Clinical trial NCT03226067: Study to Assess Safety & Efficacy of GKT137831 in Patients With Primary Biliary Cholangitis Receiving Ursodiol.
Official title: A Double-Blind, Randomized, Placebo-Controlled Clinical Trial to Assess the Efficacy & Safety of Oral GKT137831 in Patients With Primary Biliary Cholangitis Receiving Ursodeoxycholic Acid and With Persistently Elevated Alkaline Phosphatase
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Primary Biliary Cirrhosis
Lead sponsor: Calliditas Therapeutics AB
Sponsor class: INDUSTRY
First posted: 2017-07-21
Enrollment: 111
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This will be a double-blind, randomized, placebo-controlled, multicenter, parallel group phase 2 trial. A total of 102 subjects will be randomized and allocated to placebo or one of the 2 active treatment arms, according to a 1:1:1 randomization ratio, stratified at study entry by disease severity defined as baseline serum gamma glutamyl transferase (GGT) \< 2.5 x ULN or ≥ 2.5 x ULN). Accordingly, approximately 34 subjects will be allocated to each of the 3 treatment arms.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: The Percent Change in Serum GGT.
timeFrame: Baseline to week 24 (visit 7)
Secondary outcomes:
measure: Absolute Change in Serum GGT
timeFrame: From baseline to Weeks 2, 6, 12, 18 and 24
measure: Percent Change in Serum GGT
timeFrame: From baseline to Weeks 2, 6, 12, 18 and 24
measure: Percent Change in Serum ALP
timeFrame: From baseline to Weeks 2, 6, 12, 18 and 24
measure: Absolute Change in Serum ALP
timeFrame: From baseline to Weeks 2, 6, 12, 18 and 24
measure: Absolute Change in Serum Conjugated Bilirubin.
timeFrame: From baseline to Weeks 2, 6, 12, 18 and 24
measure: Percent Change in Serum Conjugated Bilirubin.
timeFrame: From baseline to Weeks 2, 6, 12, 18 and 24
measure: Absolute Change in Serum Total Bilirubin.
timeFrame: from baseline to Weeks 2, 6, 12, 18 and 24
measure: Percent Change in Serum Total Bilirubin.
timeFrame: from baseline to Weeks 2, 6, 12, 18 and 24
measure: Absolute Change in Liver Stiffness as Assessed by Transient Elastography (FibroScan® or Similar Technology).
timeFrame: From baseline to Week 24, in patients with values at baseline and Week 24.
measure: Percent Change in Liver Stiffness as Assessed by Transient Elastography (FibroScan® or Similar Technology).
timeFrame: From baseline to Week 24, in patients with values at baseline and Week 24.
measure: Percent Change in Serum Levels of Collagen Fragments Indicative of Collagen Formation and Degradation.
timeFrame: From baseline to Weeks 12 and 24.
measure: Absolute Change in Liver Stiffness as Assessed by Transient Elastography by Subgroup (FibroScan® or Similar Technology).
timeFrame: From baseline to Week 24, in patients with values at baseline and Week 24.
measure: Percent Change in Liver Stiffness as Assessed by Transient Elastography by Subgroup (FibroScan® or Similar Technology).
timeFrame: From baseline to Week 24, in patients with values at baseline and Week 24.
measure: Absolute Change in Pruritis Visual Analogue Scale (VAS) Scores
timeFrame: From baseline to Weeks 12 and 24
measure: Percent Change in Pruritis Visual Analogue Scale (VAS) Scores
timeFrame: From baseline to Weeks 12 and 24
measure: Absolute Change in PBC-40 (Primary Biliary Cholongitis) Domain Scores
timeFrame: From baseline to Weeks 12 and 24
measure: Percent Change in PBC-40 (Primary Biliary Cholongitis) Domain Scores
timeFrame: From baseline to Weeks 12 and 24
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic
state: Arizona
city: Sacramento
country: United States
facility: University California Davis
state: California
city: Ventura
country: United States
facility: Ventura Clinical Trials
state: California
city: New Haven
country: United States
facility: Yale School of Medicine
state: Connecticut
city: Washington
country: United States
facility: MedStar Georgetown University Hospital
state: District of Columbia
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: New Orleans
country: United States
facility: Tulane University Medical Center
state: Louisiana
city: Jackson
country: United States
facility: Jackson Liver and GI Specialist c/o (STAR) LLC
state: Mississippi
city: Manhasset
country: United States
facility: North Shore University Hospital
state: New York
city: New York
country: United States
facility: NYU Hepatology Associates
state: New York
city: New York
country: United States
facility: Mount Sinai Health System
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Centre
state: New York
city: Beavercreek
country: United States
facility: Dayton Gastroenterology Inc.
