A double-blinded, randomized, placebo-controlled phase I/IIa study in healthy subjects and patients with liver cirrhosis evaluating safety, pharmacokinetics and preliminary effect of single and multiple doses of GR3027.
- Conditions
- Hepatic encephalopathy (HE)Therapeutic area: Diseases [C] - Nervous System Diseases [C10]
- Registration Number
- EUCTR2016-003651-30-HU
- Lead Sponsor
- mecrine Cognition AB
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 101
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 < 1% to prevent pregnancy and drug exposure of a partner and refrain from donating sperm from the date of dosing until three months after dosing of the IMP.
5.Willing and able to give written informed consent for participation in the study.
Subjects with liver cirrhosis:
1.Male subject or female subject of non-childbearing potential aged 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 7-9) 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 >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 < 1% to prevent pregnancy and drug exposure of a partner and refrain from donating sperm from the date of dosing until three months after dosing of the IMP.
11. 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]).
12.Willing and able to give written informed consent for participation in the study.
13.Lucid and oriented to person, place, time and situation when giving the informed consent as judged by the Investigator.
14.Able to comply with study activities (including urine collections), as judged by the Investigator.
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 83
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 15
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 < 40 or > 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
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