Clinical trial NCT03987451: A Research Study on How Semaglutide Works in People With Fatty Liver Disease and Liver Damage
Official title: Investigation of Efficacy and Safety of Semaglutide s.c. Once-weekly Versus Placebo in Subjects With Non-alcoholic Steatohepatitis and Compensated Liver Cirrhosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Non-alcoholic Steatohepatitis
Lead sponsor: Novo Nordisk A/S
Sponsor class: INDUSTRY
First posted: 2019-06-17
Enrollment: 71
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Semaglutide is a medicine studied in patients with non-alcoholic steatohepatitis (NASH), as it may improve liver damage. Participants will either get semaglutide or placebo (a dummy medicine) - which treatment participants get is decided by chance. The study will last for about 61 weeks in total. Participants will have 10 clinic visits and 3 phone calls with the study doctor or staff during the study. Some of the clinic visits may be spread over more days. Participants will need to inject themselves with medicine under the skin. Participants will have to do this once a week for 48 weeks. The study includes magnetic resonance imaging (MRI) scans of the liver, 1 or 2 liver tissue samples, ultrasound scans of the stomach and a possible examination of the food pipe. For some tests participants may need to remove some items of clothing. Participants will stop in the study if the doctor thinks that there are any risks for their health. The information collected from participants during the study may help them and other patients with NASH in the future. Women cannot take part if pregnant, breast-feeding or planning to become pregnant during the study period.


Eligibility criteria: Inclusion Criteria:

* Male or female, aged 18-75 years (both inclusive) at the time of signing informed consent.
* Histologic evidence of NASH and fibrosis stage 4 according to the NASH CRN classification based on central pathologist evaluation of a liver biopsy obtained within 360 days prior to screening. In subjects who have never had a liver biopsy showing NASH and F4, liver stiffness above 14 kPa by FibroScan® at screening must be documented before subjects can have a trial-related liver biopsy
* A histological NAFLD activity score (NAS) equal to or above 3 with a score of 1 or more in lobular inflammation and hepatocyte ballooning based on central pathologist evaluation
* Body mass index equal to or above 27 kg/m\^2

Exclusion Criteria:

* Presence or history of hepatic decompensation (e.g. ascites, variceal bleeding, hepatic encephalopathy or spontaneous bacterial peritonitis) or liver transplantation
* Presence or history of gastroesophageal varices within the past 360 days prior to screening. For subjects with no known history of gastroesophageal varices and with a Fibroscan® equal to or above 20 kPa and thrombocytes equal to or below 150,000, a esophagogastroduodenoscopy must be performed to evaluate presence of gastroesophageal varices
* Presence or history of hepatocellular carcinoma
* Treatment with vitamin E (at doses equal to or above 800 IU/day) or pioglitazone which has not been at a stable dose in the opinion of the investigator in the period from 90 days prior to screening
* Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in the period from 90 days prior to screening
* Treatment with other glucose lowering agent(s) (apart from what is listed in the exclusion criterion above) or weight loss medication not stable in the opinion of the investigator in the period from 28 days prior to screening

Primary outcomes:
measure: Percentage of Participants With At Least One Stage of Liver Fibrosis Improvement With No Worsening of Non-Alcoholic Steatohepatitis (NASH) After 48 Weeks
timeFrame: Week 48
Secondary outcomes:
measure: Change From Baseline in Liver Fat Content Measured by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF)-Ratio to Baseline
timeFrame: Baseline (week 0), Week 48
measure: Change From Baseline in Liver Stiffness Measured by Magnetic Resonance Elastography (MRE)-Ratio to Baseline
timeFrame: Baseline (week 0), Week 48
measure: Percentage of Participants With NASH Resolution After 48 Weeks
timeFrame: Week 48
measure: Change From Baseline in Fibrosis-4 Score-Ratio to Baseline
timeFrame: Baseline (week 0), Week 48
measure: Percentage of Participants With Change in Non-Alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS)
timeFrame: Baseline (week 0), Week 48
measure: Percentage of Participants With Change in The Fibrosis Stage According to The Kleiner Fibrosis Classification
timeFrame: Baseline (week 0), Week 48
measure: Percentage of Participants With Change in Hepatocyte Ballooning
timeFrame: Baseline (week 0), Week 48
measure: Percentage of Participants With Change in Lobular Inflammation
timeFrame: Baseline (week 0), Week 48
measure: Percentage of Participants With Change in Steatosis
timeFrame: Baseline (week 0), Week 48
measure: Percentage of Participants With Change in The Steatosis-Activity-Fibrosis (SAF) Activity Component Score
timeFrame: Baseline (week 0), Week 48
measure: Percentage of Participants With Change in The Ishak Fibrosis Score
timeFrame: Baseline (week 0), Week 48
measure: Change From Baseline in Hepatic Collagen
timeFrame: Baseline (week 0), Week 48
measure: Percentage of Participants With Improvement in Fibrosis Stage According to The Kleiner Fibrosis Classification (Yes/No)
timeFrame: Baseline (week 0), Week 48
measure: Percentage of Participants With Improvement in Hepatocyte Ballooning (Yes/No)
timeFrame: Baseline (week 0), Week 48
measure: Percentage of Participants With Improvement in Lobular Inflammation (Yes/No)
timeFrame: Baseline (week 0), Week 48
measure: Percentage of Participants With Improvement in Steatosis (Yes/No)
timeFrame: Baseline (week 0), Week 48
measure: Percentage of Participants With Improvement in NAS (Yes/No)
timeFrame: Baseline (week 0), Week 48
measure: Percentage of Participants With Improvement in SAF Activity Component Score (Yes/No)
timeFrame: Baseline (week 0), Week 48
measure: Percentage of Participants With Improvement in Ishak Fibrosis Score (Yes/No)
timeFrame: Baseline (week 0), Week 48
measure: Change From Baseline in Body Weight
timeFrame: Baseline (week 0), Week 48
measure: Relative Change From Baseline in Body Weight
timeFrame: Baseline (week 0), Week 48
measure: Change From Baseline in Waist Circumference
timeFrame: Baseline (week 0), Week 48
measure: Change From Baseline in Body Mass Index (BMI)
timeFrame: Baseline (week 0), Week 48
measure: Percentage of Participants With Weight Loss of >= 5% of Baseline Body Weight at Week 48
timeFrame: Week 48
measure: Percentage of Participants With Weight Loss of >= 10% of Baseline Body Weight at Week 48
timeFrame: Week 48
measure: Change From Baseline in Glycosylated Haemoglobin A1c (HbA1c)
timeFrame: Baseline (week 0), Week 48
measure: Change From Baseline in Fasting Plasma Glucose (FPG)
timeFrame: Baseline (week 0), Week 48
measure: Change From Baseline in Fasting C-peptide-Ratio to Baseline
timeFrame: Baseline (week 0), Week 48
measure: Change From Baseline in Systolic And Diastolic Blood Pressure
timeFrame: Baseline (week 0), Week 48
measure: Change From Baseline in Total Cholesterol-Ratio to Baseline
timeFrame: Baseline (week 0), Week 48
measure: Change From Baseline in Low-Density Lipoprotein (LDL) Cholesterol-Ratio to Baseline
timeFrame: Baseline (week 0), Week 48
measure: Change From Baseline in High-Density Lipoprotein (HDL) Cholesterol-Ratio to Baseline
timeFrame: Baseline (week 0), Week 48
measure: Change From Baseline in Very Low-Density Lipoprotein (VLDL) Cholesterol-Ratio to Baseline
timeFrame: Baseline (week 0), Week 48
measure: Change From Baseline in Triglycerides-Ratio to Baseline
timeFrame: Baseline (week 0), Week 48
measure: Change From Baseline in Free Fatty Acids (FFA)-Ratio to Baseline
timeFrame: Baseline (week 0), Week 48
measure: Change From Baseline in High-Sensitivity C-reactive Protein (hsCRP)-Ratio to Baseline
timeFrame: Baseline (week 0), Week 48
measure: Change From Baseline in Alanine Aminotransferase (ALT)-Ratio to Baseline
timeFrame: Baseline (week 0), Week 48