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Pittsburgh
country: United States
facility: UPMC Center for Liver Diseases
state: Pennsylvania
city: Memphis
country: United States
facility: Methodist University Hospital
state: Tennessee
city: Houston
country: United States
facility: St Lukes Episcopal Hospital
state: Texas
city: Live Oak
country: United States
facility: Pinnacle Clinical Research, PLLC
state: Texas
city: Newport News
country: United States
facility: Bon Secours Liver Institute of Hampton Roads
state: Virginia
city: Richmond
country: United States
facility: Bon Secours Liver Institute of Richmond
state: Virginia
city: Brussels
country: Belgium
facility: CUB Hôpital Erasme
city: Gent
country: Belgium
facility: UZ Gent
city: Leuven
country: Belgium
facility: UZ Leuven
city: Calgary
country: Canada
facility: University of Calgary Liver Unit
state: Alberta
city: Winnipeg
country: Canada
facility: University of Manitoba
state: Manitoba
city: Montreal,
country: Canada
facility: Centre hospitalier de l'Universite de Montreal (CHUM) Centre de Recherche Service d'Hepatologie
state: Quebec
city: Montréal
country: Canada
facility: McGill University Health Centre (MUHC)
state: Quebec
city: Erlangen
country: Germany
facility: Friedrich-Alexander University Erlangen-Nürnberg
state: Bavaria
city: Frankfurt
country: Germany
facility: Johann Wolfgang Goethe-University
state: Hessen
city: Bonn
country: Germany
facility: Universitatsklinikum Bonn
state: North Rhine-Westphalia
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Mainz
country: Germany
facility: Universitätsmedizin Mainz
city: Athens
country: Greece
facility: General Hospital of Athens "Hippocratio"
city: Athens
country: Greece
facility: Laiko General Hospital
city: Larissa
country: Greece
facility: University Hospital of Larissa
city: Haifa
country: Israel
facility: Rambam Health Centre
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Medical Organization
city: Petach-Tiqva
country: Israel
facility: Rabin Medical Centre
city: Ramat Gan
country: Israel
facility: Sheba Medical Centre
city: Tel Aviv
country: Israel
facility: Sourasky Tel-Aviv Medical Center
city: Monza
country: Italy
facility: University of Milan-Bicocca
state: Lombardia
city: Ancona
country: Italy
facility: Università Politecnica delle Marche - Facoltà di Medicina e Chirurgia
city: Bologna
country: Italy
facility: Policlinico of Bologna
city: Foggia
country: Italy
facility: San Giovanni Rotondo Hospital (Puglia)
city: Padova
country: Italy
facility: University Hospital Padova
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Hospital Puerta de Hierro-Majadahonda
city: Madrid
country: Spain
facility: University of Alcalá
city: Malaga
country: Spain
facility: Virgen De La Victoria University Hospital
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
state: Cambridgeshire
city: Plymouth
country: United Kingdom
facility: Plymouth Hospital NHS Trust
state: Devon
city: Hull
country: United Kingdom
facility: Hull and East Yorkshire Hospitals NHS Trust
state: East Yorkshire
city: Gloucester
country: United Kingdom
facility: Gloucestershire Royal Hospital
state: Gloucestershire
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Foundation Trust
state: Oxfordshire
city: Dundee
country: United Kingdom
facility: Tayside Medical Science Centre (TASC)
state: Tayside
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
city: Swansea
country: United Kingdom
facility: Singleton Hospital
Study officials:
affiliation: Calliditas Therapeutics AB
name: Philippe Wiesel, MD
role: STUDY_DIRECTOR
References: