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.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Umecrine Cognition AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Digestive System and Oral Physiological Phenomena [G10]

Trial duration

23 May 2025 → ongoing

Decision date (initial)

2024-10-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-515907-20-00

EudraCT number

2022-000422-16

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy, Others, Pharmacokinetic

Part A: 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.
Part B: 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 7

1. Part A: To assess the PK characteristics of golexanolone administered 40 mg BID for 5 days in the target population.
2. Part A: To investigate the metabolite profile of golexanolone in human plasma and urine.
3. Part B: To assess effects of golexanolone on health-related quality of life (HRQoL), including fatigue.
4. Part B: To assess effects of golexanolone on day-time sleepiness.
5. Part B: To assess effects of golexanolone on cognitive function.
6. Part B: To evaluate the Investigator's overall impression of treatment effect.
7. Part B: To assess the exposure of two dose levels of golexanolone in the target population treated for 28 days.

Conditions and MedDRA coding

Primary biliary cholangitis (PBC)

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

Medicines And Healthcare Products Regulatory Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Male and female subjects age ≥ 18 years.
2. 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
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), which may include UDCA, OCA, bezafibrate and/or fenofibrate, 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 will be required.
7. 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.
8. 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]).
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%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.
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 27

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 estimated using the CKD-EPI equation.
6. Haemoglobin (HB) <110 g/L, i.e. subjects with moderate/severe anaemia.
7. S-B12 < 125 pmol/L or P-folate < 7 nmol/L.
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). Subjects positive for HCV antibodies should be tested for PCR HCV RNA and in case of positive result considered as not eligible.
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 (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.
12. Clinically significant bowel disease, including obstruction, active inflammatory bowel disease, or malabsorption.
13. Poorly controlled obstructive sleep apnoea, as defined by >5 episodes/hour more than 70% of occasions, despite use of continuous positive airway pressure (CPAP).
14. 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.
15. 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).
16. Clinical diagnosis of autoimmune hepatitis overlap defined using the Paris overlap criteria
17. Criterion deleted but numbering unchanged.
18. 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.
19. 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.
20. Use of prohibited medications within 14 days prior to randomisation, as specified in Section 9.4.8.2.
21. Anticipated change in PBC medication and/or significant medical or surgical intervention within the duration of the study.
22. Regular (more than 1 week per month) alcohol consumption in excess of 14 units per week.
23. 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.
24. Females who are pregnant, nursing or actively trying to conceive a child.
25. Expected inability to swallow the required number of IMP capsules at the applicable dose level.
26. 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).
27. Investigator considers the subject unlikely to comply with study procedures, restrictions, and requirements.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Part A: Frequency, intensity, and seriousness of adverse events (AEs), changes from baseline to Day 5 in laboratory parameters and clinical safety parameters.
2. Part B: Frequency, intensity, and seriousness of AEs, changes from baseline to Day 28 in laboratory parameters and clinical safety parameters.

Secondary endpoints 7

1. Part A: PK parameters: after the first dose; after the last dose and accumulation ratio between first and last dose.
2. Part A: Metabolite profile in human plasma and urine (to be reported separately).
3. Part B : Change from baseline to Day 28 in the following HRQoL measures: − PBC-40 scores for each of the domains (cognition, itch, fatigue, social, emotional, and general symptoms). − EQ-5D-3L tool
4. Part B: Change from baseline to Day 28 in daytime sleepiness related symptoms using the Epworth Sleepiness Scale (ESS).
5. Part B: Change from baseline to Day 28 in a battery of cognitive tests, including: − Portosystemic Hepatic Encephalopathy Score (PHES) total score − Rey Auditory Verbal Learning test (RAVLT) − Delis and Kaplan Executive Function System (D-KEFS) Letter and Category fluency subtests
6. Part B: Clinical Global Impression of change, PBC version (CGI-C-PBC).
7. Part B: Lowest plasma concentration before the next dose (Ctrough) will be assessed pre-dose on Days 1, 7, 14 and 28.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Umecrine Cognition AB

Sponsor organisation

Umecrine Cognition AB

Address

Nanna Svartz Vag 6a

City

Solna

Postcode

171 65

Country

Sweden

Scientific contact point

Organisation

Umecrine Cognition AB

Contact name

Magnus Doverskog

Public contact point

Organisation

Umecrine Cognition AB

Contact name

Magnus Doverskog

Third parties 5

Locations

5 EU/EEA countries · 24 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 6 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 57 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications