Patients with primary biliary cholangitis with fatigue and cognitive dysfunction Digestive System
Conditions
Interventions
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 da
Sponsors
Umecrine Cognition AB
Eligibility
Sex/Gender
All
Age
18 Years to 120 Years
Inclusion criteria
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
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), 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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 | — |
Secondary
| Measure | Time frame |
|---|---|
| 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. | — |
Countries
England, Germany, Greece, Hungary, Italy, Northern Ireland, Scotland, Serbia, Spain, Türkiye, United Kingdom
Contacts
Public ContactPernilla Sandwall
Outcome results
None listed