A study assessing the efficacy and safety of GKT137831 in Patients with Primary Biliary Cholangitis Receiving Ursodeoxycholic Acid and with Persistently Elevated Alkaline Phosphatase

• Register: EUCTR
• Last refreshed on: 30 April 2019
• Main ID: EUCTR2016-004599-23-DE
• Date of registration: 10/07/2017
• Prospective Registration: Yes
• Primary sponsor: Genkyotex SA
• Public title: A study assessing the efficacy and safety of GKT137831 in Patients with Primary Biliary Cholangitis Receiving Ursodeoxycholic Acid and with Persistently Elevated Alkaline Phosphatase
• Scientific 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
• Date of first enrolment: 19/09/2017
• Target sample size: 102
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-004599-23
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

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

Contacts

• Name: Isabelle Aelbrecht
• Affiliation: Genkyotex Innovation SA

• Name: Isabelle Aelbrecht
• Affiliation: Genkyotex Innovation SA

Key inclusion & exclusion criteria

Inclusion 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:
o History of elevated ALP levels (> ULN) for at least 6 months
o 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])
o 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.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 95
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 7

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. A history of severe cardiovascular disease defined as any of the following within the 12 weeks preceding initiation of study treatment:
- Acute myocardial infarction or unstable angina pectoris.
- A coronary revascularization procedure.
- Congestive heart failure New York Health Association (NYHA) Class III or IV.
- Stroke, including a transient ischemic attack.
16. 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).
17. 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.
18. A history of bone marrow disorder including aplastic anemia, or marked anemia defined as hemoglobin < 10.0 g/dL (or 6.2 mmol/L).
19. A known hypersensitivity to GKT137831 or to any of the excipients.
20. 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.





Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Primary Biliary Cholangitis
MedDRA version: 20.1 Level: LLT Classification code 10036680 Term: Primary biliary cirrhosis System Organ Class: 100000004871

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Intervention(s)

Product Code: GKT137831
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: GKT137831
CAS Number: 1218942-37-0
Other descriptive name: GKT137831
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Primary Outcome(s)

Primary end point(s): Primary:
•The percent change from baseline to Week 24 (Visit 7) in serum GGT.

Timepoint(s) of evaluation of this end point: The percent change from baseline to Week 24 (Visit 7) in serum GGT.
Serum GGT will be assessed during every treatment visit. (visit's 2-7)

Main Objective: To evaluate the efficacy of oral GKT137831 in comparison with placebo, in subjects with PBC receiving UDCA and with persistently elevated Alkaline Phosphatase (ALP).

Secondary Objective: - To evaluate the safety of oral GKT137831 in comparison with placebo, in subjects with PBC.
- To estimate the population pharmacokinetics (PK) of GKT137831 and explore any potential Pharmacokinetics-Pharmacodynamics (PK-PD) relationships in this subject population.
- To explore any relationship between genetic parameters and therapeutic responses in a subset of subjects.

Secondary Outcome(s)

Secondary end point(s): - Absolute and percent change in serum GGT from baseline to each assessment.

- Absolute change in Enhanced Liver Fibrosis (ELF) score from baseline to Weeks 12 and 24.

- Absolute and percent change in serum ALP from baseline to each assessment.

- Absolute and percent change in serum levels of highsensitivity C-reactive protein (hsCRP) and fibrinogen from baseline to each assessment.

- Absolute and percent change in serum Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and conjugated and total bilirubin, from baseline to each assessment.

- Absolute and percent change in the Fibrosis-4 (FIB-4) and AST to Platelet Ratio Index (APRI) scores, from baseline to each assessment (FIB-4: age (years) x AST (IU/L)/(platelet count (109/L) x (ALT (IU/L)1/2, APRI: AST (IU/L)/ upper normal limit AST)x100/platelet count (109/L).

- Absolute and percent change in liver stiffness as assessed by transient elastography (FibroScan® or similar technology), from baseline to Week 24, in patients with values at baseline and Week 24.

- Absolute and percent change in serum levels of collagen fragments indicative of collagen formation and degradation from baseline to Weeks 12 and 24.

Absolute and percent change in Quality of Life (QoL), Fatigue and Pruritus scores based on the PBC-40 and Pruritus Visual Analogue Score (VAS), from baseline to Weeks 12 and 24.

Timepoint(s) of evaluation of this end point: Timepoints of the secondary endponts are included within the secondary objective endpoints section E.5.2 (above)

Most secondary assessments will be assessed from baseline to each visit however the ELF score and collagen fragments will be assessed from baseline to week 12 and week 24.
The change in liver stiffness (FibroScan® or similar technology) will be assessed from baseline to week 24.

Secondary ID(s)

GSN000300

2016-004599-23-BE

Source(s) of Monetary Support

Genkyotex Innovation SA

Ethics review

Status: Approved
Approval date:
Contact: