Clearance of NRL972 in Patients With Cirrhosis, Nonalcoholic Steatohepatitis (NASH) and in Healthy Volunteers

Study Overview
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Brief Summary
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The study was conducted to describe and compare the plasma pharmacokinetics of NRL972 administered after a standard meal and while fasted in patients with hepatic cirrhosis (Child-Turcotte-Pugh [CTP] class A-C), NASH, young and elderly healthy males, and young and elderly healthy females, to assess the effects of liver dysfunction, gender, age and prandial intestinal hyperaemia on the clearance of NRL972. In addition, the study was to provide information on the safety and tolerability of repeated intravenous doses of NRL972 in these populations.

Official Title
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A Study in Healthy Volunteers and Patients With Liver Cirrhosis and Non-Alcoholic Steatohepatitis (NASH) to Assess the Effects of Age, Gender, Chronic Liver Disease, and Prandial Effects on the Clearance of Cholyl-Lysyl-Fluorescein (NRL972) an an in-Vivo Marker of Liver Function in Man.

Conditions
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Hepatic Cirrhosis, Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: NRL972
* Drug: NRL972
* Drug: NRL972
* Drug: NRL972
* Drug: NRL972
* Drug: NRL972
* Drug: NRL972


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: General - all subjects Males or females (females of non-childbearing potential or of childbearing potential while taking medically appropriate contraception) Caucasian BMI: between 19 and 34 kg.m-2 BW: between 45 and 110 kg willing and able to provide informed consent Healthy volunteers (group N) Age: 18 - 40 years (inclusive) e.g. > 60 years Assessed as healthy based on the pre study examination Hepatic cirrhosis Age: 18 - 75 years stable compensated liver cirrhosis (cryptogenic, posthepatic, alcoholic) with histo-logical or macroscopic (e.g. laparascopy, biopsy, ultrasound sonography or other adequate imaging techniques) confirmation Nonalcoholic steatohepatitis (NASH) Age: 18 - 75 years Diagnosis of NASH confirmed by liver biopsy Exclusion Criteria: General - all subjects Previous participation in the trial Participant in any other trial during the last 90 days Donation of blood during the last 60 days or a history of blood loss exceeding 450 mL within the last 3 months History of any clinically relevant allergy Uncontrolled diabetes mellitus or any further intolerability of the Galactose test Presence of acute or chronic infection Resting systolic blood pressure > 160 or < 90 mmHg, diastolic blood pressure > 95 or < 50 mmHg Clinically relevant ECG-abnormalities, prolonged QTc with > 450 msec in males and > 460 msec in females in particular Clinically relevant ECG-abnormalities that constitute a contraindication for the Lido-cain-MEG'-X-test Positive HIV test Positive alcohol or urine drug test on recruitment Daily use of > 30 gr alcohol Smoking more than 15 cigarettes/day or equivalent of other tobacco products Use of prohibited medication Suspicion or evidence that the subject is not trustworthy and reliable Suspicion or evidence that the subject is not able to make a free consent or to under-stand the information in this regard General - all females Positive pregnancy test Lactating Not using appropriate contraception in premenopausal women All healthy subjects Presence or history of any relevant comorbidity (list of past and present diseases will be reviewed by an expert panel) Presence of any relevant abnormality in the laboratory safety tests, especially low haemoglobin, increased liver enzymes, reduced serum creatinine (laboratory test abnormalities will be reviewed by an expert panel) Positive serology for HBsAg, anti HBc and anti HCV History of alcohol and/or drug abuse. Patients with hepatic disease Biliary liver cirrhosis Liver impairment due to space-occupying processes (e.g. carcinoma) State after liver transplantation or patient scheduled for liver transplantation Fluctuating or rapidly deteriorating hepatic function Significant bleeding diathesis Oesophageal bleeding within the last 8 weeks before study entry Ascites > 6 L on abdominal US Number Connection test: time to connect 25 consecutive numbers > 30 sec Presence or history of any relevant comorbidity other than hepatic disease (list of past and present diseases will be reviewed by an expert panel) Clinically relevant abnormal laboratory values other than those associated or sufficiently explained by the existing liver disease (laboratory test abnormalities will be reviewed by an expert panel) History of drug or alcohol abuse within 2 months prior to dosing

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1 YM<br>Healthy young males | Drug: NRL972<br>* Single 2 mg intravenous injection administered once after an overnight fast and once after a standard meal<br>|
| Experimental: 2 EM<br>Healthy elderly males | Drug: NRL972<br>* Single 2 mg intravenous injection administered once after an overnight fast and once after a standard meal<br>|
| Experimental: 3 YF<br>Healthy young females | Drug: NRL972<br>* Single 2 mg intravenous injection administered once after an overnight fast and once after a standard meal<br>|
| Experimental: 4 EF<br>Healthy elderly females | Drug: NRL972<br>* Single 2 mg intravenous injection administered once after an overnight fast and once after a standard meal<br>|
| Experimental: 5 NASH<br>Patients with presumed NASH | Drug: NRL972<br>* Single 2 mg intravenous injection administered once after an overnight fast and once after a standard meal<br>|
| Experimental: 6 CTP-A<br>Patients with hepatic cirrhosis CTP-class A | Drug: NRL972<br>* Single 2 mg intravenous injection administered once after an overnight fast and once after a standard meal<br>|
| Experimental: 7 CTP-BC<br>Patients with hepatic cirrhosis CTP-class B and C | Drug: NRL972<br>* Single 2 mg intravenous injection administered once after an overnight fast and once after a standard meal<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clearance of NRL972 after a standard meal and while fasted in healthy volunteers, patients with NASH and patients with hepatic cirrhosis. |  | Up to 4 hours post administration of NRL972 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events and changes in physical findings from baseline |  | Up to 4 hours post-dosing | 
| Effects of vital signs: blood pressure, pulse rate |  | Up to 4 hours post-dosing | 
| Effects on electrocardiogram |  | Up to 4 hours post-dosing | 
| Changes in haematology, clinical chemistry, urinalysis |  | Up to 4 hours post-dosing |