Clinical Trials Register

Summary
EudraCT Number:	2022-000422-16
Sponsor's Protocol Code Number:	UCAB-CT-05
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-05-24
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2022-000422-16

A.3

Full title of the trial

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.

Randomizált, kettős vak, placebo-kontrollos, kétrészes vizsgálat a golexanolon két dózisszintje farmakokinetikájának, biztonságosságának és tolerálhatóságának értékelésére primer biliáris cholangitisben, kimerültségben és kognitív diszfunkcióban szenvedő betegeknél.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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 dysfunction

Kétrészes vizsgálat egy új, golexanolon nevű gyógyszer két dózisa hatásainak vizsgálatára kimerültséggel és kognitív diszfunkcióval járó primer biliáris cholangitisben szenvedő felnőtt betegek körében

A.4.1

Sponsor's protocol code number

UCAB-CT-05

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Umecrine Cognition AB
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Umecrine Cognition AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Umecrine Cognition AB
B.5.2	Functional name of contact point	Magnus Doverskog
B.5.3	Address:
B.5.3.1	Street Address	Fogdevreten 2
B.5.3.2	Town/ city	Solna
B.5.3.3	Post code	S-171 65
B.5.3.4	Country	Sweden
B.5.4	Telephone number	+4685248 44 84
B.5.6	E-mail	magnus.doverskog@umecrine.se

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Golexanolone
D.3.2	Product code	GR3027
D.3.4	Pharmaceutical form	Capsule, soft
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	GOLEXANOLONE
D.3.9.1	CAS number	208922238-18
D.3.9.2	Current sponsor code	GR3027
D.3.9.4	EV Substance Code	SUB198061
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10.0
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, soft
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Primary biliary cholangitis (PBC)

E.1.1.1

Medical condition in easily understood language

Liver disease caused by autoimmune attack on the small to medium bile ducts

E.1.1.2

Therapeutic area

Body processes [G] - Digestive System and Oral Physiological Phenomena [G10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	SOC
E.1.2	Classification code	10019805
E.1.2	Term	Hepatobiliary disorders
E.1.2	System Organ Class	10019805 - Hepatobiliary disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

Part A:
1. To assess the PK characteristics of golexanolone administered 40 mg BID for 5 days in the target population.
2. To investigate the metabolite profile of golexanolone in human plasma and urine.

Part B:
1. To assess effects of golexanolone on health-related quality of life (HRQoL), including fatigue.
2. To assess effects of golexanolone on day-time sleepiness.
3. To assess effects of golexanolone on cognitive function.
4. To evaluate the Investigator’s overall impression of treatment effect.
5. To assess the exposure of two dose levels of golexanolone in the target population treated for 28 days.

E.2.3

Trial contains a sub-study

E.3

Principal 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, 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.

E.4

Principal 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. Clinically significant 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).
Confidential 50 (94)
20. Use of prohibited medications within 14 days prior to randomisation, including medications sensitive to CYP3A4 and/or Pgp inhibition/induction with a narrow therapeutic window, including use of warfarin and warfarin-like anticoagulants (see 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.

E.5 End points

E.5.1

Primary end point(s)

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

E.5.1.1

Timepoint(s) of evaluation of this end point

Part A: from baseline to Day 5
Part B: from baseline to Day 28

E.5.2

Secondary end point(s)

Part A:
1. PK parameters:
a. after the first dose: Area under the plasma concentration time curve (AUC)0-24h, 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).
b. after the last dose: AUC at steady state (AUCss), maximum and minimum concentration at steady state (Cmax, ss and Cmin, ss), Tmax, % fluctuation, lambdaz, T1/2, CL/F, Vz/ F.
c. accumulation ratio between first and last dose
2. Metabolite profile in human plasma and urine (to be reported separately).

Part B:
1. 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
2. Change from baseline to Day 28 in daytime sleepiness related symptoms using the Epworth Sleepiness Scale (ESS).
3. 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
4. Clinical Global Impression of change, PBC version (CGI-C-PBC).
5. Lowest plasma concentration before the next dose (Ctrough) will be assessed pre-dose on Days 1, 7, 14 and 28.

E.5.2.1

Timepoint(s) of evaluation of this end point

Part A: from baseline to Day 5
Part B: from baseline to Day 28

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

1b/2

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Germany

Italy

Serbia

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

101

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

This is a phase 1b/2 study with the unregistered product golexanolone and thus there will be no treatment with golexanolone available after end of study participation.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-07-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-06-24

P. End of Trial
P.	End of Trial Status	Ongoing

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