A two-part study to investigate the effects in adults of two doses of golexanolone in patients with primary biliary cholangitis with fatigue and cognitive dysfunction

ISRCTN	ISRCTN67592622
DOI	https://doi.org/10.1186/ISRCTN67592622
Clinical Trials Information System (CTIS)	2024-515907-20-00
Integrated Research Application System (IRAS)	1003871
Protocol serial number	UCAB-CT-05
Sponsor	Umecrine Cognition AB
Funder	Umecrine Cognition AB

Submission date: 01/12/2025
Registration date: 09/12/2025
Last edited: 09/12/2025

Recruitment status: Recruiting
Overall study status: Ongoing
Condition category: Digestive System

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
Primary biliary cholangitis (PBC) is a serious chronic liver disease that harms the liver’s ability to function. Patients with PBC can experience cognitive dysfunction: inability to think, learn and remember clearly. Also, they experience significant fatigue (tiredness).

The active investigational medicinal product - golexanolone – is a new drug that was developed for the treatment of the spectrum of cognitive dysfunction associated with chronic liver disease. Based on research in animals and patients with cirrhosis, it is assumed that golexanolone may offer normalization of cognitive dysfunction and fatigue in patients with PBC.

The present study has been designed to evaluate how safe and well-tolerated golexanolone is, how golexanolone is absorbed, modified, and removed from the body, and to evaluate the effects of golexanolone on PBC symptoms. The effects of golexanolone will be compared with a placebo (inactive substance).

Who can participate?
Adult patients who are diagnosed with PBC, fatigue and cognitive dysfunction and who meet all the specified criteria for the study, according to the doctor.

What does the study involve?
The study is divided into two parts, Part A and Part B.

In Part A (completed), participants who qualified were randomly assigned in a 3:1 ratio to receive either golexanolone 40 mg or a placebo orally twice daily for 5 days at the clinic.

In Part B, participants who qualify will be randomly assigned in a 1:1:1 ratio to receive either golexanolone 40 mg or golexanolone 80 mg or placebo orally twice daily for 28 days. Previously prescribed PBC therapy will be allowed as long as it is stable during the study.

The total duration of part B for a participant will be a maximum of 8 weeks (± 3 days), with 5 visits to a clinic and 2 phone calls.

The following examinations, tests and procedures are planned to be done during different periods of the study:
- Collection of basic information regarding age, gender, race, and ethnic origin, medical history and PBC treatment history, as well as medications currently being taken, including vitamins and supplements, and any recent changes to medications.
- Physical examination will be done.
- Blood and urine samples will be collected for analysis.
- Questions about their current health condition will be asked.
- Questionnaires about overall health, fatigue, anxiety, mental well-being, sleep, and sleepiness are to be completed. One of the questionnaires, called the Clinical Global Impression Scale, requires a 30-45-minute interview with an independent, qualified clinician who does not belong to the study team. The interview will be conducted at Visit 2 and Visit 6 in the local language as a video call. This interview will be organised by the company working on behalf of the Sponsor, called Signant Health. The study doctor will schedule and organise it for you at the study centre. The clinician will ask questions, make notes, and the interview will be video-recorded. Notes are needed to assess changes in the condition during the second interview and might also be used for quality control. Video recordings will be used by a second independent clinician to make sure that all assessments are made correctly. The second clinician also doesn’t belong to the study team.
- Cognitive tests (such as recall words or say words) will be conducted.
- Each participant will be asked to record the date and time of study drug self-administration and recording of changes in medications and medical events occurring between visits in the Participant’s Diary.

What are the possible benefits and risks of participating?
There may or may not be direct medical benefits from taking part in this study. Based on research in animals and patients with cirrhosis, it is assumed that golexanolone may offer normalisation of cognitive dysfunction and fatigue in patients with PBC. There is no guarantee, however, that the study drug will have an influence on the disease.
If the participant receives a placebo, there are no medical benefits.

The participation in this study will contribute to increasing information that may help treat patients with PBC and may contribute to improvements in medicine in general.

Where is the study run from?
This study is organised by Umecrine Cognition AB (the “Sponsor” of the study) from Sweden. Hospitals in several countries (the United Kingdom, Germany, Hungary, Italy, Spain, Serbia and Turkey) are involved in the study.

When is the study starting and how long is it expected to run for?
April 2023 to June 2026.

Who is funding the study?
Umecrine Cognition AB, Sweden.

Who is the main contact?
Dr David Jones, david.jones@newcastle.ac.uk.

