Study to Assess Safety & Efficacy of GKT137831 in Patients With Primary Biliary Cholangitis Receiving Ursodiol.

NCT ID: NCT03226067

Last Updated: 2022-06-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 111 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-06-26
• Study Completion Date: 2019-04-11

Brief Summary

The purpose of this study is to assess the safety and efficacy of GKT13783 in patients with Primary Biliary Cholangitis (PBC) who are taking a stable dose of ursodeoxycholic acid (UDCA) treatment, and have persistently high levels of a liver enzyme called Alkaline Phosphatase (ALP).

Detailed Description

Primary biliary cholangitis (PBC) is a disease of the liver. It is caused a sustained attack by the body's immune system on the bile ducts (canals) inside the liver. This continuous assault leads to their gradual destruction and eventual disappearance. This results in obstruction to the flow of bile which gets worse with disease progression. Once the bile duct injury has been established, the disease progresses due to ongoing obstruction of bile flow, inflammation and scarring of the liver tissue(fibrosis). The liver eventually fails.

This research is looking into whether the study drug is better than a dummy drug when given to patients with PBC. This trial will monitor the patients taking part with regular blood tests and ultrasound liver scans before, during, and at the end of the trial. These measures will allow for the ongoing assessment of liver function, and liver stiffness. It is hoped that in patients in whom the study drug is beneficial, the liver function or stiffness may progress at a slower pace, or may even improve during or at the end of the trial. Liver injury, inflammation and fibrosis Participants will be randomly assigned to 1 of 3 treatment groups (active drug once daily, active drug twice daily or placebo). This is a double blinded study so neither the participants nor the staff responsible for their care will know which group they have been assigned to. During the treatment period, participants will take 4 capsules orally at home in the morning and 4 capsules in the evening for 24 weeks.

Participants will be in the trial for 32 weeks in total (about 8 months) and will attend approximately 8 clinic visits.

Conditions

Primary Biliary Cirrhosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

GKT137831 400mg twice daily

GKT137831 400mg twice daily

Patients will self-administer 4 capsules in the morning and 4 capsules in the evening.

Group Type: EXPERIMENTAL

GKT137831

Intervention Type: DRUG

GKT137831 100mg capsules. To be taken as part of two dose arms which are 400mg twice daily or 400mg once daily.

GKT137831 400mg once daily

GKT137831 400mg once daily

Patients will self-administer 4 capsules in the morning and 4 capsules in the evening. The capsules in the evening will be placebos.

Group Type: EXPERIMENTAL

GKT137831

Intervention Type: DRUG

GKT137831 100mg capsules. To be taken as part of two dose arms which are 400mg twice daily or 400mg once daily.

Placebo oral capsule

Intervention Type: DRUG

Matching capsules.

Placebo Arm

Patients will self-administer 4 capsules in the morning and 4 capsules in the evening. All capsules will be placebos.

Group Type: PLACEBO_COMPARATOR

Placebo oral capsule

Intervention Type: DRUG

Matching capsules.

Interventions

GKT137831

GKT137831 100mg capsules. To be taken as part of two dose arms which are 400mg twice daily or 400mg once daily.

Intervention Type: DRUG

Placebo oral capsule

Matching capsules.

Intervention Type: DRUG

Other Intervention Names

setanaxib; Placebo

Eligibility Criteria

Inclusion Criteria

1. Male or female aged 18 to 80 years, inclusive.

2. Willing and able to give written informed consent and to comply with the requirements of the study.

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

• History of elevated ALP levels (> ULN) for at least 6 months
• Positive anti-mitochondrial antibody (AMA) titer or if AMA negative or in low titer (< 1:80) PBC-specific antibodies (anti-GP210 and/or anti-SP100 and/or antibodies against the major M2 components [PDC-E2, 2-oxo-glutaric acid dehydrogenase complex])
• Liver biopsy consistent with PBC (based on historic liver biopsy), including non-suppurative, destructive cholangitis affecting mainly the interlobular and septal bile ducts.

4. Serum ALP ≥ 1.5 x ULN.

5. Serum GGT ≥ 1.5 x ULN.

6. UDCA treatment for at least 6 months and stable dose for at least 3 months prior to Visit 1.

7. Subjects being treated for pruritus with colestyramine must be on a stable dose of colestyramine for at least 8 weeks prior to baseline/Day 1 (Visit 2). Subjects must be willing and able to take colestyramine at least 2 hours before or after study medication.

