Primary biliary cholangitis (PBC) MedDRA version: 20.0 Level: SOC Classification code 10019805 Term: Hepatobiliary disorders System Organ Class: 10019805 - Hepatobiliary disorders
Conditions
Interventions
Product Name: Golexanolone
Product Code: GR3027
Pharmaceutical Form: Capsule, soft
INN or Proposed INN: GOLEXANOLONE
CAS Number: 208922238-18
Current Sponsor code: GR3027
Concentration unit: mg millig
Sponsors
Umecrine Cognition AB
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male and female subjects age = 18 and =75 years. 2. Diagnosis of PBC based on the presence of =2 of the 3 key disease characteristics: a. Anti-mitochondrial antibody or PBC-specific anti-nuclear antibody titre =1/40 b. Elevated alkaline phosphatase (ALP) (> upper limit of normal [ULN] for the relevant laboratory) c. Compatible or diagnostic liver biopsy 3. Clinically significant fatigue defined for the purposes of this study as a PBC-40 fatigue domain score of =29 at screening. 4. Clinically significant cognitive symptoms, defined for the purposes of this study as a PBC-40 cognitive domain =16 at screening. 5. Stable PBC SoC therapy, which may include UDCA, OCA, bezafibrate and/or fenofibrate. for at least 3 months prior to randomisation. 6. For all women of childbearing potential (WOCBP) a negative pregnancy test at screening and a negative urine dip-stick pregnancy test at baseline, prior to first dose of IMP will be required. 7. WOCBP must be willing to use a contraceptive method with a failure rate of =65 years) yes F.1.3.1 Number of subjects for this age range 20
Exclusion criteria
Exclusion criteria: 1. Child-Pugh class B or C cirrhosis. 2. Clinical evidence of hepatic decompensation (e.g. current or prior HE, ascites, or variceal bleeding). 3. History of hepatocellular carcinoma. 4. Bilirubin >1.5 x ULN. 5. Glomerular filtration rate (GFR) 500 ms), cardiac arrhythmia, or any clinically significant abnormality in the resting ECG, as judged by the Investigator (at screening). 11. Concomitant disease characterised by chronic fatigue and/or cognitive impairment (e.g. Alzheimer’s, Parkinson’s, etc.) which in the judgement of the Investigator would either limit the potential benefit to the subject and/or confound the interpretation of results. 12. Clinically significant bowel disease, including obstruction, inflammatory bowel disease, or malabsorption. 13. Clinically significant sleep apnoea, as defined by >5 episodes/hour more than 70% of occasions, despite use of continuous positive airway pressure (CPAP). 14. An uncontrolled thyroid disorder: a. Uncontrolled hyperthyroidism: defined as any history of hyperthyroidism that has either not been treated with either radioactive iodine and/or surgery or that has been treated with radioactive iodine and/or surgery but has required ongoing continuous or intermittent use of thyroid hormone synthesis inhibitors (i.e. methimazole or propylthiouracil) in the 24 weeks before screening. b. Uncontrolled hypothyroidism: defined as initiation of thyroid hormone replacement therapy or dose adjustment of replacement therapy in the 12 weeks before screening. c. Subjects without a diagnosed thyroid disease should be excluded if thyroid-stimulating hormone (TSH)-value is above ULN, or/and if free triiodothyronine (FT3)- or free thyroxine (FT4)-values are outside normal limits. 15. Subjects with a history of or currently active immune disorders other that PBC (including autoimmune disease) and/or diseases requiring immunosuppressive drugs (including azathioprine, prednisone, prednisolone, budesonide, cyclosporine, tacrolimus, methotrexate, or mycophenolate mofetil). 16. Clinical diagnosis of autoimmune hepatitis overlap defined using the Paris overlap criteria (see Appendix 13.2) [30, 31]. 17. Concurrent liver disease of another aetiology. 18. The presence, as judged by the Investigator, of clinically significant concomitant illness which would jeopardise safe participation in the study and /or the interpretation of study findings, e.g. major psychiatric disorder and major depressive disorder (HADS-D >10) formally diagnosed by a psychiatrist. 