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 (PBC), Fatigue, and Cognitive Dysfunction
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 84
- 试验地点
- 78
- 主要终点
- 1. Frequency, intensity, and seriousness of adverse events (AEs) from baseline to Day 28 (part B)
研究概览
简要总结
The present phase 1b/2 randomised, double-blind, placebo-controlled, two-part study is designed to evaluate the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of two dose levels of golexanolone compared with placebo among subjects with a history of non-cirrhotic or Child-Pugh class A cirrhotic Primary Biliary Cholangitis (PBC) with clinically significant fatigue and cognitive symptoms on stable background standard of care (SoC) PBC medication. The objectives of this research study are to assess the safety and tolerability as well the pharmacokinetic (PK) characteristics of golexanolone administered 40 mg BID for 5 days in the target population (part A) and to assess the safety and tolerability, the effects of golexanolone on health-related quality of life (HRQoL), including fatigue, day-time sleepiness and cognitive function as well as Investigator's overall impression of treatment effect of 28 days twice per day (BID) treatment with two dose levels of golexanolone versus placebo (part B).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Double-blind
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male and female subjects age ≥ 18 years
- •Diagnosis of PBC based on the presence of ≥2 of 3 key disease characteristics
- •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),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
- •WOCBP must be willing to use a contraceptive method with a failure rate of < 1% 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
- •Females of non-childbearing potential must have documented tubal ligation or hysterectomy; or be post-menopausal
- •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%
- •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
排除标准
- •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
- •Low Haemoglobin (HB), i.e. subjects with moderate/severe anaemia
- •Low S-B12 or low P-folate
- •Evidence of biliary obstruction
- •Any positive result on screening for human immunodeficiency virus (HIV), or hepatitis B (serum hepatitis B surface antigen positive)
- •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
- •Clinically significant bowel disease, including obstruction, active inflammatory bowel disease, or malabsorption
- •Clinically significant sleep apnoea
- •An uncontrolled thyroid disorder
- •Subjects with a history of or currently active immune disorders (i.e. uncontrolled) other that PBC (including autoimmune disease) and/or diseases requiring immunosuppressive drugs
- •Clinical diagnosis of autoimmune hepatitis overlap
- •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
- •Regular use of prescribed or over the counter (OTC) medications known to cause fatigue or cognitive dysfunction
- •Use of prohibited medications within 14 days prior to randomisation
- •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 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
研究组 & 干预措施
Placebo
Part B: Placebo BID
干预措施: Placebo (Drug)
Part B: Treatment arm 2 (golexanolone 80 mg)
80 mg golexanolone BID
干预措施: golexanolone (Drug)
Part A: Placebo
Placebo BID
干预措施: Placebo (Drug)
Part A: Golexanolone
40 mg golexanolone BID
干预措施: golexanolone (Drug)
Part B: Treatment arm 1 (golexanolone 40 mg)
40 mg golexanolone BID
干预措施: golexanolone (Drug)
结局指标
主要结局
1. Frequency, intensity, and seriousness of adverse events (AEs) from baseline to Day 28 (part B)
时间窗: From enrollment to the end of treatment at 28 days
Frequency, intensity, and seriousness of adverse events (AEs) from baseline to Day 28
Frequency, intensity, and seriousness of adverse events (AEs) from baseline to Day 5 (part A)
时间窗: From Baseline to Day 5
Frequency, intensity, and seriousness of adverse events (AEs)
次要结局
- 1. Change from baseline to Day 28 in PBC-40 scores for each of the domains (cognition, itch, fatigue, social, emotional, and general symptoms) (part B)(From baseline to Day 28)
- 2. Change from baseline to Day 28 in EQ-5D-3L tool (part B)(From baseline to Day 28)
- 3. Change from baseline to Day 28 in daytime sleepiness related symptoms using the Epworth Sleepiness Scale (ESS) (part B)(From baseline to Day 28)
- 4. Change from baseline to Day 28 in Portosystemic Hepatic Encephalopathy Score (PHES) total score (part B)(From baseline to Day 28)
- 5. Change from baseline to Day 28 in Rey Auditory Verbal Learning test (RAVLT) (part B)(From baseline to Day 28)
- 6. Change from baseline to Day 28 in Delis and Kaplan Executive Function System (D-KEFS) Letter and Category fluency subtests (part B)(From baseline to Day 28)
- 7. To evaluate the Investigator's overall impression of treatment effect by Clinical Global Impression of change, PBC version (CGI-C-PBC) from baseline to Day 28 (part B)(From baseline to Day 28)
- 8. To assess the exposure of two dose levels of golexanolone in the target population treated for 28 days (part B)(At Day 1, 14 and 28)