The present phase 1b/2 randomised, double-blind, placebo-controlled, two-part study is designed to evaluate the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of two dose levels of golexanolone compared with placebo among subjects with a history of non-cirrhotic or Child-Pugh class A cirrhotic Primary Biliary Cholangitis (PBC) with clinically significant fatigue and cognitive symptoms on stable background standard of care (SoC) PBC medication. The objectives of this research study are to assess the safety and tolerability as well the pharmacokinetic (PK) characteristics of golexanolone administered 40 mg BID for 5 days in the target population (part A) and to assess the safety and tolerability, the effects of golexanolone on health-related quality of life (HRQoL), including fatigue, day-time sleepiness and cognitive function as well as Investigator's overall impression of treatment effect of 28 days twice per day (BID) treatment with two dose levels of golexanolone versus placebo (part B).
Male and female subjects age ≥ 18 years
Diagnosis of PBC based on the presence of ≥2 of 3 key disease characteristics
Clinically significant fatigue defined for the purposes of this study as a PBC-40 fatigue domain score of ≥29 at screening
Clinically significant cognitive symptoms, defined for the purposes of this study as a PBC-40 cognitive domain ≥16 at screening
Child-Pugh class B or C cirrhosis
Clinical evidence of hepatic decompensation (e.g. current or prior HE, ascites, or variceal bleeding)
History of hepatocellular carcinoma
Bilirubin >1.5 x ULN
Parallel
golexanolone
Drugsoft gelatin capsules, oral dosage twice per day for up to 28 days
golexanolone
Drugsoft gelatin capsules, oral dosage twice a day for up to 28 days
Placebo
Drugsoft gelatin capsules, oral dosage twice a day for up to 28 days
golexanolone
Drugsoft gelatin capsules, oral dosage twice per day for 5 days
Placebo
Drugsoft gelatin capsules, oral dosage twice per day for 5 days
1. Frequency, intensity, and seriousness of adverse events (AEs) from baseline to Day 28 (part B)
Frequency, intensity, and seriousness of adverse events (AEs) from baseline to Day 28
Frequency, intensity, and seriousness of adverse events (AEs) from baseline to Day 5 (part A)
Frequency, intensity, and seriousness of adverse events (AEs)
1. Change from baseline to Day 28 in PBC-40 scores for each of the domains (cognition, itch, fatigue, social, emotional, and general symptoms) (part B)
The PBC-40 is a patient-derived, disease specific health-related quality of life measure for PBC. The paper questionnaire consists of 40 questions, each scored on a scale of 1 to 5 (where 1=least impact, 5=greatest impact) grouped into six domains (cognition, itch, fatigue, social, emotional, and general symptoms). For each domain, scoring involves summing individual question response scores, range of 6-30. Higher scores indicate a poorer quality of life
2. Change from baseline to Day 28 in EQ-5D-3L tool (part B)
The EQ-5D tool is a standardised measure of health status developed to provide a simple, generic measure of health for clinical and economic appraisal.
3. Change from baseline to Day 28 in daytime sleepiness related symptoms using the Epworth Sleepiness Scale (ESS) (part B)
ESS is a validated self-administered questionnaire for assessment of daytime hypersomnolence. Respondents are asked to rate, on a 4-point scale (0-3), their usual chances of dozing off or falling asleep while engaged in eight different activities. The ESS score (the sum of eight item scores, 0-3) can range from 0 to 24. The higher the ESS score, the higher that person's average sleep propensity in daily life, or their 'daytime sleepiness'.
4. Change from baseline to Day 28 in Portosystemic Hepatic Encephalopathy Score (PHES) total score (part B)
The PHES is composed of five sub-tests, number connection test-A (NCT-A), number connection test-B (NCT-B), serial dotting test (SDT), line tracing test (LTT) and digit symbol test (DST). PHES assesses motor speed, motor accuracy, concentration, attention, visual perception, visual-spatial orientation, visual construction, and memory.
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