19. Regular use of prescribed or over the counter medications known to cause fatigue or cognitive dysfunction (including, but not limited to, benzodiazepines, opioids other than codeine phosphate, sleeping pills, regular (daily) antihistamine use in the last 4 weeks, anti-psychotic agents, barbiturates, or recreational drug use). Confidential 50 (94) 20. Use of prohibited medications within 14 days prior to randomisation, including medications sensitive to CYP3A4 and/or Pgp inhibition/induction with a narrow therapeutic window, including use of warfarin and warfarin-
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part A: To assess the safety and tolerability of treatment with 40 mg golexanolone BID for 5 days in non-cirrhotic or Child-Pugh class A cirrhotic PBC subjects with clinically significant fatigue and cognitive symptoms. Part B: To assess the safety and tolerability of 28 days BID treatment with two dose levels of golexanolone in non-cirrhotic or Child-Pugh class A PBC subjects with clinically significant fatigue and cognitive symptoms.;Secondary Objective: Part A: 1. To assess the PK characteristics of golexanolone administered 40 mg BID for 5 days in the target population. 2. To investigate the metabolite profile of golexanolone in human plasma and urine. Part B: 1. To assess effects of golexanolone on health-related quality of life (HRQoL), including fatigue. 2. To assess effects of golexanolone on day-time sleepiness. 3. To assess effects of golexanolone on cognitive function. 4. To evaluate the Investigator’s overall impression of treatment effect. 5. To assess the exposure of two dose levels of golexanolone in the target population treated for 28 days.;Primary end point(s): Part A: Frequency, intensity, and seriousness of adverse events (AEs), changes from baseline to Day 5 in laboratory parameters and clinical safety parameters. Part B: Frequency, intensity, and seriousness of AEs, changes from baseline to Day 28 in laboratory parameters and clinical safety parameters.;Timepoint(s) of evaluation of this end point: Part A: from baseline to Day 5 Part B: from baseline to Day 28 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Part A: 1. PK parameters: a. after the first dose: Area under the plasma concentration time curve (AUC)0-24h, maximum plasma concentration (Cmax), time to Cmax (Tmax), terminal elimination rate constant (lambdaz), terminal half-life (T1/2), apparent volume of distribution associated with the terminal elimination phase of the plasma curve (Vz/F), total apparent clearance of drug from plasma (Cl/F). b. after the last dose: AUC at steady state (AUCss), maximum and minimum concentration at steady state (Cmax, ss and Cmin, ss), Tmax, % fluctuation, lambdaz, T1/2, CL/F, Vz/ F. c. accumulation ratio between first and last dose 2. Metabolite profile in human plasma and urine (to be reported separately). Part B: 1. Change from baseline to Day 28 in the following HRQoL measures: - PBC-40 scores for each of the domains (cognition, itch, fatigue, social, emotional, and general symptoms). - EQ-5D-3L tool 2. Change from baseline to Day 28 in daytime sleepiness related symptoms using the Epworth Sleepiness Scale (ESS). 3. Change from baseline to Day 28 in a battery of cognitive tests, including: - Portosystemic Hepatic Encephalopathy Score (PHES) total score - Rey Auditory Verbal Learning test (RAVLT) - Delis and Kaplan Executive Function System (D-KEFS) Letter and Category fluency subtests 4. Clinical Global Impression of change, PBC version (CGI-C-PBC). 5. Lowest plasma concentration before the next dose (Ctrough) will be assessed pre-dose on Days 1, 7, 14 and 28.;Timepoint(s) of evaluation of this end point: Part A: from baseline to Day 5 Part B: from baseline to Day 28 | — |
Countries
Germany, Greece, Hungary, Italy, Serbia, Spain, United Kingdom
Contacts
Public ContactMagnus Doverskog
Umecrine Cognition AB
Outcome results
None listed