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Trial record 18 of 34 for:    Biliary Cirrhosis, Primary, 4

Study to Assess Safety and Efficacy of GKT137831 in Patients With Primary Biliary Cholangitis Receiving Ursodeoxycholic Acid.

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ClinicalTrials.gov Identifier: NCT03226067
Recruitment Status : Completed
First Posted : July 21, 2017
Last Update Posted : October 10, 2019
Sponsor:
Information provided by (Responsible Party):
Genkyotex SA

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).

Condition or disease Intervention/treatment Phase
Primary Biliary Cirrhosis Drug: GKT137831 Drug: Placebo oral capsule Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 111 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: This is a double-blind study: the Sponsor, subjects, investigator staff, persons performing the assessments and data reviewers and statisticians will remain blinded to the identity of the study treatments.
Primary Purpose: Treatment
Official Title: A Double-Blind, Randomized, Placebo-Controlled Clinical Trial to Assess the Efficacy and Safety of Oral GKT137831 in Patients With Primary Biliary Cholangitis Receiving Ursodeoxycholic Acid and With Persistently Elevated Alkaline Phosphatase
Actual Study Start Date : June 26, 2017
Actual Primary Completion Date : April 11, 2019
Actual Study Completion Date : April 11, 2019


Arm Intervention/treatment
Experimental: GKT137831 400mg twice daily

GKT137831 400mg twice daily

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

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

Experimental: 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.

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

Drug: Placebo oral capsule
Matching capsules.

Placebo Comparator: Placebo Arm
Patients will self-administer 4 capsules in the morning and 4 capsules in the evening. All capsules will be placebos.
Drug: Placebo oral capsule
Matching capsules.




Primary Outcome Measures :
  1. The percent change in serum GGT. [ Time Frame: Baseline to week 24 (visit 7) ]

Secondary Outcome Measures :
  1. Absolute change in serum GGT [ Time Frame: From baseline to Weeks 2, 6, 12, 18, 24 and 28 ]
  2. Percent change in serum GGT [ Time Frame: Fom baseline to Weeks 2, 6, 12, 18, 24 and 28 ]
  3. Absolute change in Enhanced Liver Fibrosis (ELF) score [ Time Frame: From baseline to Weeks 12 and 24. ]
    The ELF test is used to detect the presence of liver fibrosis and to monitor therapeutic responses.

  4. Percent change in serum ALP [ Time Frame: From baseline to Weeks 2, 6, 12, 18, 24 and 28 ]
  5. Absolute change in serum ALP [ Time Frame: From baseline to Weeks 2, 6, 12, 18, 24 and 28 ]
  6. Absolute change in serum levels of high-sensitivity C-reactive protein (hsCRP) [ Time Frame: From baseline to Weeks 2, 6, 12, 18, 24 and 28 ]
  7. Percent change in serum levels of high-sensitivity C-reactive protein (hsCRP) [ Time Frame: From baseline to Weeks 2, 6, 12, 18, 24 and 28 ]
  8. Absolute change in serum levels of fibrinogen [ Time Frame: From baseline to Weeks 2, 6, 12, 18, 24 and 28 ]
  9. Percent change in serum levels of fibrinogen [ Time Frame: From baseline to Weeks 2, 6, 12, 18, 24 and 28 ]
  10. Absolute change in serum Alanine Aminotransferase (ALT) [ Time Frame: From baseline to Weeks 2, 6, 12, 18, 24 and 28 ]
  11. Percent change in serum Alanine Aminotransferase (ALT) [ Time Frame: From baseline to Weeks 2, 6, 12, 18, 24 and 28 ]
  12. Absolute change in serum Aspartate Aminotransferase (AST) [ Time Frame: From baseline to Weeks 2, 6, 12, 18, 24 and 28 ]
  13. Percent change in serum Aspartate Aminotransferase (AST) [ Time Frame: From baseline to Weeks 2, 6, 12, 18, 24 and 28 ]
  14. Absolute change in serum conjugated bilirubin. [ Time Frame: From baseline to Weeks 2, 6, 12, 18, 24 and 28 ]
  15. Percent change in serum conjugated bilirubin. [ Time Frame: From baseline to Weeks 2, 6, 12, 18, 24 and 28 ]
  16. Absolute change in serum total bilirubin. [ Time Frame: from baseline to Weeks 2, 6, 12, 18, 24 and 28 ]
  17. Percent change in serum total bilirubin. [ Time Frame: from baseline to Weeks 2, 6, 12, 18, 24 and 28 ]
  18. Absolute change in AST to Platelet Ratio Index (APRI) scores [ Time Frame: from baseline to Weeks 2, 6, 12, 18, 24 and 28 ]
  19. Percent change in AST to Platelet Ratio Index (APRI) scores [ Time Frame: from baseline to Weeks 2, 6, 12, 18, 24 and 28 ]
  20. Absolute change in the Fibrosis-4 (FIB-4) [ Time Frame: from baseline to Weeks 2, 6, 12, 18, 24 and 28 ]
  21. Percent change in the Fibrosis-4 (FIB-4) [ Time Frame: from baseline to Weeks 2, 6, 12, 18, 24 and 28 ]
  22. Absolute change in liver stiffness as assessed by transient elastography (FibroScan® or similar technology). [ Time Frame: From baseline to Week 24, in patients with values at baseline and Week 24. ]
  23. Percent change in liver stiffness as assessed by transient elastography (FibroScan® or similar technology). [ Time Frame: From baseline to Week 24, in patients with values at baseline and Week 24. ]
  24. Absolute change in serum levels of collagen fragments indicative of collagen formation and degradation. [ Time Frame: From baseline to Weeks 12 and 24. ]
  25. Percent change in serum levels of collagen fragments indicative of collagen formation and degradation. [ Time Frame: From baseline to Weeks 12 and 24. ]
  26. Absolute change in total bile acids [ Time Frame: From baseline to Week 12 and 24. ]
  27. Percent change in total bile acids [ Time Frame: From baseline to Week 12 and 24. ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03226067


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Sponsors and Collaborators
Genkyotex SA

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Responsible Party: Genkyotex SA
ClinicalTrials.gov Identifier: NCT03226067     History of Changes
Other Study ID Numbers: GSN000300
2016-004599-23 ( EudraCT Number )
First Posted: July 21, 2017    Key Record Dates
Last Update Posted: October 10, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Liver Cirrhosis, Biliary
Biliary Tract Diseases
Liver Cirrhosis
Cholangitis
Bile Duct Diseases
Digestive System Diseases
Cholestasis, Intrahepatic
Cholestasis
Liver Diseases
Ursodeoxycholic Acid
Cholagogues and Choleretics
Gastrointestinal Agents