measure: Change From Baseline in Aspartate Aminotransferase (AST)-Ratio to Baseline
timeFrame: Baseline (week 0), Week 48
measure: Change From Baseline in Gamma-Glutamyl Transferase (GGT)-Ratio to Baseline
timeFrame: Baseline (week 0), Week 48
measure: Change From Baseline in Albumin-Ratio to Baseline
timeFrame: Baseline (week 0), Week 48
measure: Changes From Baseline in Thrombocytes-Ratio to Baseline
timeFrame: Baseline (week 0), Week 48
measure: Change From Baseline in International Normalized Ratio (INR)-Ratio to Baseline
timeFrame: Baseline (week 0), Week 48
measure: Change From Baseline in Direct Bilirubin-Ratio to Baseline
timeFrame: Baseline (week 0), Week 48
measure: Change From Baseline in Total Bilirubin-Ratio to Baseline
timeFrame: Baseline (week 0), Week 48
measure: Number of Treatment-Emergent Adverse Events (TEAEs)
timeFrame: From baseline (week 0) to week 55
measure: Number of Treatment-Emergent Hypoglycaemic Episodes
timeFrame: From baseline (week 0) to week 55
measure: Change From Baseline in Pulse
timeFrame: Baseline (week 0), Week 48
Other outcomes:
Locations:
city: Chandler
country: United States
facility: Arizona Liver Health
state: Arizona
city: Peoria
country: United States
facility: The Institute for Liver Health dba Arizona Liver Health
state: Arizona
city: Coronado
country: United States
facility: Southern California Research Center
state: California
city: La Jolla
country: United States
facility: Altman Clinical Translational Research Institute
state: California
city: Rialto
country: United States
facility: Inland Empire Clinical Trials LLC
state: California
city: Boca Raton
country: United States
facility: Excel Medical Center Clinical Trials, LLC
state: Florida
city: Gainesville
country: United States
facility: University of Florida-CTRB
state: Florida
city: Miami
country: United States
facility: University of Miami/Schiff Center for Liver Diseases
state: Florida
city: Atlanta
country: United States
facility: Piedmont Research Institute
state: Georgia
city: Marietta
country: United States
facility: Gastrointestinal Specialists of Georgia
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: South Bend
country: United States
facility: Digestive Research Alliance of Michiana
state: Indiana
city: Lexington
country: United States
facility: University of Kentucky Hospital
state: Kentucky
city: Baltimore
country: United States
facility: Mercy Medical Center, GI Research
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Germantown
country: United States
facility: Gastroenterology Center For The Mid-South
state: Tennessee
city: Hermitage
country: United States
facility: Digestive Health Research - Tristar Summit Medical Center
state: Tennessee
city: Nashville
country: United States
facility: Quality Medical Research
state: Tennessee
city: Arlington
country: United States
facility: Texas Clinical Research Institute, LLC
state: Texas
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center - Dallas
state: Texas
city: San Antonio
country: United States
facility: American Research Corporation at the Texas Liver Institute
state: Texas
city: Richmond
country: United States
facility: VCU Health Systems
state: Virginia
city: Clichy
country: France
facility: Hôpital Beaujon
city: Lyon Cedex 4
country: France
facility: Hôpital de la Croix Rousse
city: Paris
country: France
facility: Hôpital Cochin
city: Paris
country: France
facility: Groupe Hospitalier PITIE-SALPETRIERE
city: Venissieux
country: France
facility: Groupe Hospitalier Mutualiste des Portes du Sud
city: Frankfurt
country: Germany
facility: Hepatologie Universitätsklinikum Frankfurt/M
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig, Klinik und Poliklinik
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes-Gutenberg-Universität Mainz
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Sevilla
country: Spain
facility: Hospital Virgen del Rocío
city: Birmingham
country: United Kingdom
facility: New Queen Elizabeth Hospital Birmingham
city: London
country: United Kingdom
facility: Liver Research
city: Newcastle upon Tyne
country: United Kingdom
facility: Freeman Hospital, Newcastle
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospital
Study officials:
affiliation: Novo Nordisk A/S
name: Clinical Reporting Anchor and Disclosure (1452)
role: STUDY_DIRECTOR
References:
citation: Loomba R, Abdelmalek MF, Armstrong MJ, Jara M, Kjaer MS, Krarup N, Lawitz E, Ratziu V, Sanyal AJ, Schattenberg JM, Newsome PN; NN9931-4492 investigators. Semaglutide 2.4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. Lancet Gastroenterol Hepatol. 2023 Jun;8(6):511-522. doi: 10.1016/S2468-1253(23)00068-7. Epub 2023 Mar 16.