Laparoscopic Adjustable Gastric Banding Biology Essay

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A review of the literature indicates that the development of bariatric procedures, in general, has mainly involved human subjects and very little efforts have been put forth to understand the underlying mechanism by which these surgical methodologies work. The mechanism by which LABG achieves increased rate of satiety is not completely understood. In fact, 'restricted amount of food entering the stomach' is the only available explanation of how LABG works1.

Kampe et al., has criticized this explanation of the mechanism by which LABG achieves its effective outcomes. Their criticism is based on the evidence that patients experience reduced hunger even after an overnight fast. In addition, there is also evidence of early improvements in type II diabetes after the procedure2. Thus, providing a strong indication that mechanisms by which LABG treatment provide efficacy are much more complex and involve other bodily systems as well (i.e., Central Nervous System and Endocrine System). Nevertheless, LABG is an invasive process and it is ideal to conduct pre-clinical research. This will serve the purpose of not only strengthening the 'Device License Application' submission to regulatory authorities but also provide a better understanding of how LABG affects human body systemically.

Considering these issues, pre-clinical research has begun with the first rat model (male Wistar rats) for restrictive bariatric surgery, with gastric banding being developed in 20063. Several studies have utilized this rat model because; its metabolism is well known and examined in detail, cost effective and readily available. This model, however, is not suitable for research involving adjustable gastric banding. Therefore, in 2008, researchers in Australia developed the first rodent model for adjustable gastric band surgery using Sprague-Dawley rats4. This model has several characteristics that are analogous to human situation. For example, the band used is applied to gastro-esophageal junction, activated remotely, adjustable and allows incremental adjustment of the stomach while animal is conscious. Since Sprauge-Dawley rat is currently the best model available for LAGB studies, the following pre-clinical study design will utilize this particular model.

Pre-Clinical Study Design

Pre - Surgery Preparation

Based on weight, two groups of Sprauge-Dawley rats will be divided into two groups. One of the groups will receive LAGB surgery and other sham surgery. All rats will be housed in separate cages in a temperature and humidity control rooms where light is controlled on a 12 hour cycle to stimulate the effects of night and day. In addition, all rats will be given ad libitum access to food (rat chow) and tap water. All rats must be given 7 days to acclimatize to the facility environment and be 12 hour overnight fasted prior to the day of surgery. All study procedures must be approved by the ethics board.

Post - Surgery

Rats will be monitored and test for 29 days after surgery and sacrificed on the last day.

Food Consumption - Pre-measured amount of food will be provided one hour before the night cycle begins. All rats, along with remaining food, will be weighed two hours after the day cycle begins. Food consumption will also be measured after every 2 hours during the light and dark phase. Results of this procedure will allow the investigators to assess the effects of adjustable gastric band surgery on the weight of rats and their food consumption.

Laboratory Tests - Blood samples will be drawn based on the following schedule for 4 weeks:

Day 1 of 7 - 3 hours after beginning of each light cycle

Day 2 of 7 - 0.5 hrs before the ending of each light cycle

Day 3 of 7 - 0.5 hrs after the beginning of each light cycle

Day 4 of 7 - No blood samples

Day 5 of 7 - Repeat day 3 schedule

Day 6 of 7 - Repeat day 2 schedule

Day 7 of 7 - Repeat day 1 schedule

Each blood sample will be analyzed for:

Glucose & Insulin levels - monitoring of glucose and insulin levels will allow the investigators to assess the metabolic differences between LABG and sham surgery operated rats.

Ghrelin level - Ghrelin is a gastrointestinal hormone, responsible for stimulating hunger and feeding. Analysis of ghrelin in rats will allow investigators to determine whether ghrelin levels change in between the experimental groups and whether the reduction in food intake is correlated with Ghrelin level.

Leptin level - Leptin is released from adipose tissue. Along with many other important functions, this hormone is responsible for communicating with the CNS and evoking the feeling of satiety, thus allowing the individual to stop eating. Purpose of monitoring Leptin levels is to determine whether rats with LABG surgery have different levels than those of rats in control group. In addition, determine if there is any correlation between changes in Leptin levels and food consumption.

