Clinical Trial Details
— Status: Enrolling by invitation
Administrative data
| NCT number |
NCT04841057 |
| Other study ID # |
2032062 |
| Secondary ID |
|
| Status |
Enrolling by invitation |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
November 1, 2021 |
| Est. completion date |
March 1, 2031 |
Study information
| Verified date |
June 2023 |
| Source |
University of Missouri-Columbia |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Variable outcomes after weight loss surgery are likely attributable to complex, poorly
understood mechanisms. Due to the significant impact that morbid obesity has on a patient's
health, successful management of obesity and its related comorbid medical conditions is
important and thus necessitates continued improved therapies for treating obesity. Although
the mechanisms of weight loss after surgical intervention are poorly understood, improved
understanding of molecular and metabolic changes that occur after weight loss surgery may
offer the ability to provide targeted precision therapy for patients with morbid obesity
undergoing surgical therapy. In this proposal, the investigators will combine a clinical
trial whereby modifications to the gold-standard for weight loss surgery, the gastric bypass,
are evaluated while simultaneously measuring molecular and metabolic changes that occur in
response to these weight loss procedures. Through creating variable lengths of bypass
intestine after gastric bypass, the investigators will be able to determine the effect of
malabsorption on clinical outcomes and mechanisms involved in weight loss after gastric
bypass. The investigators will also use two control groups. One will be a surgical weight
loss control group and consist of patients undergoing a laparoscopic sleeve gastrectomy, a
non-intestinal bypass procedure. The other group will consist of patients having non-surgical
weight loss therapy. To asses metabolic changes that occur in response to surgical weight
therapy and specifically intestinal bypass and malabsorption, the investigators will examine
changes in the gut microbiome and plasma gut enteroendocrine hormones. To evaluate molecular
pathways that are impacted as a result of gastric bypass and malabsorption, the investigators
will measure circulating microRNAs (miRNAs) in the blood. Measurement of miRNAs will provide
data on an easily measurable molecular marker for each treatment group. This is a first step
in translational exploration of mechanisms of weight loss after surgery by evaluating both
clinical and molecular/metabolic outcomes and begin an explorative process towards creating
an individualized approach to improving outcomes after weight loss surgery.
Description:
Outcomes after weight loss surgery are quite variable with some patients regaining a
significant amount of weight in the postoperative period. Increasing evidence suggests
gastric bypass leads to weight loss and improvement in associated metabolic illness through
mechanisms other than just restriction and malabsorption and may include circulating bile
acids, gut hormones, genetic/epigenetic variability, changes in gut microbiota as well as
other mechanisms. Whether modifications to bypassed intestine length may improve outcomes
after gastric bypass has not been adequately studied with inconsistent results in the
literature. Whether increasing the amount of bypassed intestine may positively amplify the
multi-factorial mechanisms involved in successful weight loss has not been studied.
The primary goal of the research is to determine if increasing the amount of bypassed
intestine during gastric bypass surgery improves outcomes and effects molecular and metabolic
changes that may impact outcomes after gastric bypass. The proposed research will evaluate
not only biologic mechanisms of weight loss and correlation between these mechanisms and
successful weight loss but also investigate the role intestinal bypass has on molecular and
metabolic mechanisms involved in effective weight loss therapy. Regardless if weight loss
outcomes are similar in patients with different lengths of bypassed intestine, the role of
the gut in gastric bypass will be investigated through evaluation of gut microbiota,
circulating miRNAs and gut hormones, three mechanisms thought to play a role in the
effectiveness of the gastric bypass for weight loss surgery.
Aim 1: Determine if increasing length of bypassed intestine leads to improved clinical
outcomes after gastric bypass. A randomized-controlled trial design will be used with
patients randomized to variable lengths of bypassed intestine when undergoing gastric bypass.
A randomized trial will help avoid procedure selection bias. Surgical and non-surgical
control groups will consist of patients having sleeve gastrectomy (non-intestinal bypass
surgical control) and those undergoing best non-surgical, medical therapy. Primary outcomes
measured will include weight loss and relief of medical comorbidities of obesity specifically
diabetes and dyslipidemia. Secondary outcomes include complications related to malabsorption.
Aim 2: Measure gut hormone changes after increased intestinal bypass during gastric bypass.
The investigators will measure gut hormones after variable amounts of intestinal bypass to
determine the role of intestinal bypass in improvement of gut hormone production that affects
metabolism, hunger and possibly weight loss. Blood collected from patient's in Aim 1 will be
used to measure gut hormone levels which will then be correlated to clinical outcomes.
Aim 3: miRNA profiling in patients having gastric bypass with variable intestinal bypass
lengths. The investigators will perform miRNA arrays on plasma from patients from Aim 1 to
determine possible pathways impacted by weight loss and in particular increased intestinal
bypass lengths in patients undergoing gastric bypass. The variable expression of miRNA will
also be correlated to weight loss outcomes and metabolic disease improvement in the surgical
patients.
Aim 4: Measure variation in gut microbiome due to increased intestinal bypass during gastric
bypass. The investigators will examine the impact of weight loss and variable intestinal
bypass lengths during gastric bypass on the gut microbiome. This will be determined through
collection of stool samples preoperatively as well as postoperatively in patients having
weight loss surgery. Samples will be collected from patients in Aim 1 above. Sleeve
gastrectomy patients will be used to determine the impact of surgical weight loss on gut
microbiome and variation in intestinal bypass lengths will provide insight into the role of
bypassed intestine in the effects of gastric bypass on changes in gut microbiota after weight
loss surgery. Through correlation with clinical outcomes the investigators will be able to
determine any association with weight loss and relief of metabolic disease when the gut
microbiota are modified after weight loss surgery.
Approach
Protocol Aim 1: Determine if increasing length of bypassed intestine leads to improved
clinical outcomes after gastric bypass.
Primary outcomes will include weight loss and relief of medical comorbidities of obesity, in
particular diabetes and dyslipidemia. Secondary outcomes include determining complications
that occur such as protein calorie malnutrition, vitamin and micronutrient deficiencies and
chronic diarrhea.
1a. Randomization of patients and surgical technique. A total of five groups will be used.
The surgical control group will consist of patients having a laparoscopic sleeve gastrectomy
as described below under procedure descriptions. The non-surgical control group will include
patients undergoing best medical therapy through our medical weight loss program. The other
three groups will be randomized through a sealed-envelope method. The assigned group will be
in a sealed envelope and the patient will be blinded to the treatment group that they are
assigned to. Patients will be randomized to variable lengths of intestinal bypass during
performance of a laparoscopic Roux-en-Y gastric bypass. See description of procedure below.
These groups will function to examine the impact of increasing lengths of bypassed small
intestine through modifications of the BPL length. The following three groups will be
utilized:
1. Alimentary limb length 100 cm and biliopancreatic limb length (true bypassed intestinal
length) of 50 cm
2. Alimentary limb length 100 cm and biliopancreatic limb length (true bypassed intestinal
length) of 100 cm
3. Alimentary limb length 100 cm and biliopancreatic limb length (true bypassed intestinal
length) of 150 cm Sample size for randomization to the three gastric bypass groups will
be approximately 75 patients in each group. 75 sleeve gastrectomy patients will also be
included. Sample size was determined based on previously published literature. The total
number of these patients will be used only for the clinical portion of the study. Sample
size for this pilot study for each of the gut hormone assays, gut microbiome analyses
and miRNA arrays will be 15 subjects in each group. This will include 15 patients
selected from each of the groups of randomized gastric bypass patients, the sleeve
gastrectomy group, and the medical control group for a total of 75 patients. Each
patient will have stool and blood collected at pre-treatment (surgical or non-surgical
therapy), 6 months post therapy and 12 months post therapy.