Contact information

Ms Pernilla Sandwall
Scientific, Public

Nanna Svartz Väg 6A
Solna
171 65
Sweden

Phone	+46 70 630 65 19
Email	pernilla.sandwall@umecrine.se

Dr David Jones
Principal investigator

Freeman Road, High Heaton
Newcastle
NE7 7DN
United Kingdom

Phone	+44 1912 137 210
Email	david.jones@newcastle.ac.uk

Study information

Primary study design	Interventional
Allocation	Randomized controlled trial
Masking	Blinded (masking used)
Control	Placebo
Assignment	Parallel
Purpose	Treatment
Scientific 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, fatigue, and cognitive dysfunction
Study objectives	Part A: Primary objective is 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. Secondary objectives is to assess the PK characteristics of golexanolone administered 40 mg BID for 5 days in the target population, and to investigate the metabolite profile of golexanolone in human plasma and urine. Part B: The primary objective is 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 objectives include assessment of: effects of golexanolone on health-related quality of life (HRQoL), including fatigue, effects of golexanolone on day-time sleepiness, effects of golexanolone on cognitive function, evaluation of the Investigator’s overall impression of treatment effect, and the exposure of two dose levels of golexanolone in the target population treated for 28 days.
Ethics approval(s)	1. Approved 12/10/2022, East Midlands – Leicester Central Research Ethics Committee (2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 02071048066; leicestercentral.rec@hra.nhs.uk), ref: 22/EM/0196 2. Approved 08/11/2023, CET (Comitato Etico Territoriale [Territorial Ethics Committee]) Lombardia 5 (Via Manzoni 56, Milan, 20089, Italy; 0882247216; comitato.etico@humanitas.it), ref: 25/23 3. Approved 21/04/2023, Hellenic Republic Ministry of Health National Ethics Committee (284 Mesogeion Ave., Cholargos, 155 62, Greece; 213-2040259; eed@eof.gr), ref: 5/23 4. Approved 16/02/2023, Ethics Committee of the Hamburg Medical Association (Weidestraße 122 b, Hamburg, 22083, Germany; 040/202299-240; ethik@aekhh.de), ref: 2022-100928-AMG-ff 5. Approved 28/06/2022, Medical Research Council Ethics Committee for Clinical Pharmacology (ETT-KFEB) (Báthory str. 10, Budapest, 1054, Hungary; (+36 1) 795 1192; kfebtitkarsag@emmi.gov.hu), ref: IV/4297-0/2022-EKL 6. Approved 28/02/2023, Drug Research Ethics Committee (Comité de Ética de Investigacón de Investigación con Medicamentos) (Hospital 12 de Octubre, Avda. de Córdoba, s/n 28041, Madrid, Spain, Madrid, 28041, Spain; +34 91 779 28 39; info.imas12@h12o.es), ref: 22/603 7. Approved 28/03/2023, Ethical Board of Serbia (11221 Belgrade, 458 Vojvode Stepe Str., Belgrade, 458, Serbia; +381113951131; hygia@alims.gov.rs), ref: 515-20-27325-22-003 8. Approved 25/07/2023, Hacetiepe Oniversitesi Klinik Ara~tirmalar Etik Kurulu (06100 Altmdag, Ankara, 06100, Türkiye; 0312 305 34 98; kliniketik@hacettepe.edu.tr), ref: 2023/13-02(KA-22108)
Health condition(s) or problem(s) studied	Patients with primary biliary cholangitis with fatigue and cognitive dysfunction
Intervention	This is a multicenter interventional randomised, double-blind, placebo-controlled, two-part Phase Ib/2a study Part A: Subjects are randomised using an online tool to either active treatment for 5 days (40 mg golexanolone bid) or placebo bid for 5 days (randomised 6:2) Part B: Subjects are randomised using an online tool to either active treatment (40 mg golexanolone bid) or active treatment (80 mg golexanolone bid) or placebo bid for 28 days (randomised 1:1:1)
Intervention type	Drug
Phase	Phase I/II
Drug / device / biological / vaccine name(s)	Golexanolone
Primary outcome measure(s)	Part A: 1. Frequency, intensity, and seriousness of adverse events (AEs) recorded from baseline to Day 5 2. Changes from baseline to Day 5 in safety laboratory parameters (blood samples for analysis of clinical chemistry, haematology, and coagulation parameters, urine dipstick) 3. Changes from baseline to Day 5 in clinical safety parameters: 3.1. Physical examination, including assessments of the lungs, cardiovascular, and abdomen 3.2. Vital signs: systolic and diastolic blood pressure, pulse and body temperature 3.3. Electrocardiogram (12-lead ECG) 3.4. Hospital Anxiety and Depression Scale (HADS), to screen anxious and depressive states Part B: 1. Frequency, intensity, and seriousness of adverse events (AEs) recorded from baseline to Day 28 2. Changes from baseline to Day 28 in safety laboratory parameters (blood samples for analysis of clinical chemistry, haematology, and coagulation parameters, urine dipstick) 3. Changes from baseline to Day 28 in clinical safety parameters: 3.1. Physical examination, including assessments of the lungs, cardiovascular, and abdomen 3.2. Vital signs: systolic and diastolic blood pressure, pulse and body temperature 3.3. Electrocardiogram (12-lead ECG) 3.4. Hospital Anxiety and Depression Scale (HADS), to screen anxious and depressive states
Key secondary outcome measure(s)	Part A: 1. The pharmacokinetic (PK) characteristics of golexanolone administered 40 mg BID for 5 days in the target population (baseline to Day 5): 1.1. After the first dose: area under the plasma concentration time curve (AUC) 0-24 h, 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) 1.2. After the last dose: AUC at steady state (AUCss), Cmax and Cmin at steady state (Cmax, ss and Cmin, ss), Tmax, % fluctuation, lambdaz, T1/2, CL/F, Vz/ F 1.3. Accumulation ratio between first and last dose 2. Metabolite profile in human plasma and urine Part B: 1. Change from baseline to Day 28 in PBC-40 scores for each of the domains (cognition, itch, fatigue, social, emotional, and general symptoms) 2. Change from baseline to Day 28 in health status measured using EQ-5D-3L 3. Change from baseline to Day 28 in daytime sleepiness related symptoms assessed using the Epworth Sleepiness Scale (ESS) 4. Change from baseline to Day 28 in Portosystemic Hepatic Encephalopathy Score (PHES) total score 5. Change from baseline to Day 28 in Rey Auditory Verbal Learning Test (RAVLT) 6. Change from baseline to Day 28 in Delis and Kaplan Executive Function System (D-KEFS) Letter and Category fluency subtests 7. The Investigator’s overall impression of treatment effect evaluated by Clinical Global Impression of Change, PBC version (CGI-C-PBC) from baseline to Day 28 8. The exposure of two dose levels of golexanolone in the target population treated for 28 days. The lowest plasma concentration before the next dose (Ctrough) assessed pre-dose on Days 1, 14, and 28.
Completion date	30/06/2026

