Vertical Sleeve Gastrectomy and Lifestyle Modification for the Treatment of Non-Alcoholic Steatohepatitis

• ClinicalTrials.gov Identifier: NCT03587831
• Recruitment Status: Suspended
• First Posted: July 16, 2018
• Last Update Posted: December 16, 2020
• Sponsor: University of Minnesota
• Information provided by (Responsible Party): University of Minnesota

Tracking Information

• First Submitted Date: July 3, 2018
• First Posted Date: July 16, 2018
• Last Update Posted Date: December 16, 2020
• Actual Study Start Date: April 15, 2019
• Estimated Primary Completion Date: December 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 10, 2018)

Histologic improvements in NAFLD Activity Score (NAS) [ Time Frame: Month 12 ]

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.

Original Primary Outcome Measures (submitted: July 3, 2018)

Histologic improvements in NAFLD Activity Score (NAS) score [ Time Frame: Month 12 ]

Addition of VSG to lifestyle modification will result in more robust histologic improvements in NAFLD Activity Score (NAS) score compared to lifestyle modification alone.

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Vertical Sleeve Gastrectomy and Lifestyle Modification for the Treatment of Non-Alcoholic Steatohepatitis
• Official Title: Vertical Sleeve Gastrectomy and Lifestyle Modification for the Treatment of Non-Alcoholic Steatohepatitis
• Brief Summary: Participants meeting study entry criteria are randomized with equal probability to one of two study groups: (1) Lifestyle modification or (2) Vertical Sleeve Gastrectomy (VSG) with Iifestyle modification, followed for 12 months. The primary goal for the trial is to determine if the investigators can recruit, randomize, and retain participants to perform invasive and non-invasive measurements of NASH and fibrosis, deliver lifestyle modification and demonstrate the safety of VSG. The investigators wish to also understand which of these two interventions is more effective in achieving, 12 months after entry into the trial, a reduction in NAS composed of the non-weighted scores: (1) steatosis 0-3 (2) Inflammation 0-3 and (3) ballooning 0-2. Secondary goals include comparing the two treatment groups for changes in other measured outcomes including MRI assessments of intrahepatic triglyceride and liver elasticity and serum markers. As a pilot study, a sample size of 19 in each group should offer significant information as to the difference in NAS score reduction between to two groups and achieve adequate power to distinguish clinically significant changes in the primary and secondary outcome measures. These data support the overarching objective i.e. to provide evidence that a larger, longer-term clinical outcomes trial is feasible. A goal is for a longer term follow up for 5 years to assess the durability of treatment effects and treatment differences.

Detailed Description

The pilot study proposed in this protocol will determine whether patients with a BMI of 30-39.9 kg/m2 will consent to liver biopsy, accept randomization to VSG, participate in lifestyle modification for a one-year period and consent to a paired liver biopsy at 12 months. Sixty candidates will be biopsied with 42 randomizations within the first year yielding 19 (including dropouts) participants/group. This should be sufficient to further estimate meaningful differences in liver histology given the estimated weight loss of lifestyle modification with and without VSG and a correlation of percent weight loss and histological score improvement over the short term (12 months). Determining the impact of the VSG is essential for expanding the traditional indications for bariatric surgery and thus, broadening the potential impact of this pilot study.

The investigators will screen patients by telephone between the ages of 40 and 67 with a self-reported BMI of 30-39.9 kg/m2, a history of prediabetes, or type 2 diabetes. Prospective participants will be asked to provide a copy of their most recent liver chemistries to see if the AST or ALT fall in the inclusion range. The investigators will screen for a history of alcohol or other substance abuse and a surgical history that would preclude a safe VSG. Prospective participants will be invited to attend a seminar. They will be instructed to keep a food and exercise log for two weeks and return for a second visit. After consent is signed, during the eligibility review period participants will have their height and weight recorded, history reviewed, liver function tests, HbA1c, a urine sample, a basic metabolic profile, and INR will be obtained at this time and the participant will be referred for a liver biopsy. If the biopsy is consistent with NASH with a NAS >=5, then the participant will undergo MRI assessment and serum markers for inflammation. Vital signs (pulse, temperature, respiration, blood pressure, weight and BMI) will be obtained at each study visit. Participants will then begin an 800 calorie per day diet for 7 days during which they will receive their randomization assignment to VSG or not; all participants will receive lifestyle modification as the investigators need to see if surgery can provide any additional benefit to lifestyle modification. A basic metabolic panel will be performed at the conclusion of the 800 calorie diet. VSG will be performed laparoscopically and the greater curvature resected 6 cm for the pylorus to the angle of His over a 40 French Bougie. Lifestyle modification can begin immediately after surgery, though the VSG participants will not have calorie limits until 6 months after surgery. Participants will be seen regularly by the hepatologist and surgeon at 1 week, 4 weeks, 12 weeks, 6 months, and 12 months. Lifestyle modification will be overseen by Nancy Sherwood, Ph.D. Lifestyle will be delivered on an individual basis once per week for the first 6 months, twice per month for the next 3 months, and monthly up to one year. Vitamins A, B1, B12 and D and a comprehensive metabolic panel including liver chemistries will be performed at 3 months and 12 months in both groups. At 12 months a repeat liver biopsy will be performed (participants will have the opportunity to select an alternative approach if they did not have a good experience with the initial liver biopsy in order to ensure a paired specimen). This decision will be made in conjunction with the interventional radiologist. MRI for steatosis and elasticity will be performed and serum inflammatory and fibrosis markers will be obtained at 12 months as well as the collection of another urine sample. Participants will exit the study but will continue usual care after 12 months. We will create a biorepository for stool samples to measure the microbiome and for remaining liver tissue to measure the transcriptome.

Participants meeting study entry criteria are randomized with equal probability to one of two study groups: (1) Lifestyle modification (LSM) or (2) Vertical Sleeve Gastrectomy (VSG + LSM) with Iifestyle modification, followed for 12 months. The primary goal for the trial is to determine if we can recruit, randomize, and retain participants to perform invasive and non-invasive measurements of NASH and fibrosis, deliver lifestyle modification and demonstrate the safety of VSG. The investigators wish to also understand which of these two interventions is more effective in achieving, 12 months after entry into the trial, a reduction in NAS composed of the non-weighted scores: (1) steatosis 0-3 (2) Inflammation 0-3 and (3) ballooning 0-2. Secondary goals include comparing the two treatment groups for changes in other measured outcomes including MRI assessments of intrahepatic triglyceride and liver elasticity and serum markers. As a pilot study, a sample size of 19 in each group should offer significant information as to the difference in NAS score reduction between to two groups and achieve adequate power to distinguish clinically significant changes in the primary and secondary outcome measures. These data support the overarching objective i.e. to provide evidence that a larger, longer-term clinical outcomes trial is feasible. A goal is for a longer term follow up for 5 years to assess the durability of treatment effects and treatment differences.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: NASH - Nonalcoholic Steatohepatitis

Intervention

• Procedure: Vertical Sleeve Gastrectomy
  Surgical Procedure: Vertical Sleeve Gastrectomy
• Behavioral: Lifestyle Modification Counseling
  Behavioral Intervention: Lifestyle Modification Counseling

Study Arms

• Experimental: VSG + LSM

  Procedure/Surgery: Vertical Sleeve Gastrectomy will be performed using five laparoscopic ports. The short gastric and epiploic vessels will be taken down With a 40 French Bougie in place, the greater curvature will be excised starting 6 cm proximal to the pylorus.

  Behavioral: Lifestyle Modification Counseling - The intensive lifestyle intervention will align with methods listed in the LSM arm description. However, participants assigned to the VSG will not have calorie ceilings during the first 6 months of rapid weight loss, and they will receive additional instruction regarding food volume and adequate protein intake.

