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.

Prior treatment

• Concomitant disease characterised by chronic fatigue and/or cognitive impairment (e.g. Alzheimer's, Parkinson's, etc.) which in the judgement of the Investigator would either limit the potential benefit to the subject and/or confound the interpretation of results.
• 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, such as major psychiatric disorder and major depressive disorder formally diagnosed by a psychiatrist.
• Regular use of prescribed or over the counter (OTC) medications known to cause fatigue or cognitive dysfunction. Approval by the Medical Monitor is required if a subject takes any drug known to cause fatigue or alter cognitive functioning. Examples include benzodiazepines, sedating antihistamines (first generation), anticonvulsants, sedating antidepressants (e.g. tricyclic and sedating heterocyclic antidepressants), anticholinergics (benztropine), antiparkinsonian medications (amantadine, selegiline, benztropine), psychostimulants, narcotic medications within 4 weeks prior to baseline. The purpose is to assure that any change observed in cognition can be associated with study drug and not any concomitant medication.
• Clinical evidence of hepatic decompensation (e.g. current or prior HE, ascites, or variceal bleeding).
• Use of prohibited medications within 14 days prior to randomisation, as specified in Section 9.4.8.2.
• Anticipated change in PBC medication and/or significant medical or surgical intervention within the duration of the study.
• Administration of another new chemical entity (defined as a compound that has not been approved for marketing) 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.
• History of severe allergy/hypersensitivity or on-going allergy/hypersensitivity, as judged by the Investigator. Known allergy or hypersensitivity to drugs with a similar chemical structure or class to golexanolone, i.e. GABAA receptor modulating steroid antagonists (GAMSA). Known allergy of or hypersensitivity to any other component of the investigational drug (i.e. glyceryl mono and dicaprylocaprate).

Other illness

• Clinically significant bowel disease, including obstruction, active inflammatory bowel disease, or malabsorption.
• Subjects with a history of or currently active immune disorders other that PBC (including autoimmune disease) and/or diseases requiring immunosuppressive drugs (including azathioprine, prednisone, prednisolone, budesonide, cyclosporine, tacrolimus, methotrexate, or mycophenolate mofetil).
• Clinical diagnosis of autoimmune hepatitis overlap defined using the Paris overlap criteria
• History of hepatocellular carcinoma.

Lab values

• An uncontrolled thyroid disorder: a. Uncontrolled hyperthyroidism: defined as any history of hyperthyroidism that has either not been treated with either radioactive iodine and/or surgery or that has been treated with radioactive iodine and/or surgery but has required ongoing continuous or intermittent use of thyroid hormone synthesis inhibitors (i.e. methimazole or propylthiouracil) in the 24 weeks before screening. b. Uncontrolled hypothyroidism: defined as initiation of thyroid hormone replacement therapy or dose adjustment of replacement therapy in the 12 weeks before screening. c. Subjects without a diagnosed thyroid disease should be excluded if thyroid-stimulating hormone (TSH)-value is above ULN, or/and if free triiodothyronine (FT3)- or free thyroxine (FT4)-values are outside normal limits.
• Bilirubin >1.5 x ULN.
• Glomerular filtration rate (GFR) <35 ml/min/1.73m2 estimated using the CKD-EPI equation.
• Haemoglobin (HB) <110 g/L, i.e. subjects with moderate/severe anaemia.
• Any positive result on screening for human immunodeficiency virus (HIV), or hepatitis B (serum hepatitis B surface antigen positive). Subjects positive for HCV antibodies should be tested for PCR HCV RNA and in case of positive result considered as not eligible.

Other

• Child-Pugh class B or C cirrhosis.
• Prolonged QTcF (>500 ms), or any clinically significant abnormality in the resting ECG, as judged by the Investigator (at screening).
• Poorly controlled obstructive sleep apnoea, as defined by >5 episodes/hour more than 70% of occasions, despite use of continuous positive airway pressure (CPAP).
• Criterion deleted but numbering unchanged.
• Regular (more than 1 week per month) alcohol consumption in excess of 14 units per week.
• 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.
• Investigator considers the subject unlikely to comply with study procedures, restrictions, and requirements.
• S-B12 < 125 pmol/L or P-folate < 7 nmol/L.
• Evidence of biliary obstruction.

• Male and female subjects age ≥ 18 years.
• 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.
• Diagnosis of PBC based on the presence of ≥2 of the 3 key disease characteristics: a. Anti-mitochondrial antibody or PBC-specific anti-nuclear antibody titre ≥1/40 b. Elevated alkaline phosphatase (ALP) (> upper limit of normal [ULN] for the relevant laboratory) c. Compatible or diagnostic liver biopsy
• 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), which may include UDCA, OCA, bezafibrate and/or fenofibrate, 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 will be required.
• WOCBP must be willing to use a contraceptive method with a failure rate of < 1% (intrauterine device [IUD], intrauterine hormone-releasing system [IUS], transdermal or local hormonal contraception, bilateral tubal occlusion, vasectomised partner, sexual abstinence), 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. Note that IUS, transdermal (e.g. patches, gels and sprays) or local (e.g. vaginal tablets, gels, creams, rings, suppositories) administration of oestrogen or progesterone are the only hormonal contraceptive methods allowed due to possible interactions with the IMP.
• Females of non-childbearing potential must have documented tubal ligation or hysterectomy; or be post-menopausal (defined as 12 months of amenorrhoea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) 25-140 IE/L and oestradiol <200 pmol/L is confirmatory]).
• 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%1 to prevent pregnancy and drug exposure of a fertile female partner and refrain from donating sperm from the date of dosing until 1 month after dosing of the IMP. Men who are surgically sterile may be included without they/their partner fulfilling the above criteria on birth control.