A double-blinded, randomized, placebo-controlled phase I/IIa study in healthy subjects and patients with liver cirrhosis evaluating safety, tolerablity, pharmacokinetics and preliminary effect of single and multiple doses of GR3027.

Phase 1

• Conditions: Hepatic encephalopathy (HE); MedDRA version: 20.0 Level: LLT Classification code 10014630 Term: Encephalopathy hepatic System Organ Class: 100000004852; Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

• Registration Number: EUCTR2016-003651-30-FI
• Lead Sponsor: mecrine Cognition AB

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2018-04-11
• Last Update Posted: 1 February 2020

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: Not specified
• Target Recruitment: 98

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 < 20 (ANT1 does not apply for the first cohort.
9.For patients participating in study (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

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 < 90 mm Hg
-Diastolic BP < 50 mm Hg
-Heart rate < 50 or > 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 < 125 mmol/L, platelet count of < 50,000/µL, INR>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.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified