A Two-part Study to Investigate the Effects in Adults of Two Doses of Golexanolone in Patients With Primary Biliary Cholangitis (PBC) With Fatigue and Cognitive Dysfunction

Official title

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

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).

Interventions

• Drug golexanolone
  soft gelatin capsules, oral dosage twice per day for up to 28 days
• Drug golexanolone
  soft gelatin capsules, oral dosage twice a day for up to 28 days
• Drug Placebo
  soft gelatin capsules, oral dosage twice a day for up to 28 days
• Drug golexanolone
  soft gelatin capsules, oral dosage twice per day for 5 days
• Drug Placebo
  soft gelatin capsules, oral dosage twice per day for 5 days

Primary outcome measures

• 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 5 (part A) [Time frame: From Baseline to Day 5]

Secondary outcome measures (8)

• 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) [Time frame: From baseline to Day 28]
• 2. Change from baseline to Day 28 in EQ-5D-3L tool (part B) [Time frame: 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) [Time frame: From baseline to Day 28]
• 4. Change from baseline to Day 28 in Portosystemic Hepatic Encephalopathy Score (PHES) total score (part B) [Time frame: From baseline to Day 28]
• 5. Change from baseline to Day 28 in Rey Auditory Verbal Learning test (RAVLT) (part B) [Time frame: 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) [Time frame: 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) [Time frame: 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) [Time frame: At Day 1, 14 and 28]

Eligibility criteria

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
• The subject should be judged by the Investigator to be lucid and oriented to person, place, time, and situation when giving the 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)
• Concomitant disease characterised by chronic fatigue and/or cognitive impairment
• Clinically significant bowel disease, including obstruction, active inflammatory bowel disease, or malabsorption
• Clinically significant sleep apnoea
• An uncontrolled thyroid disorder
• Subjects with a history of or currently active immune disorders (i.e. uncontrolled) other that PBC (including autoimmune disease) and/or diseases requiring immunosuppressive drugs
• Clinical diagnosis of autoimmune hepatitis overlap
• 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
• Regular use of prescribed or over the counter (OTC) medications known to cause fatigue or cognitive dysfunction
• Use of prohibited medications within 14 days prior to randomisation
• Anticipated change in PBC medication and/or significant medical or surgical intervention within the duration of the study
• Regular (more than 1 week per month) alcohol consumption in excess of 14 units per week
• Administration of another new chemical entity or has participated in any other clinical study that included drug treatment with the last administration within 3 months prior to administration of IMP in this study
• Females who are pregnant, nursing or actively trying to conceive a child
• Expected inability to swallow the required number of IMP capsules at the applicable dose level
• History of severe allergy/hypersensitivity or on-going allergy/hypersensitivity, as judged by the Investigator

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Spain · 9 centers

• Hospital Universitario Parc Taulí — Barcelona
• Hospital Clinic Barcelona — Barcelona
• Hospital General Universitario Gregorio Marañón — Madrid
• Hospital 12th October, Madrid — Madrid
• Hospital Universitario Virgen De La Victoria — Málaga
• University Hospital Complex of Pontevedra & IIS Galicia South, Pontevedra — Pontevedra
• University Hospital Marquez de Valdecilla, Santander — Santander
• Virgen del Rocio University Hospital — Seville
• … and 1 more center

United Kingdom · 9 centers

• NIHR Birmingham BRC — Birmingham
• Glasgow Royal Infirmary — Glasgow
• Royal Free London NHS Foundation Trust — London
• Guy's and St Thomas' Hospital, London — London
• Freeman Hospital — Newcastle
• Nottingham Digestive Diseases Centre and Biomedical Research Centre Nottingham University — Nottingham
• Oxford University Hospitals NHS Foundation Trust — Oxford
• Dept of Gastroenterology & Hepatology Portsmouth Hospitals University NHS Trust Queen Alex — Portsmouth
• … and 1 more center

Turkey (Türkiye) · 8 centers

• Hacettepe University, Fakulty of Medicine, Department of Gastroenterology and Hepatology — Ankara
• 9 Eylul University Research and Application Hospital Department of Gastroenterology — Balçova
• Dicle University Faculty of Medicine Department of Gastroenterology — Diyarbakır
• Ege University Faculty of Medicine, Department of Gastroenterology — Izmir
• Kocaeli University Faculty of Medicine Gastroenterology and Hepatology Department — Kocaeli
• Recep Tayyip Erdoğan University Training and Research Hospital, Department of Gastroentero — Rize
• Harran Üniversitesi Osmanbey Campus Department of Gastroenterology — Sanliurfa
• Karadeniz Technical University, Farabi Hospital, Department of Gastroenterology — Trabzon

Italy · 7 centers

• Università di Milano-Bicocca, S.C. ASST Grande Ospedale Metropolitano Niguarda, Dipartimen — Milan
• Fondazione IRCCS San Gerardo dei Tintori, Autoimmune Liver Disease Centre, ERN-Rare Liver, — Monza
• University of Padova, Department of Surgery, Oncology and Gastroenterology — Padova
• University Hospital Paolo Giaccone, University of Palermo — Palermo
• A. Gemelli Polyclinic, Sacro Cuore Catholic University — Roma
• Humanitas University — Rozzano
• University of Udine — Udine

Germany · 2 centers

• University Hospital Düsseldorf — Düsseldorf
• University of Leipzig — Leipzig

Greece · 2 centers

• Hippokration General Hospital of Athens — Athens
• University Hospital of Patras — Pátrai

Hungary · 2 centers

• Bekes County Central Hospital — Gyula
• Facility of CRU Hungary Ltd. — Kistarcsa

Serbia · 1 center

• University Medical Center "Zvezdara" — Belgrade

Identifiers

NCT: NCT07304843 · UCAB-CT-05 · 2024-515907-20-00 · IRAS ID 1003871 · 515-04-27580-22-1 · E-66175679-514.02.02-1264666

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