A Randomised, Double-blind, Placebo-controlled, Two-part Study to Evaluate the Pharmacokinetics, Safety and Tolerability, and Preliminary Efficacy of Two Dose Levels of Golexanolone in Subjects With Primary Biliary Cholangitis (PBC), Fatigue, and Cognitive Dysfunction
Overview
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- Umecrine Cognition AB
- Enrollment
- 84
- Locations
- 36
- Primary Endpoint
- 1. Frequency, intensity, and seriousness of adverse events (AEs) from baseline to Day 28 (part B)
Overview
Brief Summary
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).
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description
Double-blind
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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
- •Stable PBC SoC therapy (if any),for at least 3 months prior to randomisation
- •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
- •WOCBP must be willing to use a contraceptive method with a failure rate of \< 1% and agree to continue use of this method for the duration of the study and thereafter for 1 month after the last dosing of the IMP
- •Females of non-childbearing potential must have documented tubal ligation or hysterectomy; or be post-menopausal
- •Fertile male subjects must be willing to use condom and assure that their female partner will use contraceptive methods with a failure rate of \< 1%
- •Willing and able to give informed consent
Exclusion Criteria
- •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
- •Glomerular filtration rate (GFR) \<35 mL/min/1.73m2
- •Low Haemoglobin (HB), i.e. subjects with moderate/severe anaemia
- •Low S-B12 or low P-folate
- •Evidence of biliary obstruction
- •Any positive result on screening for human immunodeficiency virus (HIV), or hepatitis B (serum hepatitis B surface antigen positive)
- •Prolonged QTcF (\>500 ms), or any clinically significant abnormality in the resting ECG, as judged by the Investigator (at screening)
Arms & Interventions
Part B: Treatment arm 1 (golexanolone 40 mg)
40 mg golexanolone BID
Intervention: golexanolone (Drug)
Part B: Treatment arm 2 (golexanolone 80 mg)
80 mg golexanolone BID
Intervention: golexanolone (Drug)
Placebo
Part B: Placebo BID
Intervention: Placebo (Drug)
Part A: Golexanolone
40 mg golexanolone BID
Intervention: golexanolone (Drug)
Part A: Placebo
Placebo BID
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
1. Frequency, intensity, and seriousness of adverse events (AEs) from baseline to Day 28 (part B)
Time Frame: From enrollment to the end of treatment at 28 days
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)
Time Frame: From Baseline to Day 5
Frequency, intensity, and seriousness of adverse events (AEs)
Secondary Outcomes
- 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)(From baseline to Day 28)
- 2. Change from baseline to Day 28 in EQ-5D-3L tool (part B)(From baseline to Day 28)
- 3. Change from baseline to Day 28 in daytime sleepiness related symptoms using the Epworth Sleepiness Scale (ESS) (part B)(From baseline to Day 28)
- 4. Change from baseline to Day 28 in Portosystemic Hepatic Encephalopathy Score (PHES) total score (part B)(From baseline to Day 28)
- 5. Change from baseline to Day 28 in Rey Auditory Verbal Learning test (RAVLT) (part B)(From baseline to Day 28)
- 6. Change from baseline to Day 28 in Delis and Kaplan Executive Function System (D-KEFS) Letter and Category fluency subtests (part B)(From baseline to Day 28)
- 7. To evaluate the Investigator's overall impression of treatment effect by Clinical Global Impression of change, PBC version (CGI-C-PBC) from baseline to Day 28 (part B)(From baseline to Day 28)
- 8. To assess the exposure of two dose levels of golexanolone in the target population treated for 28 days (part B)(At Day 1, 14 and 28)