Evaluation of Pharmacokinetics, Safety, and Efficacy of Golexanolone in Primary Biliary Cholangitis Patients with Fatigue and Cognitive Dysfunction

Trial ID: 2024-515907-20-00
Protocol: UCAB-CT-05
Sponsor: Umecrine Cognition AB

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Diseases & Conditions

Primary biliary cholangitis

Objectives

The primary objective of this study is to evaluate the **safety** and **tolerability** of golexanolone in subjects with **primary biliary cholangitis** (PBC) who exhibit clinically significant fatigue and cognitive symptoms. Part A focuses on the administration of 40 mg golexanolone twice daily (BID) for 5 days in non-cirrhotic or Child-Pugh class A cirrhotic PBC subjects. Part B extends the assessment to a 28-day BID treatment with two dose levels of golexanolone in a similar patient population. This evaluation is clinically relevant as it aims to determine the potential of golexanolone to manage symptoms associated with PBC, a chronic liver disease, thereby improving patient outcomes.

Secondary objectives include:

Part A: Assessing the pharmacokinetic (PK) characteristics of golexanolone and investigating its metabolite profile in human plasma and urine.
Part B: Evaluating the effects of golexanolone on health-related quality of life (HRQoL), including fatigue, day-time sleepiness, and cognitive function. Additionally, the study will assess the exposure of two dose levels of golexanolone over 28 days and the Investigator's overall impression of treatment effect.

These secondary objectives are crucial for understanding the broader impact of golexanolone on patient health and its potential therapeutic benefits beyond safety and tolerability.

Participants

The clinical trial involves a total of **66 participants** diagnosed with **primary biliary cholangitis (PBC)**. The study population includes both male and female subjects aged between 18 and 75 years. Participants are either non-cirrhotic or classified as Child-Pugh class A cirrhotic, with clinically significant fatigue and cognitive symptoms. The selection criteria required participants to have a stable PBC standard of care therapy, if applicable, for at least three months prior to randomization. The trial includes individuals who are willing and able to provide informed consent and are judged to be lucid and oriented. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to specific contraceptive measures if of childbearing potential. The trial does not focus on any particular vulnerable population, although it includes both genders and a wide age range. The sponsor has not provided additional information regarding lifestyle or health status beyond the inclusion criteria.

Plans and Procedures

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the pharmacokinetics, safety, tolerability, and preliminary efficacy of two dose levels of **golexanolone** in subjects with **primary biliary cholangitis** (PBC), fatigue, and cognitive dysfunction. The trial is divided into two parts: Part A and Part B. Part A involves assessing the safety and tolerability of a 40 mg dose of golexanolone administered twice daily (BID) for 5 days, while Part B evaluates the safety and tolerability of two dose levels of golexanolone over a 28-day BID treatment period. The trial is expected to conclude by September 30, 2025, with recruitment having commenced on October 25, 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, informed consent, and diagnosis of PBC. The screening will also assess clinically significant fatigue and cognitive symptoms using the PBC-40 fatigue and cognitive domain scores. Following randomization, participants will attend follow-up visits to monitor safety and efficacy parameters, including adverse events, laboratory parameters, and clinical safety assessments. The end-of-study visit will conclude the participant's involvement, with assessments to evaluate changes from baseline in health-related quality of life measures and cognitive tests.

The expected length of participant involvement varies between the two parts of the study. Part A participants will be involved for approximately 5 days, while Part B participants will be involved for 28 days. Conditions that may lead to early termination from the study include the occurrence of serious adverse events or significant deviations from the study protocol. The trial aims to ensure the safety and well-being of participants while gathering valuable data on the effects of golexanolone in treating PBC-related symptoms.

Treatment

The clinical trial involves the administration of **GR3027**, an experimental medication containing the active substance **golexanolone**. This medication is provided in the form of oral capsules, each containing 10 mg of golexanolone. The pharmaceutical form is a capsule, and the route of administration is oral. Participants in the trial will receive the medication twice daily (BID) for a specified duration, depending on the part of the study they are enrolled in. In Part A, the treatment duration is 5 days, while in Part B, it extends to 28 days. The primary objective is to assess the safety and tolerability of the treatment in subjects with primary biliary cholangitis (PBC) who exhibit clinically significant fatigue and cognitive symptoms. Compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol.

In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, placebo-controlled study. The placebo is formulated as soft oral capsules, designed to match the appearance of the GR3027 capsules, ensuring blinding of both participants and investigators. The placebo capsules are administered orally with the same frequency and duration as the experimental medication, either for 5 days in Part A or 28 days in Part B. The use of a placebo allows for the evaluation of the pharmacokinetics, safety, tolerability, and preliminary efficacy of golexanolone by providing a baseline for comparison. Participant compliance with the placebo regimen will also be monitored to maintain the integrity of the study results.

Efficacy

The clinical trial aims to evaluate the preliminary efficacy of two dose levels of **golexanolone** in subjects with primary biliary cholangitis (PBC), fatigue, and cognitive dysfunction. Efficacy will be assessed through several secondary endpoints, particularly in Part B of the study. These include changes from baseline to Day 28 in health-related quality of life (HRQoL) measures using the PBC-40 scores across various domains such as cognition, itch, fatigue, social, emotional, and general symptoms. Additionally, the EQ-5D-3L tool will be utilized to further evaluate HRQoL.

Daytime sleepiness-related symptoms will be measured using the Epworth Sleepiness Scale (ESS), and cognitive function will be assessed through a battery of tests, including the Portosystemic Hepatic Encephalopathy Score (PHES) total score, the Rey Auditory Verbal Learning test (RAVLT), and the Delis and Kaplan Executive Function System (D-KEFS) Letter and Category fluency subtests. The Clinical Global Impression of change, PBC version (CGI-C-PBC), will also be used to evaluate overall clinical change. Pharmacokinetic parameters, such as the lowest plasma concentration before the next dose (Ctrough), will be assessed pre-dose on Days 1, 7, 14, and 28 to support the efficacy evaluation.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male and female subjects age ≥ 18 years.
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.
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.

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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 estimated using the CKD-EPI equation.
Haemoglobin (HB) <110 g/L, i.e. subjects with moderate/severe anaemia.
S-B12 < 125 pmol/L or P-folate < 7 nmol/L.
Evidence of biliary obstruction.
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.
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 (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.
Clinically significant bowel disease, including obstruction, active inflammatory bowel disease, or malabsorption.
Poorly controlled obstructive sleep apnoea, as defined by >5 episodes/hour more than 70% of occasions, despite use of continuous positive airway pressure (CPAP).
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.
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
Criterion deleted but numbering unchanged.
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.
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.
Regular (more than 1 week per month) alcohol consumption in excess of 14 units per week.
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.
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. 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).
Investigator considers the subject unlikely to comply with study procedures, restrictions, and requirements.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Germany	Not Recruiting	25 Oct 2022	13
Greece	Not Recruiting	25 Oct 2022	20
Hungary	Not Recruiting	25 Oct 2022	18
Italy	Not Recruiting	25 Oct 2022	40
Spain	Not Recruiting	25 Oct 2022	25