8. Female subjects 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 for 90 days after last administration of investigational medicinal product (IMP). Male participants with female partners of childbearing potential must be willing to use a condom and require their partner to use an additional form of adequate contraception as approved by the Investigator. This requirement begins at the time of informed consent and ends 90 days after the last administration of IMP. Male study participants must also not donate sperm from baseline until 90 days after the last administration of IMP.

Exclusion Criteria

1. A positive pregnancy test or breast-feeding for female subjects.

2. Any hepatic decompensation, defined as a past or current history of hepatic encephalopathy, gastrointestinal tract bleeding due to esophageal varices, or ascites.

3. International normalized ratio (INR) > 1.2 unless subject is on anticoagulant therapy.

4. ALT > 3 x ULN.

5. Total bilirubin > 1 x ULN.

6. Planned or current plasmapheresis or other extra-corporeal treatments (e.g., molecular adsorbent recirculation system (MARS)) for treatment-refractory pruritus.

7. History of liver transplantation, current placement on a liver transplant list or current Model for End Stage Liver Disease (MELD) score ≥ 15.

8. Cirrhosis with complications, including history or presence of: spontaneous bacterial peritonitis, hepatocellular carcinoma.

9. Hepatorenal syndrome (type I or II) or Screening serum creatinine > ULN.

10. Competing etiology for liver disease (e.g., hepatitis C, active hepatitis B, non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), autoimmune hepatitis, primary sclerosing cholangitis, Gilbert's Syndrome).

11. Subjects receiving prohibited medications within 3 months of Screening (Visit 1) according to the list (a, b and c) provided in Section 6.6.2.

12. Treatment with any investigational agent within 4 weeks of Visit 1 or 5 half-lives of the investigational medicinal product (whichever is longer).

13. A history of long QT syndrome.

14. Evidence of any of the following cardiac conduction abnormalities during the screening period:

• A QTc Fredericia interval >450 milliseconds for males and >470 milliseconds for females.
• A second or third degree atrioventricular block not successfully treated with a pacemaker.

15. History of cancer in the preceding 5 years, except adequately treated non-melanoma skin cancer, carcinoma in situ of the cervix, in situ prostate cancer, in situ breast ductal carcinoma, or superficial bladder cancer stage 0).

16. The occurrence of any acute infection requiring systemic antibiotic therapy within the 2 weeks prior the Screening Visit (Visit 1), or human immunodeficiency virus (HIV) infection.

17. A history of bone marrow disorder including aplastic anemia, or marked anemia defined as hemoglobin < 10.0 g/dL (or 6.2 mmol/L).

18. Any condition which, in the opinion of the Investigator, constitutes a risk or contraindication for the participation of the subject in the study, or which could interfere with the study objectives, conduct, or evaluation.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Calliditas Therapeutics AB

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Philippe Wiesel, MD

Role: STUDY_DIRECTOR

Calliditas Therapeutics AB

Locations

Mayo Clinic

Phoenix, Arizona, United States

University California Davis

Sacramento, California, United States

Ventura Clinical Trials

Ventura, California, United States

Yale School of Medicine

New Haven, Connecticut, United States

MedStar Georgetown University Hospital

Washington D.C., District of Columbia, United States

University of Miami

Miami, Florida, United States

Northwestern University

Chicago, Illinois, United States

Tulane University Medical Center

New Orleans, Louisiana, United States

Jackson Liver and GI Specialist c/o (STAR) LLC

Jackson, Mississippi, United States

North Shore University Hospital

Manhasset, New York, United States

NYU Hepatology Associates

New York, New York, United States

Mount Sinai Health System

New York, New York, United States

University of Rochester Medical Centre

Rochester, New York, United States

Dayton Gastroenterology Inc.