Surgical Procedure A gastric bypass will be performed using our standard technique. In brief,
all procedures will be performed laparoscopically as is standard practice. Specifically at
our institution, the gastric pouch will be constructed with a linear stapler approximately 5
cm long and 3 cm wide. The gastrojejunostomy anastomosis will be constructed either with a 25
mm circular stapler or a linear stapler. The linear stapler common gastroenterotomy will be
closed in a running 2 layer manner to narrow to approximately 13-15 mm. The jejunojejunostomy
will be created with a liner stapler after creation of BPL length of 50 cm, 100 cm or 150 cm
and an alimentary limb length of 100 cm which will be connected to the gastric pouch via the
gastrojejunostomy. The remaining small bowel, which will represent the common small bowel
channel will also be measured. Measurements will be achieved using premeasured markings on a
laparoscopic grasper used to handle the small intestine.
Patients undergoing a sleeve gastrectomy will serve as the control group in order to
determine the effect that intestinal bypass has on the measured outcomes. The sleeve
gastrectomy is performed laparoscopically to resect and remove approximately 80% by volume of
the outer portion of the stomach. At our institution, specifically the sleeve gastrectomy is
performed using multiple firings of a laparoscopic stapler using a bougie as an intraluminal
template for sizing purposes. The bougie is either 36 or 40 French per our usual practice.
2a. Sample collection preoperatively and postoperatively for metabolic and molecular studies.
Sample Collection
Samples will be collected and processed by the OneHealth Biorepository or other on site
research laboratory. The following samples will be collected in each patient:
1. Blood: will be collected at a preoperative time point then at 6 months and 12 months
postoperatively. The blood will be drawn by MU Health Care laboratories or associated
research personnel and transported by courier per standard protocol to the OneHealth
Biorepository or other research lab. It will be fractionated into its components and
plasma collected and stored at -80℃ as previously described.
2. Stool: Stool samples will be collected by patients at home using provided kits and
mailed to the OneHealth Biorepository or other affiliated research lab and stored, as
previously described. Samples will be aliquoted and stored at -20℃.
3a. Prospective collection of clinical data. Weight related data will be collected to
determine effectiveness of weight loss operations. Weight data collected will include high
weight when entering the weight loss surgery program, immediate preoperative weight collected
on day of operation and postoperative weights at 1 week, 1 month, 3 months, 6 months and 12
month follow-up appointments. Additional outcomes collected will include presence of diabetes
mellitus with glycated hemoglobin (HgbA1C) levels measured preoperatively and at 6 and 12
months postoperatively Remission of diabetes will be considered if the patient is off all
anti-diabetic medications with a normal HgbA1C. Presence of preoperative dyslipidemia will
also be documented to include abnormalities of LDL cholesterol, HDL cholesterol and
triglyceride levels. Remission of dyslipidemia will be considered if preoperative abnormal
levels of LDL and HDL cholesterol and triglycerides return to normal in the absence of
lipid-lowering agents.
Aim 2: Measure gut hormone changes after increased intestinal bypass during gastric bypass
Millipore Human Metabolic Hormone Magnetic Bead Panel - Metabolism Multiplex Assay will be
used to investigate a panel of gut hormones including GLP-1, GIP, leptin, PYY, and ghrelin.
Plasma from 15 patients from each group (as described above) for a total of 75 total patients
will be examined. Hormone levels in the plasma will be measured. Data will be analyzed both
for intergroup differences as well as correlation with clinical outcomes will be performed.
Aim 3: miRNA profiling in patients having gastric bypass with variable intestinal bypass
lengths 15 patients from each group (as described above) for a total of 75 total patients
will be examined. Plasma will be used to perform Affymetrix miRNA arrays to measure
expression of all currently known miRNA. Corresponding pathways that miRNA affect will be
identified using publicly available databases. Differences in miRNA expression between
treatment groups will be compared. Differential levels of expression of miRNA will also be
compared to clinical outcomes.
Aim 4: Measure variation in gut microbiome due to increased intestinal bypass during gastric
bypass.
Stool samples will be collected as described above. They will be stored in the OneHealth
Biorepository or other laboratory until processing. 15 patients from each group (as described
above) for a total of 75 total patients will be examined. Composition of microbiota in each
group will be determined as previously described. Comparison between treatment groups will be
performed. Correlation to clinical outcome variables will be determined
