Non-Alcoholic Fatty Liver Disease, the HEpatic Response to Oral Glucose, and the Effect of Semaglutide (NAFLD HEROES)
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|ClinicalTrials.gov Identifier: NCT03884075|
Recruitment Status : Recruiting
First Posted : March 21, 2019
Last Update Posted : September 1, 2020
In non-alcoholic fatty liver disease (NAFLD), fat accumulates in the liver and can cause damage. Researchers want to learn what causes the damage NAFLD, and to see if a medication can help.
To find out how the liver in people with NAFLD responds to feeding, and how this relates to their response to the drug semaglutide.
People with NAFLD and healthy volunteers ages 18 and older
Participants will be screened with:
Imaging: A machine will take pictures of the participant s body.
Within 2-8 weeks of enrollment, participants will stay in the clinic for several days. This includes:
Blood, urine, heart, and imaging tests
For NAFLD participants only: A needle-like device will remove a small biopsy of the liver and fatty tissue.
Participants will be alone in a special room for 5 hours. They will breathe through a tube under the nostrils. They will have blood drawn several times.
The baseline visit concludes participation for healthy volunteers but NAFLD participants will contine.
About 6 weeks after discharge, participants will stay in the clinic again and repeat the tests. They will get their first semaglutide dose by injection.
Participants will have visits weeks 1, 2, 4, 8, 12, 16, 20, and 24 of treatment. Visits include blood tests.
Participants will inject semaglutide once a week at home.
At week 30, participants will stay in the clinic again and repeat the tests.
Participants will have a final visit 12 weeks after stopping treatment. This includes blood and urine tests.
|Condition or disease||Intervention/treatment||Phase|
|Non-Alcoholic Steatohepatitis Non-Alcoholic Fatty Liver Disease||Drug: Semaglutide||Phase 2|
Non-alcoholic fatty liver disease (NAFLD) and its progressive form, non-alcoholic steatohepatitis (NASH), are leading causes of liver injury and are tightly associated with obesity, diabetes and the metabolic syndrome. Despite recent advances, there is still a considerable knowledge gap regarding the fundamental pathogenic mechanisms, and especially regarding the transition from benign steatosis to steatohepatitis. Although NAFLD reflects disordered energy metabolism in the liver, little information exists on the response of the human liver to the acute caloric load of a meal. We hypothesize, based on preliminary non-invasive results, that in patients with NAFLD, an oral carbohydrate load results in preferential de novo lipogenesis (due to selective insulin resistance) and generation of fatty acids (FA). We further hypothesize a spillover effect, wherein NASH patients have an impairment of the hepatic ability to esterify the load of FA to triglycerides (TG) compared to patients with steatosis, resulting in accumulation of lipotoxic intermediary metabolites.
GLP-1 receptor agonists (GLP-1RA) have demonstrated significant benefit in the treatment of diabetes and obesity. Liraglutide was shown in a prospective trial to improve NASH histology and other GLP-1RA have shown benefit in secondary analyses, consistent with a class effect. However, response rates to GLP-1RA, as well as to other pharmacological interventions in NAFLD, have not exceeded 50%, and there are no adequate baseline predictors of response that could allow for selection of subjects for personalized treatment. Given that GLP-1RAs exert their main activity in the post-prandial state, it is plausible that post-prandial parameters may be more effective in predicting treatment response and can shed light on its mechanism.
Our aims in this study are (1) to assess the hepatic response to an acute oral carbohydrate load; (2) to identify which baseline parameters can predict the clinical response of NAFLD patients to a course of semaglutide, a novel GLP-1RA.
We propose a non-randomized, single-center, pilot exploratory study in which up to 32 subjects with NAFLD (16) or NASH (16) will initially undergo two liver biopsies, one in the fasting state and one performed 2 hours after an oral 75g glucose load (OGTT biopsy). Tissue samples obtained will be subjected to a comparative, paired analysis of gene expression, protein phosphorylation in key signaling pathways, composition of tissue lipid species and oxidative stress. Subjects will be treated with semaglutide (escalated to 1 mg/week) for 30 weeks in all subjects, and their clinical response will be assessed by ALT and 1H-Magnetic resonance spectroscopy and a final (3rd) liver biopsy. Clinical responders will be compared to non-responders with regards to their baseline fasting and post-prandial parameters, to identify predictors of response.
The human hepatic response to a meal has never been studied at the tissue level and the findings of this study are likely to generate important data and clarify some of the fundamental questions regarding mechanisms of injury and insulin resistance. Furthermore, our study aims at identifying predictors of response to GLP-1RA and allow for appropriate selection of subjects for this class of medications, as well as to shed light on mechanism of response.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||84 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Primary Purpose:||Basic Science|
|Official Title:||Non-Alcoholic Fatty Liver Disease, the Hepatic Response to Oral Glucose, and the Effect of Semaglutide (NAFLD HEROES)|
|Actual Study Start Date :||July 24, 2019|
|Estimated Primary Completion Date :||January 31, 2023|
|Estimated Study Completion Date :||January 31, 2023|
Experimental: Arm A: Steatosis
Participants with steatosis on baseline biopsy
Semaglutide once weekly
Experimental: Arm B: NASH
Participants with NASH on baseline biopsy
Semaglutide once weekly
No Intervention: Arm C: Healthy
- Histological Improvement [ Time Frame: 30 weeks ]>=2 point decrease in NAFLD activity score (range 0-8, highscores indicate more activity)
- Clinical improvement [ Time Frame: 30 weeks ]Reduction of liver fat content (measure with 1H-magneticresonance spectroscopy) by >= 25% and reduction of ALT by >=25% or normalization of ALT
- Change in hepatic gene expression [ Time Frame: 2 hours after an oral 75g glucose load ]Change in hepatic gene expression for biopsies performed at baseline and 2 hours after an oral 75g glucose load
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03884075
|Contact: Yaron Rotman, M.D.||(301) email@example.com|
|United States, Maryland|
|National Institutes of Health Clinical Center||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 firstname.lastname@example.org|
|Principal Investigator:||Yaron Rotman, M.D.||National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)|