Beavercreek, Ohio, United States

University Hospitals Cleveland Medical Center

Cleveland, Ohio, United States

UPMC Center for Liver Diseases

Pittsburgh, Pennsylvania, United States

Methodist University Hospital

Memphis, Tennessee, United States

St Lukes Episcopal Hospital

Houston, Texas, United States

Pinnacle Clinical Research, PLLC

Live Oak, Texas, United States

Bon Secours Liver Institute of Hampton Roads

Newport News, Virginia, United States

Bon Secours Liver Institute of Richmond

Richmond, Virginia, United States

CUB Hôpital Erasme

Brussels, , Belgium

UZ Gent

Ghent, , Belgium

UZ Leuven

Leuven, , Belgium

University of Calgary Liver Unit

Calgary, Alberta, Canada

University of Manitoba

Winnipeg, Manitoba, Canada

Centre hospitalier de l'Universite de Montreal (CHUM) Centre de Recherche Service d'Hepatologie

Montreal, Quebec, Canada

McGill University Health Centre (MUHC)

Montreal, Quebec, Canada

Friedrich-Alexander University Erlangen-Nürnberg

Erlangen, Bavaria, Germany

Johann Wolfgang Goethe-University

Frankfurt am Main, Hesse, Germany

Universitatsklinikum Bonn

Bonn, North Rhine-Westphalia, Germany

Universitätsklinikum Heidelberg

Heidelberg, , Germany

Universitätsmedizin Mainz

Mainz, , Germany

General Hospital of Athens "Hippocratio"

Athens, , Greece

Laiko General Hospital

Athens, , Greece

University Hospital of Larissa

Larissa, , Greece

Rambam Health Centre

Haifa, , Israel

Shaare Zedek Medical Center

Jerusalem, , Israel

Hadassah Medical Organization

Jerusalem, , Israel

Rabin Medical Centre

Petach-Tiqva, , Israel

Sheba Medical Centre

Ramat Gan, , Israel

Sourasky Tel-Aviv Medical Center

Tel Aviv, , Israel

University of Milan-Bicocca

Monza, Lombardy, Italy

Università Politecnica delle Marche - Facoltà di Medicina e Chirurgia

Ancona, , Italy

Policlinico of Bologna

Bologna, , Italy

San Giovanni Rotondo Hospital (Puglia)

Foggia, , Italy

University Hospital Padova

Padua, , Italy

Hospital Clinic de Barcelona

Barcelona, , Spain

Hospital Puerta de Hierro-Majadahonda

Madrid, , Spain

University of Alcalá

Madrid, , Spain

Virgen De La Victoria University Hospital

Málaga, , Spain

Hospital Universitario Virgen del Rocio

Seville, , Spain

Cambridge University Hospitals NHS Foundation Trust

Cambridge, Cambridgeshire, United Kingdom

Plymouth Hospital NHS Trust

Plymouth, Devon, United Kingdom

Hull and East Yorkshire Hospitals NHS Trust

Hull, East Yorkshire, United Kingdom

Gloucestershire Royal Hospital

Gloucester, Gloucestershire, United Kingdom

Oxford University Hospitals NHS Foundation Trust

Oxford, Oxfordshire, United Kingdom

Tayside Medical Science Centre (TASC)

Dundee, Tayside, United Kingdom

University Hospitals Birmingham NHS Foundation Trust

Birmingham, , United Kingdom

King's College Hospital NHS Foundation Trust

London, , United Kingdom

Singleton Hospital

Swansea, , United Kingdom

Countries

United States; Belgium; Canada; Germany; Greece; Israel; Italy; Spain; United Kingdom

References

Invernizzi P, Carbone M, Jones D, Levy C, Little N, Wiesel P, Nevens F; study investigators. Setanaxib, a first-in-class selective NADPH oxidase 1/4 inhibitor for primary biliary cholangitis: A randomized, placebo-controlled, phase 2 trial. Liver Int. 2023 Jul;43(7):1507-1522. doi: 10.1111/liv.15596. Epub 2023 May 15.

Reference Type: DERIVED

PMID: 37183520 (View on PubMed)

Jones D, Carbone M, Invernizzi P, Little N, Nevens F, Swain MG, Wiesel P, Levy C. Impact of setanaxib on quality of life outcomes in primary biliary cholangitis in a phase 2 randomized controlled trial. Hepatol Commun. 2023 Feb 20;7(3):e0057. doi: 10.1097/HC9.0000000000000057. eCollection 2023 Mar 1.

Reference Type: DERIVED

PMID: 36809195 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2016-004599-23

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

GSN000300

Identifier Type: -

Identifier Source: org_study_id