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

Primary Biliary Cirrhosis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03226067
• Other study ID #: GSN000300
• Secondary ID: 2016-004599-23
• Status: Completed
• Phase: Phase 2
• Start date: June 26, 2017
• Est. completion date: April 11, 2019

Study information

• Verified date: March 2022
• Source: Calliditas Therapeutics AB
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 111
• Est. completion date: April 11, 2019
• Est. primary completion date: April 11, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Cholangitis
• Liver Cirrhosis, Biliary
• Primary Biliary Cirrhosis

Intervention

Drug:
• GKT137831
GKT137831 100mg capsules. To be taken as part of two dose arms which are 400mg twice daily or 400mg once daily.
• Placebo oral capsule
Matching capsules.

Locations

Country	Name	City	State
Belgium	CUB Hôpital Erasme	Brussels
Belgium	UZ Gent	Gent
Belgium	UZ Leuven	Leuven
Canada	University of Calgary Liver Unit	Calgary	Alberta
Canada	McGill University Health Centre (MUHC)	Montréal	Quebec
Canada	Centre hospitalier de l'Universite de Montreal (CHUM) Centre de Recherche Service d'Hepatologie	Montreal,	Quebec
Canada	University of Manitoba	Winnipeg	Manitoba
Germany	Universitatsklinikum Bonn	Bonn	North Rhine-Westphalia
Germany	Friedrich-Alexander University Erlangen-Nürnberg	Erlangen	Bavaria
Germany	Johann Wolfgang Goethe-University	Frankfurt	Hessen
Germany	Universitätsklinikum Heidelberg	Heidelberg
Germany	Universitätsmedizin Mainz	Mainz
Greece	General Hospital of Athens "Hippocratio"	Athens
Greece	Laiko General Hospital	Athens
Greece	University Hospital of Larissa	Larissa
Israel	Rambam Health Centre	Haifa
Israel	Hadassah Medical Organization	Jerusalem
Israel	Shaare Zedek Medical Center	Jerusalem
Israel	Rabin Medical Centre	Petach-Tiqva
Israel	Sheba Medical Centre	Ramat Gan
Israel	Sourasky Tel-Aviv Medical Center	Tel Aviv
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 of Milan-Bicocca	Monza	Lombardia
Italy	University Hospital Padova	Padova
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Puerta de Hierro-Majadahonda	Madrid
Spain	University of Alcalá	Madrid
Spain	Virgen De La Victoria University Hospital	Malaga
Spain	Hospital Universitario Virgen del Rocio	Sevilla
United Kingdom	University Hospitals Birmingham NHS Foundation Trust	Birmingham
United Kingdom	Cambridge University Hospitals NHS Foundation Trust	Cambridge	Cambridgeshire
United Kingdom	Tayside Medical Science Centre (TASC)	Dundee	Tayside
United Kingdom	Gloucestershire Royal Hospital	Gloucester	Gloucestershire
United Kingdom	Hull and East Yorkshire Hospitals NHS Trust	Hull	East Yorkshire
United Kingdom	King's College Hospital NHS Foundation Trust	London
United Kingdom	Oxford University Hospitals NHS Foundation Trust	Oxford	Oxfordshire
United Kingdom	Plymouth Hospital NHS Trust	Plymouth	Devon
United Kingdom	Singleton Hospital	Swansea
United States	Dayton Gastroenterology Inc.	Beavercreek	Ohio
United States	Northwestern University	Chicago	Illinois
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	St Lukes Episcopal Hospital	Houston	Texas
United States	Jackson Liver and GI Specialist c/o (STAR) LLC	Jackson	Mississippi
United States	Pinnacle Clinical Research, PLLC	Live Oak	Texas
United States	North Shore University Hospital	Manhasset	New York
United States	Methodist University Hospital	Memphis	Tennessee
United States	University of Miami	Miami	Florida
United States	Yale School of Medicine	New Haven	Connecticut
United States	Tulane University Medical Center	New Orleans	Louisiana
United States	Mount Sinai Health System	New York	New York
United States	NYU Hepatology Associates	New York	New York
United States	Bon Secours Liver Institute of Hampton Roads	Newport News	Virginia
United States	Mayo Clinic	Phoenix	Arizona
United States	UPMC Center for Liver Diseases	Pittsburgh	Pennsylvania
United States	Bon Secours Liver Institute of Richmond	Richmond	Virginia
United States	University of Rochester Medical Centre	Rochester	New York
United States	University California Davis	Sacramento	California
United States	Ventura Clinical Trials	Ventura	California
United States	MedStar Georgetown University Hospital	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Calliditas Therapeutics AB

