Hepatic encephalopathy (HE)
Conditions
Sponsors
Umecrine Cognition AB
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Healthy subjects: 1.Healthy male subject aged 18-50 years, inclusive, at the time of signing the informed consent. 2.Body Mass Index (BMI) = 18 and = 30 kg/m2 and body weight at least 50 kg and no more than 100 kg at screening. 3.Clinically normal medical history, physical findings, vital signs, ECG and laboratory values at the time of screening, as judged by the Investigator. 4.Willing to use condom and contraceptive methods with a failure rate of 20 (ANT1 does not apply for the first cohort). 9.For patients participating in the extended treatment (part D): Availability of at least one designated family member or care-giver who, in the judgment of the Investigator, is capable of and willing to assume responsibility for facilitating subject compliance with study procedures (e.g. monitoring medication use, assisting the subject in attending study visits, communicating with the Investigator/study site as needed). 10. Male subjects must be willing to use condom and contraceptive methods with a failure rate of =65 years) yes F.1.3.1 Number of subjects for this age range 15
Exclusion criteria
Exclusion criteria: Healthy subjects: 1.History of any clinically significant disease or disorder which may either put the subject at risk, or influence the results or the subject’s ability to participate. 2.History of or present clinically significant psychiatric or neurological diagnosis. 3.Any planned major surgery within the duration of the study. 4.Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and/or HIV. 5.Any vital signs values outside the following ranges: -Systolic BP > 140 mm Hg -Diastolic BP > 100 mm Hg -Heart rate 85 beats per minute 6.Prolonged QTcF (>450 ms), cardiac arrhythmia, or any clinically significant abnormality in the resting ECG. 7.Regular use of any prescribed or non-prescribed medication within two weeks prior to the first administration of the IMP, except the occasional intake of paracetamol and nasal decongestants without cortisone or antihistamine for a maximum of 10 days. 8.Any medications or herbal remedies known to chronically alter drug absorption or elimination processes within four weeks prior to first IMP administration. 9.Plasma donation within one month of screening or blood donation during approx. three months prior to screening. 10.Inability to be venipunctured and/or tolerate venous access. 11.Inability to swallow the required number of IMP capsules. 12.History of or present alcohol abuse, or excessive intake of alcohol. 13.Positive screen for drugs of abuse or alcohol at screening or on admission to the clinic. 14.Any present or historic use of drugs of abuse or anabolic steroids. 15.Intake of xanthine and/or taurine containing energy drinks within two days prior to screening. 16.Current smoker or user of nicotine products. Irregular use of nicotine is allowed before the screening visit. 17.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. 18.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. 19.Investigator considers the subject unlikely to comply with study procedures, restrictions and requirements. 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 outs
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 compared to placebo | — |
Countries
Denmark, Finland, Hungary, Poland, Sweden, Ukraine
Contacts
Public ContactMagnus Doverskog
Umecrine Cognition AB
Outcome results
None listed