  Interventions:

  • Procedure: Vertical Sleeve Gastrectomy
  • Behavioral: Lifestyle Modification Counseling
• Active Comparator: LSM
  Behavioral: Lifestyle Modification Counseling - The intensive lifestyle intervention is modeled after the LookAHEAD trial, with modules modified for participants undergoing surgery, and designed to produce maximum achievable weight loss. Both groups will increase their level of moderate-intensity physical activity (such as walking) to a total of 325 minutes per week. All lifestyle-medical management participants will be given calorie intake targets of 1200, 1500, or 1800 kilocalories per day, depending on body weight, with the goal of producing a weight loss of 1 to 2 pounds per week. There will be 24 weekly counseling meetings during the first 6 months, bi-weekly meetings between months 7 and 9, and monthly meetings between months 10 and 12.
  Intervention: Behavioral: Lifestyle Modification Counseling

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Suspended
• Estimated Enrollment (submitted: July 3, 2018): 60
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2022
• Estimated Primary Completion Date: December 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Age 40 to 67 years at eligibility visit.
2. Diagnosed with T2DM (type 2 diabetes mellitus) 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, HbA1c< 9% and NOT requiring insulin.
3. AST >32 IU/L or an ALT>39.9 IU/L
4. Body Mass Index (BMI): 30.0-39.9 kg/m2 at eligibility visit.
5. Willingness to accept random assignment to either treatment group.
6. All patients must have insurance with no exclusion for obesity related treatments or management of obesity surgery complications. This applies to all participants enrolled in the study
7. Expect to live or work within approximately one-hour traveling time from the study clinic for the duration of the one-year trial.
8. Willingness to comply with the follow-up protocol and successful completion of the run-in (described below).
9. Written informed consent.

Exclusion Criteria:

1. Cardiovascular event (myocardial infarction, acute coronary syndrome, coronary artery angioplasty or bypass, stroke) in the past six months.
2. Current evidence of congestive heart failure, angina pectoris, or symptomatic peripheral vascular disease.
3. Cardiac stress test indicating that surgery would not be safe.
4. Pulmonary embolus or thrombophlebitis in the past six months.
5. Cancer of any kind (except basal cell skin cancer or cancer in situ) unless documented to be disease-free for five years.
6. Significant anemia (hemoglobin 1.0 g/dL or more below normal range) or history of coagulopathy.
7. Serum creatinine >1.5 mg/dL.
8. 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 INR.
9. Alcohol intake more than one drink or >20 grams per day
10. History of stomach surgery, bile duct surgery, pancreatic surgery, splenectomy, or colon resection.
11. Gastric or duodenal ulcer in the past six months.
12. History of intra-abdominal sepsis (except for uncomplicated appendicitis or diverticulitis more than six months prior to enrollment).
13. Previous organ transplantation.
14. Self-reported HIV-positive status, active tuberculosis, active malaria, chronic hepatitis B or C, cirrhosis, or inflammatory bowel disease.
15. Currently pregnant or nursing, or planning to become pregnant in the next two years.
16. History of alcohol, drug, or opioid dependency (excluding nicotine) in the past five years.
17. Active psychosocial or psychiatric problem that is likely to interfere with adherence to the protocol.
18. Depression: A CES-D score more than 17.
19. Current participation in a conflicting research protocol.
20. Presence of any chronic or debilitating disease that would make adherence to the protocol difficult.
21. 12-lead EKG indicating that surgery would not be safe.
22. Serum c-peptide <1.0 ng/ml post prandial.
23. Exclusions may also be made at the discretion of the attending physician or the eligibility committee.
24. Contraindication to MRI scanning. MRI contraindications are assessed by MR technologists on the day of scanning using a standard safety screening form.
25. Gastroesophageal reflux disease requiring medications. History of endoscopy demonstrating esophagitis or Barrett's changes in the esophagus. Any history of dysphagia.
26. More than 2 cups of coffee per day.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 40 Years to 67 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03587831
• Other Study ID Numbers: SURG-2018-26636
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: University of Minnesota
• Study Sponsor: University of Minnesota
• Collaborators: Not Provided

Investigators

• Principal Investigator: Sayeed Ikramuddin, M.D., M.H.A.; University of Minnesota

• PRS Account: University of Minnesota
• Verification Date: December 2020