Eligibility

Participant type(s)	Patient
Age group	Mixed
Lower age limit	18 Years
Upper age limit	120 Years
Sex	All
Target sample size at registration	100
Key inclusion criteria	1. Male and female subjects age ≥18 years 2. Diagnosis of PBC based on the presence of ≥2 of 3 key disease characteristics 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 (if any),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 7. 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 8. Females of non-childbearing potential must have documented tubal ligation or hysterectomy; or be post-menopausal 9. 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% 10. Willing and able to give informed consent 11. The subject should be judged by the Investigator to be lucid and oriented to person, place, time, and situation when giving the informed consent
Key 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) <35 mL/min/1.73m2 6. Low Haemoglobin (HB), i.e. subjects with moderate/severe anaemia 7. Low S-B12 or low P-folate 8. Evidence of biliary obstruction 9. Any positive result on screening for human immunodeficiency virus (HIV), or hepatitis B (serum hepatitis B surface antigen positive) 10. Prolonged QTcF (>500 ms), 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 12. Clinically significant bowel disease, including obstruction, active inflammatory bowel disease, or malabsorption 13. Clinically significant sleep apnoea 14. An uncontrolled thyroid disorder 15. 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 16. Clinical diagnosis of autoimmune hepatitis overlap 17. 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 18. Regular use of prescribed or over the counter (OTC) medications known to cause fatigue or cognitive dysfunction 19. Use of prohibited medications within 14 days prior to randomisation 20. Anticipated change in PBC medication and/or significant medical or surgical intervention within the duration of the study 21. Regular (more than 1 week per month) alcohol consumption in excess of 14 units per week 22. 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 23. Females who are pregnant, nursing or actively trying to conceive a child 24. Expected inability to swallow the required number of IMP capsules at the applicable dose level 25. History of severe allergy/hypersensitivity or on-going allergy/hypersensitivity, as judged by the Investigator
Date of first enrolment	14/04/2023
Date of final enrolment	31/03/2026

