Hepatic encephalopathy (HE) MedDRA version: 20.0 Level: LLT Classification code 10014630 Term: Encephalopathy hepatic System Organ Class: 100000004852
Conditions
Sponsors
Umecrine Cognition AB
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Subjects with liver cirrhosis: 1.Male subject or female subject of non-childbearing potentialaged 18-70 years, inclusive, at the time of signing the informed consent. 2.BMI = 18 and = 40 kg/m2 and body weight at least 50 kg at screening. 3.Clinical diagnosis of liver cirrhosis of any cause based on biopsy, imaging, or other criteria. 4.MELD score between 8 and 20 (inclusive) (see Appendix 12.3). 5.Child-Pugh class B (score 5-6) for study part B, Child-Pugh class A or B (score 5-9) for study parts C and D (see Appendix 12.4). 6.Potential to benefit from HE treatment; i.e., no fixed cognitive impairment due to cerebrovascular and/or organic brain disease. 7.No changes in medication for HE or cirrhosis (e.g. lactulose, rifaximin, diuretics) for 14 days prior to randomization, except for adjustment of lactulose dose (e.g. for diarrhoea). 8.For patients participating in study part D: PHES must be equal to or below -5 and/or CRT index below 1.9 and/or ANT1 score =65 years) yes F.1.3.1 Number of subjects for this age range 15
Exclusion criteria
Exclusion criteria: Subjects with liver cirrhosis 1.Uncontrolled infection defined as persistent sepsis or bacteraemia with a lack of clinical improvement after at least one week of appropriate antibiotic treatment (chronic viral hepatitis is not an exclusion). 2.Active GI bleeding or a history of GI bleeding requiring blood transfusion (= 2 units) within 3 months of randomization. 3.Transjugular intrahepatic portosystemic shunt placement or revision within the past 90 days of randomization. 4.Occlusion of spontaneous spleno-renal shunt(s) within three months prior to screening or scheduled to undergo such occlusion within 24 weeks after randomization 5.West Haven Grade =2 at the time of enrolment or less than seven days since resolution of the last overt HE episode . 6.Diagnosis of HRS Type I or II. 7.Ascites which cannot be managed by dietary sodium restriction and maximal doses of diuretics. 8.Active or history of malignancy except for cutaneous basal cell carcinoma. 9.Clinically significant bowel disease. 10.Any planned major surgery within the duration of the study. 11.Any other significant medical conditions judged by the Investigator to preclude entry. 12.Any positive result on screening for HIV. 13.Any vital signs values outside the following ranges (at screening): -Systolic BP 110 beats per minute 14.Prolonged QTcF (>500 ms), cardiac arrhythmia, or any clinically significant abnormality in the resting ECG (at screening). 15.Serum creatinine > 177 µmol/L, serum sodium 2.0, haemoglobin < 85 g/L, haematocrit < 25L/L (at screening) 16.Use of prohibited medications within 14 days prior to randomization, including: -Ammonia lowering agents -warfarin and warfarin like anticoagulants -benzodiazepines or barbiturates -maintenance methadone -CYP2CB substrates and CYP3A4 substrates detailed in protocol 17.Inability to be venipunctured and/or tolerate venous access. 18.Inability to swallow the required number of IMP capsules. 19.Present or historic use of anabolic steroids. 20.History of severe allergy/hypersensitivity or on-going allergy/hypersensitivity or history of hypersensitivity to drugs with a similar chemical structure or class to GR3027. 21.Administration of another new chemical entity (or has participated in any other interventional study within three months prior to administration of IMP in this study. 22.Investigator considers the subject unlikely to comply with study procedures, restrictions and requirements.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of the study is to evaluate the safety and tolerability of GR3027 after multiple dose administration in healthy male volunteers and after single and multiple dose administration in cirrhotic patients.;Secondary Objective: Study parts A-C: 1.Multiple oral dose PK characteristics of GR3027 in healthy male volunteers. 2.Single and multiple oral dose PK characteristics of GR3027 in cirrhotic patients. 3.Metabolite profile of GR3027 in human plasma and urine. 4.Plasma protein binding in cirrhotic patients. 5.Preliminary effect on brain activity as measured by EEG. Study part D (extended treatment): 1.Preliminary efficacy on cognitive function as measured by Portosystemic Hepatic Encephalopathy Score (PHES). 2.Preliminary efficacy on cognitive function as measured by CRT. 3.Preliminary effect on brain activity as measured by EEG. 4.Preliminary efficacy on sleepiness measured by the Epworth Sleepiness Scale (ESS). 5.Safety and tolerability of GR3027 after 21 days treatment in cirrhotic patients. 6.Exposure of GR3027 in cirrhotic patients. 7.Evaluate subjects for evidence of OHE and assess care-giver burden. 8. Assess preliminary efficacy on cognitive function, by Animal Naming Test (ANT1). ;Primary end point(s): Safety will be assessed by occurrence and frequency of Adverse Events (AEs), changes in laboratory parameters, vital signs and physical examination. ;Timepoint(s) of evaluation of this end point: According to trial flow chart | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Study parts A-C Single dose cohort: -PK parameters: AUC 0->8, AUCt, Cmax, Tmax, terminal elimination rate constant (lambdaz), terminal half-life (T1/2), total apparent body clearance following extravascular administration (CL/F), apparent volume of distribution following extravascular administration (Vz/F) -Determination of GR3027 fraction unbound (Fub) in plasma. PK parameters will be calculated both for the total and for the unbound fraction of GR3027. -Change in quantified EEG automated spectral parameters (Mean Dominant Frequency [MDF] and relative power of the theta and delta frequencies) on the bi-parietal and temporal-occipital derivations from baseline to 90 minutes and 180 minutes post-dose, as compared to baseline. Multiple ascending dose (MAD) cohorts: -PK parameters after the first dose: AUC0-24h, Cmax, Tmax, lambdaz, T1/2, Vz/F, Cl/F, part A only: urine recovery (Ae) and fraction of the dose excreted in urine (Fe) for GR3027 -PK parameters after the last dose: AUC at steady-state (AUCss), Cmax, maximum and minimum concentration at steady-state (Cmax, ss and Cmin, ss), % fluctuation, Tmax, lambdaz, T1/2, CL/F, Vz/ F, part A only : Ae, Fe for GR3027. -Accumulation ratio between first and last dose. -Dose proportionality after multiple doses based on AUCss and Cmax, ss. -Metabolite profile in human plasma and urine. -Patient cohorts only: Determination of GR3027 Fub in plasma in cirrhotic patients. PK parameters will be calculated both for the total and for the unbound fraction of GR3027. -Patient cohorts only: Change in quantified EEG automated spectral parameters (MDF and relative power of the theta and delta frequencies) on the bi-parietal and temporal-occipital derivations from baseline to 90 minutes, 180 minutes and 6-8 hours post-dose, as compared to baseline. (Patient cohorts only). Study part D (phase IIa, extended treatment) -Change in PHES from baseline to 10 and 21 days after start of treatment, as compa | — |
Countries
Denmark, Finland, Hungary, Poland, Sweden, Ukraine
Contacts
Public ContactMagnus Doverskog
Umecrine Cognition AB
Outcome results
None listed