350
• Secondary ID: 2021-001810-13
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: February 14, 2022
• Est. completion date: July 6, 2024

Study information

• Verified date: June 2024
• Source: Calliditas Therapeutics AB
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 76
• Est. completion date: July 6, 2024
• Est. primary completion date: June 24, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cholangitis
• Liver Cirrhosis, Biliary
• Liver Stiffness
• Primary Biliary Cholangitis

Intervention

Drug:
• Setanaxib
Oral tablets, 400mg per tablet
• Placebo
Oral tablets

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Calliditas Therapeutics Suisse SA

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Czechia,  France,  Germany,  Greece,  Hungary,  Israel,  Italy,  New Zealand,  Poland,  Spain,  Sweden,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from Baseline in ALP		Baseline (Day 1) and Week 24
Secondary	Change from Baseline in Fatigue	Assessed by the Patient-Reported Outcomes Measurement Information System (PROMIS) short form-Fatigue 7b Daily.	Baseline (Day 1) and Week 24
Secondary	Change from Baseline in Patient's Global Impression of Severity (PGIS) Fatigue	PGIS is measured on a 5-point scale, with 1 indicating symptoms are not present and 5 indicating very severe symptoms.	Baseline (Day 1) and Week 24
Secondary	Change from Baseline in Patient's Global Impression of Change (PGIC) Fatigue	PGIC is measured on a 7-point scale, with 1 indicating symptoms are much better and 7 indicating symptoms are much worse.	Baseline (Day 1) and Week 24
Secondary	Change from Baseline in PBC-40 Fatigue Domain		Baseline (Day 1) and Week 24
Secondary	Change from Screening in Liver Stiffness	Assessed by transient elastography (FibroScan®).	Screening (Day -28) and Week 24
Secondary	Change from Baseline in Worst Itch Numerical Scale Rating Scale (WI-NRS)	WI-NRS is measured on a 11-point scale, with 0 indicating no itch and 10 indicating worst possible itch.	Baseline (Day 1) and Week 24
Secondary	Change from Baseline in PBC-40 Itch Domain		Baseline (Day 1) and Week 24
Secondary	Change from Baseline in PGIS Pruritus	PGIS is measured on a 5-point scale, with 1 indicating symptoms are not present and 5 indicating very severe symptoms.	Baseline (Day 1) and Week 24
Secondary	Change from Baseline in PGIC Pruritus	PGIC is measured on a 7-point scale, with 1 indicating symptoms are much better and 7 indicating symptoms are much worse.	Baseline (Day 1) and Week 24
Secondary	Percentage of Participants Achieving a Biochemical Response to Setanaxib	Biochemical response defined as the percentage of participants with: ALP reduction to <1.67× upper limit of normal (ULN) and total bilirubin =1×ULN and a =15% or =30% or =40% or =70% ALP reduction from Baseline, respectively.; ALP reduction to <1.5×ULN and total bilirubin =1×ULN and a =40% ALP reduction from Baseline.; ALP <1×ULN and total bilirubin =1×ULN.; Total bilirubin <0.6×ULN.	Baseline (Day 1) and Week 24
Secondary	Percentage of Participants with Treatment-Emergent Adverse Events (TEAEs)	A TEAE is defined as any untoward medical occurrence in participants that happens after study drug administration. Any clinically significant abnormalities in vital signs, clinical laboratory tests (including biochemistry, hematology, urinalysis, and thyroid function), or 12- lead electrocardiogram (ECG) results will be recorded as Adverse Events (AEs). AEs will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE); Version 4.03.	Up to Week 24
Secondary	Percentage of Participants Who Experience Adverse Events of Special Interest (AESIs)	AESIs include drug-induced liver injury (DILI), anemia and hypothyroidism.	Up to Week 24