A two-part study to investigate the effects in adults of two doses of a new drug called golexanolone in patients with primary biliary cholangitis with fatigue and cognitive dysfunctio

Phase 1

Conditions: Primary biliary cholangitis (PBC)
MedDRA version: 20.0Level: SOCClassification code 10019805Term: Hepatobiliary disordersSystem Organ Class: 10019805 - Hepatobiliary disorders
Therapeutic area: Body processes [G] - Digestive System and Oral Physiological Phenomena [G10]

Registration Number: EUCTR2022-000422-16-ES

Lead Sponsor: mecrine Cognition AB

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 101

Inclusion Criteria

1. Male and female subjects age = 18 and =75 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], 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 is the only hormonal contraceptive method 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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 81
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 20

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 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 and/or P-folate < 10 nmol/L.
8. Evidence of biliary obstruction.
9. Any positive result on screening for human immunodeficiency virus (HIV), hepatitis B (serum hepatitis B surface antigen positive), hepatitis C (e.g. HCV RNA positive).
10. Prolonged QTcF (>500 ms), cardiac arrhythmia, 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, 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 (see Appendix 13.2) [30, 31].
17. Concurrent liver disease of another aetiology.
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, e.g. major psychiatric disorder and major depressive disorder (HADS-D >10) formally diagnosed by a psychiatrist.
19. Regular use of prescribed or over the counter medications known to cause fatigue or cognitive dysfunction (including, but not limited to, benzodiazepines, opioids other than codeine phosphate, sleeping pills, regular (daily) antihistamine use in the last 4 weeks, anti-psychotic agents, barbiturates, or recreational drug use).
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.
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Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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