Locations

Countries of recruitment

United Kingdom
England
Northern Ireland
Scotland
Germany
Greece
Hungary
Italy
Serbia
Spain
Türkiye

Study participating centres

The Newcastle upon Tyne Hospitals NHS Foundation Trust

Freeman Hospital
Freeman Road
High Heaton
Newcastle upon Tyne
NE7 7DN
England

Nottingham University Hospitals NHS Trust - Queen's Medical Centre Campus

Nottingham University Hospital
Derby Road
Nottingham
NG7 2UH
England

Portsmouth Hospitals University NHS Trust

Queen Alexandra Hospital
Southwick Hill Road
Cosham
Portsmouth
PO6 3LY
England

Royal Free London NHS Foundation Trust

Royal Free Hospital
Pond Street
London
NW3 2QG
England

The Royal Wolverhampton NHS Trust

New Cross Hospital
Research and Development
Wolverhampton Road
West Midlands
Wolverhampton
WV10 OQP
England

NIHR Birmingham BRC

Mindelsohn Way
Birmingham
B15 2TT
England

Glasgow Royal Infirmary

84 Castle Street
Glasgow
G4 0SF
Scotland

Guy's and St Thomas' Hospital, London

Westminster Bridge Road
London
SE1 7EH
England

Oxford University Hospitals NHS Foundation Trust - Octave Duo Covid19 Trials

Headley Way
Headington
Oxford
OX3 9DU
England

University Hospital Düsseldorf

Moorenstreet 5
Düsseldorf
40225
Germany

University of Leipzig

Liebigstreet 20
Leipzig
04103
Germany

University Hospital of Patras

Department of Gastroenterology and Hepatology
Patras
26504
Greece

Hippokration General Hospital of Athens

114 Vasilissis Sofias Avenue
Athens
11527
Greece

Bekes County Central Hospital

Semmelweis street 1
Gyula
5700
Hungary

Facility of CRU Hungary Ltd.

Semmelweis ter 1
Kistarcsa
2143
Hungary

University of Padova, Department of Surgery, Oncology and Gastroenterology

Via Giustiniani 2
Padova
35128
Italy

A. Gemelli Polyclinic, Sacro Cuore Catholic University

Largo Gemelli 8
Rome
168
Italy

Humanitas University

Via A. Manzoni 56
Rozzano
20089
Italy

University Hospital Paolo Giaccone, University of Palermo

Piazza delle Cliniche 2
Palermo
90127
Italy

University of Udine

P.zale S.M. della Miseicordia 1
Udine
33100
Italy

University Medical Center "Zvezdara"

Dimitrija Tucovica 161
Belgrade
11000
Serbia

Hospital 12th October, Madrid

Avda. de Córdoba s/n.
Madrid
28041
Spain

Hospital Clinic Barcelona

C. Villarroel, 170
Barcelona
8036
Spain

Virgen del Rocio University Hospital

Adv.. Manuel Suirot S/N
Sevilla
41013
Spain

University Hospital Marquez de Valdecilla, Santander

Av. Valldecilla s/n
Santander
39008
Spain

University Hospital Complex of Pontevedra & IIS Galicia South, Pontevedra

Calle Mourente S/N
Pontevedra
36071
Spain

Hospital Universitario Parc Taulí

Parc Tauli, 1, Sabadell
Barcelona
08208
Spain

Hacettepe University, Fakulty of Medicine, Department of Gastroenterology and Hepatology

Hacettepe Mah.
Ankara
06230
Türkiye

Ege University Faculty of Medicine, Department of Gastroenterology

Kazımdirik, Üniversite Cd. No:9
Izmir
35100
Türkiye

Kocaeli University Faculty of Medicine Gastroenterology and Hepatology Department

Kabaoğlu, Old Istanbul Road 10th Km. Umuttepe Campus, İzmit
Kocaeli
41100
Türkiye

Dicle University Faculty of Medicine Department of Gastroenterology

Kıtılbıl Mah. Dicle University, Sur/Diyarbakır
Diyarbakır
21280
Türkiye

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Published as a supplement to the results publication
IPD sharing plan	Study data will be available publicly, through publication in peer reviewed scientific journals, conference presentation and publication on website.

Editorial Notes

01/12/2025: Study's existence confirmed by Health Research Authority (HRA) (UK)