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The Percent Change in Serum GGT.	Percent change in serum GGT from baseline to Week 24 (serum GGT was measured in U/L)	Baseline to week 24 (visit 7)
Secondary	Absolute Change in Serum GGT	Absolute change in serum GGT from baseline to each assessment.	From baseline to Weeks 2, 6, 12, 18 and 24
Secondary	Percent Change in Serum GGT	Percent change in serum GGT from baseline to each assessment (serum GGT was measured in U/L)	From baseline to Weeks 2, 6, 12, 18 and 24
Secondary	Percent Change in Serum ALP	Percent change in serum ALP from baseline to each assessment (serum ALP was measured in U/L).	From baseline to Weeks 2, 6, 12, 18 and 24
Secondary	Absolute Change in Serum ALP	Absolute change in serum ALP from baseline to each assessment.	From baseline to Weeks 2, 6, 12, 18 and 24
Secondary	Absolute Change in Serum Conjugated Bilirubin.	Absolute change in serum conjugated bilirubin from baseline to each assessment.	From baseline to Weeks 2, 6, 12, 18 and 24
Secondary	Percent Change in Serum Conjugated Bilirubin.	Percent change in serum Conjugated bilirubin, from baseline to each assessment (serum conjugated bilirubin is measured in µmol/L).	From baseline to Weeks 2, 6, 12, 18 and 24
Secondary	Absolute Change in Serum Total Bilirubin.	Absolute change in serum total bilirubin, from baseline to each assessment.	from baseline to Weeks 2, 6, 12, 18 and 24
Secondary	Percent Change in Serum Total Bilirubin.	Percent change in Serum Total Bilirubin from baseline to each assessment (serum total bilirubin is measured in µmol/L).	from baseline to Weeks 2, 6, 12, 18 and 24
Secondary	Absolute Change in Liver Stiffness as Assessed by Transient Elastography (FibroScan® or Similar Technology).	Absolute change in liver stiffness as assessed by transient elastography (FibroScan® or similar technology), from baseline to Week 24, in subjects with values at baseline and Week 24.	From baseline to Week 24, in patients with values at baseline and Week 24.
Secondary	Percent Change in Liver Stiffness as Assessed by Transient Elastography (FibroScan® or Similar Technology).	Percent change in liver stiffness as assessed by transient elastography (FibroScan® or similar technology), from baseline to Week 24, in subjects with values at baseline and Week 24 (liver stiffness is measured in kPa).	From baseline to Week 24, in patients with values at baseline and Week 24.
Secondary	Percent Change in Serum Levels of Collagen Fragments Indicative of Collagen Formation and Degradation.	Percent change in serum levels of collagen fragments indicative of collagen formation and degradation, from baseline to Weeks 12 and 24 (serum levels of collagen fragments are measured in ng/mL).	From baseline to Weeks 12 and 24.
Secondary	Absolute Change in Liver Stiffness as Assessed by Transient Elastography by Subgroup (FibroScan® or Similar Technology).	Absolute change in liver stiffness by subgroup (>=9.6 kPa) as assessed by transient elastography (FibroScan® or similar technology), from baseline to Week 24, in subjects with values at baseline and Week 24.	From baseline to Week 24, in patients with values at baseline and Week 24.
Secondary	Percent Change in Liver Stiffness as Assessed by Transient Elastography by Subgroup (FibroScan® or Similar Technology).	Percent change in liver stiffness by subgroup (>=9.6 kPa) as assessed by transient elastography (FibroScan® or similar technology), from baseline to Week 24, in subjects with values at baseline and Week 24 (liver stiffness is measured in kPa).	From baseline to Week 24, in patients with values at baseline and Week 24.
Secondary	Absolute Change in Pruritis Visual Analogue Scale (VAS) Scores	Absolute Change in Pruritis Visual Analogue Scale (VAS) scores from baseline to weeks 12 and 24- Score from 0 to 10, 0= no itch and 10= severe itch, continuous, day and night intolerable itch.	From baseline to Weeks 12 and 24
Secondary	Percent Change in Pruritis Visual Analogue Scale (VAS) Scores	Percent Change in Pruritis Visual Analogue Scale (VAS) scores from baseline to weeks 12 and 24- Score from 0 to 10, 0= no itch and 10= severe itch, continuous, day and night intolerable itch.	From baseline to Weeks 12 and 24
Secondary	Absolute Change in PBC-40 (Primary Biliary Cholongitis) Domain Scores	Absolute Change in PBC-40 Domain scores from baseline to weeks 12 and 24 Symptoms domain: items 1 to 7 of the PBC-40 questionnaire (score from 6 to 35). Itch domain: items 8 to 10 of the PBC-40 questionnaire (score from 0 to 15). Fatigue domain: items 11 to 21 of the PBC-40 questionnaire (score from 11 to 55). Cognitive domain: items 22 to 27 of the PBC-40 questionnaire (score from 6 to 30). Emotional domain: items 28, 30 and 33 of the PBC-40 questionnaire (score from 3 to 15). Social domain: items 29, 31, 32, 34 to 40 of the PBC-40 questionnaire (score from 8 to 50). Higher scores mean worse outcome.	From baseline to Weeks 12 and 24
Secondary	Percent Change in PBC-40 (Primary Biliary Cholongitis) Domain Scores	Percent Change in PBC-40 Domain scores from baseline to weeks 12 and 24 Symptoms domain: items 1 to 7 of the PBC-40 questionnaire (score from 6 to 35). Itch domain: items 8 to 10 of the PBC-40 questionnaire (score from 0 to 15). Fatigue domain: items 11 to 21 of the PBC-40 questionnaire (score from 11 to 55). Cognitive domain: items 22 to 27 of the PBC-40 questionnaire (score from 6 to 30). Emotional domain: items 28, 30 and 33 of the PBC-40 questionnaire (score from 3 to 15). Social domain: items 29, 31, 32, 34 to 40 of the PBC-40 questionnaire (score from 8 to 50). Higher scores mean worse outcome.	From baseline to Weeks 12 and 24