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Hepatic Energy Fluxes in NASH and NAS Patients

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ClinicalTrials.gov Identifier: NCT03997422
Recruitment Status : Recruiting
First Posted : June 25, 2019
Last Update Posted : February 11, 2022
Sponsor:
Information provided by (Responsible Party):
University of Minnesota

Brief Summary:

Diseases along the nonalcoholic fatty liver disease spectrum, which are tightly coupled to the obesity epidemic, are soon to become the commonest indication for liver transplantation in the United States. Bariatric surgery shows great promise in the treatment of these diseases. The studies proposed herein will be the first to measure in humans the relationships among (i) the liver's ability to burn fat and make glucose, two of its primary functions; (ii) the severity of nonalcoholic fatty liver disease; and (iii) the responses to bariatric surgery. These experiments will support deeper future mechanistic investigations of the metabolic mechanisms underlying nonalcoholic steatohepatitis (NASH) improvement with bariatric surgery.

The premise of this study is that deranged hepatic mitochondrial metabolism is a key biomarker and mediator of the nonalcoholic fatty liver disease (NAFLD)/NASH continuum, and the central hypothesis the investigators will test is that preoperative hepatic fat oxidation and glucose production flux parameters differ between low versus high NAFLD activity score (NAS), and response of the liver to bariatric surgery can be predicted by preoperative fluxes.


Condition or disease Intervention/treatment Phase
NASH - Nonalcoholic Steatohepatitis NAS Overweight or Obesity Weight Loss Bariatric Surgery Candidate Procedure: Vertical Sleeve Gastrectomy (VSG) Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Hepatic Energy Fluxes, NASH, and Vertical Sleeve Gastrectomy
Actual Study Start Date : July 1, 2019
Estimated Primary Completion Date : July 1, 2024
Estimated Study Completion Date : July 1, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Vertical Sleeve Gastrectomy (VSG)
Bariatric surgical procedure
Procedure: Vertical Sleeve Gastrectomy (VSG)
Vertical Sleeve gastrectomy will be performed using five laparoscopic ports using a 40 French Bougie as a template. If a hiatal hernia is identified it will be repaired. This practice has greatly reduced postoperative reflux disease (see human subjects protection). As VSG for patients with a BMI 30.0-34.9 kg/m2 is not covered by insurance the University hospital will cover costs for up to 24 patients.




Primary Outcome Measures :
  1. Hepatic Energy Fluxes [ Time Frame: 12 months ]

    Non-invasive dual isotope tracer-coupled magnetic resonance spectroscopy (MRS) will be used to measure tricarboxylic acid cycle (TCA) flux, anaplerosis, and gluconeogenesis.

    Outcome reported in micromols per minute per kg of lean body mass.



Secondary Outcome Measures :
  1. Histologic improvements in NAFLD Activity Score (NAS) [ Time Frame: 12 months ]

    The scale used is NAS - this is the NAFLD (Nonalcoholic Fatty Liver Disease) Activity Score.

    The NAS was developed to provide a numerical score for patients who most likely have NASH. Accordingly, NAS is the sum of the separate scores for steatosis (0-3), hepatocellular ballooning (0-2) and lobular inflammation (0-3). NAS scores of 0-2 are largely considered not diagnostic of NASH, scores of 3-4 are often considered not diagnostic, borderline, or potentially positive for NASH. Scores of 5-8 are largely considered diagnostic of NASH.

    It is expected that the addition of VSG to lifestyle modification will result in more robust histologic improvements in NAFLD Activity Score (NAS) compared to lifestyle modification alone.




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Ages Eligible for Study:   40 Years to 67 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosed with type-2 diabetes mellitus (T2DM) or prediabetes for at least 6 months prior to enrollment, under the active care of a doctor for at least the six months prior to enrollment, hemoglobin A1c (HbA1c)< 8% and NOT requiring insulin or other oral/ injectable hypoglycemic agents
  • Aspartate aminotransferase (AST) >32 IU/L or an alanine aminotransferase (ALT)>39.9 IU/L
  • Body Mass Index (BMI) 30.0-39.9 kg/m2 at eligibility visit
  • Willingness to accept surgical intervention after an individual seminar session
  • All patients must have insurance with no exclusion for obesity related treatments or management of obesity surgery complications. This applies to all patients enrolled in the study
  • Expect to live or work within approximately one-hour traveling time from the study clinic for the duration of the one-year trial
  • Willingness to comply with the follow-up protocol and successful completion of the run-in (described in section 5.2)
  • Written informed consent
  • Suitable for liver biopsy using the percutaneous approach
  • Vulnerable populations will not be targeted for inclusion, but those noted in section 9.1 may be allowed to participate provided they met all of the inclusion and none of the exclusion criteria.

