Intestinal Failure Associated Liver Disease
Conditions
Brief summary
This is a phase 2a, multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of NST-6179 in subjects with intestinal failure-associated liver disease (IFALD) receiving parenteral nutrition (PN). The study will be conducted in 2 sequential parts. Up to 36 subjects diagnosed with IFALD will be enrolled in the study, of which up to 18 subjects will be enrolled in each of the 2 parts and randomized (2:1) to receive NST-6179 (N=12/part) or matched placebo (N=6/part). Subjects in Part A will receive once daily (QD) oral administration of 800 mg (32 mL solution) NST-6179 or placebo for 4 weeks. The NST-6179 dose for Part B is planned to be 1200 mg QD for 12 weeks. Actual dose, however, will be determined during the safety review meeting.
Interventions
DRUGNST-6179 Part A
Once daily (QD) oral administration of 800mg (32 mL solution) of NST-6179 for 4 weeks
DRUGNST-6179 Part B
Once daily (QD) oral administration of 1200mg of NST-6179 for 12 weeks
OTHERMatched Placebo
Matched placebo for administration in Part A or Part B
Sponsors
NorthSea Therapeutics B.V.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Adult persons aged 16 years or older at the time of informed consent. * Minimum of 6 months on Parenteral supplementation. * Established clinical diagnosis of IFALD based on a persistent elevation of 1. liver enzymes (ALP, AST, ALT, or GGT ≥1.5 × upper limit of normal \[ULN\]) for ≥6 months and/or 2. total bilirubin \> ULN for ≥6 months. * Laboratory parameters consistent with stable liver disease without cirrhosis as defined by: 1. ALT and AST \<5 × ULN; 2. Total bilirubin ≤2.5 mg/dL in the absence of Gilbert's Syndrome. 3. Serum albumin ≥2.5 g/dL; 4. International normalized ratio (INR) ≤1.3 in the absence of anticoagulant therapy; 5. Platelet count ≥120,000/mm3. Key
Exclusion criteria
* Clinical, laboratory, imaging, or histopathologic evidence of other causes of acute or chronic liver disease, including autoimmune, viral, metabolic, or alcoholic liver disease. * Clinical evidence of compensated or decompensated hepatic cirrhosis as assessed by historical liver histology, ultrasound-based and/or signs and symptoms of hepatic decompensation (including, but not limited to, jaundice, ascites, variceal hemorrhage, and/or hepatic encephalopathy). * Presence of hepatic impairment, end-stage liver disease, and/or a model for end-stage liver disease (MELD) score \>12. * Transient elastography read \>20.0 kPA within 3 months prior to or during the Screening Period. * Estimated glomerular filtration rate \<45 mL/min based on the 2021 CKD-EPI creatinine equation. * Poor nutritional status defined as body mass index (BMI) \<17 kg/m2.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To assess the safety and tolerability of NST-6179 | Up to 14 Weeks | Incidences of treatment-emergent adverse events, clinically significant chances in laboratory tests, vital signs and ECGs |
| To assess the pharmacokinetics of NST-6179 | Day 1 and Day 14 | area under the concentration-time curve from time 0 to last measurable concentration (AUC0-last) |
| To assess the pharmacodynamic effects of NST-6179 on hepatic steatosis | 12 weeks | Relative change from baseline to week 12 in biomarkers for hepatic steatosis as measured by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF) and controlled attenuation parameter (CAP) |
| To assess the pharmacodynamic effects of NST-6179 on hepatic inflammation | 12 weeks | Absolute and relative change from baseline to week 12 in hepatic inflammation (aspartate transaminase \[AST\], alanine transaminase \[ALT\], and high sensitivity C-reactive protein \[hsCRP\]) |
| To assess the pharmacodynamic effects of NST-6179 on hepatic cholestasis (bilirubin, ALP, GGT) | 12 weeks | Absolute and relative change from baseline to week 12 in hepatic cholestasis (total bilirubin, direct bilirubin, alkaline phosphatase \[ALP\], and gamma-glutamyl transferase \[GGT\]) |
| To assess the pharmacodynamic effects of NST-6179 on hepatic fibrosis (ELF, Pro-C3, FIB-4) | 12 weeks | Absolute and relative change from baseline to week 12 in hepatic fibrosis as measured non-invasively by FibroScan VCTE kPa, enhanced liver fibrosis (ELF) score (and individual components), propeptide of type III collagen (PRO-C3), and fibrosis-4 (FIB-4) |
Countries
United States
Contacts
Primary ContactMichelle Yokley
Outcome results
None listed