Exclusion Criteria:

  • Cardiovascular event (myocardial infarction, acute coronary syndrome, coronary artery angioplasty or bypass, stroke) in the past six months.
  • Current evidence of congestive heart failure, angina pectoris, or symptomatic peripheral vascular disease.
  • Cardiac stress test indicating that surgery or IMM would not be safe.
  • Pulmonary embolus or thrombophlebitis in the past six months.
  • Cancer of any kind (except basal cell skin cancer or cancer in situ) unless documented to be disease-free for five years.
  • Significant anemia (hemoglobin 1.0 g/dL or more below normal range) or history of coagulopathy.
  • Serum creatinine >1.5 mg/dL.
  • Serum total bilirubin greater than the upper limit of normal in the absence of Gilbert's syndrome, or alkaline phosphatase or ALT or AST greater than twice the upper limit of normal. Elevated international normalized ratio (INR).
  • Alcohol intake more than one drink or >20 grams per day
  • History of stomach surgery, bile duct surgery, pancreatic surgery, splenectomy, or colon resection.
  • Gastric or duodenal ulcer in the past six months.
  • History of intra-abdominal sepsis (except for uncomplicated appendicitis or diverticulitis more than six months prior to enrollment).
  • Previous organ transplantation.
  • Self-reported HIV-positive status, active tuberculosis, active malaria, chronic hepatitis B or C, cirrhosis, or inflammatory bowel disease.
  • Currently pregnant or nursing, or planning to become pregnant in the next two years.
  • History of alcohol, drug, or opioid dependency (excluding nicotine) in the past five years.
  • Active psychosocial or psychiatric problem that is likely to interfere with adherence to the protocol.
  • Depression A Center for Epidemiologic Studies Depression (CESD) score more than 17 and a psychologist determination that the patient is not a good fit for surgery.
  • Current participation in a conflicting research protocol.
  • Presence of any chronic or debilitating disease that would make adherence to the protocol difficult.
  • 12-lead electrocardiogram (EKG) indicating that surgery would not be safe.
  • Serum c-peptide <1.0 ng/ml post prandial.
  • Exclusions may also be made at the discretion of the attending physician or the eligibility committee.
  • Contraindication to magnetic resonance imaging (MRI) scanning. MRI contraindications are assessed by MR technologists on the day of scanning using a standard safety screening form.
  • Gastroesophageal reflux disease requiring medications. History of endoscopy demonstrating esophagitis or Barretts changes in the esophagus. Any history of dysphagia.
  • More than 2 cups of coffee per day.
  • Treatment with drugs associated with nonalcoholic fatty liver disease (amiodarone, methotrexate, oral glucocorticoids at doses greater than 5 mg/day, tamoxifen, estrogens at doses greater than those used for hormone replacement or contraception, anabolic steroids, valproic acid) for more than 4 weeks within the last 2 months prior to the initial screening.
  • Treatment with pioglitazone or high-dose vitamin E (>400 IU/day) within the last 2 months prior to the initial screening.
  • Initiation of treatment with a glucagon-like peptide-1 (GLP-1) agonist or a dose change within the last 2 months prior to the initial screening

Information from the National Library of Medicine

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): NCT03997422


Contacts
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Contact: Mary Farnsworth 612-624-9695 ewigx005@umn.edu
Contact: Marina Pillai pill0048@umn.edu

Locations
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United States, Minnesota
University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Sayeed Ikramuddin, MD    612-625-2478    ikram001@umn.edu   
Sponsors and Collaborators
University of Minnesota
Investigators
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Principal Investigator: Sayeed Ikramuddin University of Minnesota
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Responsible Party: University of Minnesota
ClinicalTrials.gov Identifier: NCT03997422    
Other Study ID Numbers: SURG-2019-27704
First Posted: June 25, 2019    Key Record Dates
Last Update Posted: February 11, 2022
Last Verified: February 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Fatty Liver
Non-alcoholic Fatty Liver Disease
Overweight
Weight Loss
Body Weight
Body Weight Changes
Liver Diseases
Digestive System Diseases