29th day post surgery

On the 29th day after surgery, all rats will be sacrificed. Their subcutaneous white adipose tissue will be removed, weighed and compared between the two experimental groups.

Conducting this pre-clinical study will allow investigators to determine not only the physical changes due to LABG surgery, but also the biochemical changes as well. This research will provide indications of how the LABG surgery impacts the body systematically and what parameters will the clinicians have to consider when conducting this surgery in humans.

Clinical Research

Clinical research is the most important process that needs to be carried out. Its success and failure determine whether the regulatory authorities approve/reject the marketing of any pharmaceutical or medical devices for human use. Along with the effectiveness of the product, the methodologies and expertise of the researchers conducting the clinical research plays a crucial rule in the success of any clinical research trial. Following is a proposal for clinical trials to assess the safety and efficacy of LAGB device.

First In Human (FIM)

Unlike majority of pharmaceutical products, FIM trial for LAGB surgery will recruit only patients. A total of 20 patients will be recruited based on the following inclusion/exclusion criteria. In addition, there will be two sentinel subjects who will receive the treatment 2 weeks prior to rest of the cohort. Inclusion of first two sentinel subjects will provide better protection to the remaining 18 patients enrolled in the study.

Inclusion Criteria:

Patients are capable of giving informed consent or have a legal representative who can give consent on their behalf

BMI ≥ 40

Men or women who are ≥ 18 and ≤ 65

Prior to enrolment in the study, women of childbearing potential must have a negative result on their pregnancy test. They must agree to use appropriate contraceptive methods during the course of their enrolment in the study

Must have a primary care giver at their residence

Exclusion Criteria:

Diagnosis of any psychiatric illness

Eating disorder with purging

History of Substance and / or alcohol abuse

Consuming any weight loss medications

Previous bariatric surgery

Inability to comply with pre-operation and post-operation visits

Primary Efficacy End Points:

BMI of Patients receving LABG surgery reduces below 40

Primary Safety End Points:

Malnutrition - vitamin and mineral deficiency

Abdominal pain due to LAGB complication

Slippage of the band

Pre-Operative procedure

Eligible patients need to be contacted by site staff and informed about the study. Patients must be given sufficient time to study the Informed Consent Form and ask questions. They will be kept fasted for at least 12 hours prior to the procedures. Blood samples will be drawn one hour before the fasting and one hour before the surgery begins. In addition, patients will be weighed and their BMI will be recorded. The weight information, and data obtained from blood tests will serve to establish the baseline for each patient.

Post-Operative procedure

After one day of stay at the site, Primary Investigator (PI) will make the decision of discharging the patient. The gastric band will be adjusted according to patients overall health status and / or based on PI's discretion. Each patient will be given a strict dietary schedule, adherence to which needs to be ensured by the primary care giver of the patient. In addition; each patient will be assigned a glucose monitor, which has the capacity of storing data, to take home. Patients or their primary caregivers need to record their glucose levels.

After every week, for 2 months, patients will visit the site for their assessment by the Principle Investigator and blood drawings. At each visit, their weight and BMI will be recorded. Patients will be assessed for their general health, and compared against their base-line values by the PI. In addition, the band will also be adjusted (increased / decreased) as per the discretion of the PI.

Phase II

If the results of FIH study indicate promising results and provide adequate safety data, Phase II trials will be conducted to further evaluate safety and efficacy in detail. This phase will enroll 100 patients and patients will be required to make weekly visits for 4 months. This phase will follow the same procedures as FIH study.

Phase III

Phase III will be a randomized trial, consisting of two experimental arms. The study will recruit 300 patients which will be randomly assigned to receive either LAGB or LRYGB surgery. The purpose of this phase is to prove that LAGB is more effective and safer than the current standard of care (LRYGB) for morbid obesity.

Inclusion and Exclusion criteria, along with the study procedures, will remain the same. However, post-operative stay of 7 days will be required by each patient. The reason for extended post-operative stay at the site is due to the fact that LRYGB is a relatively more invasive procedure than LAGB. In addition, patients will be required to visit the site weekly for 6 months. Furthermore, recruited patients will be asked to fill-out a Quality of Life Questionaire (QoLQ) prior the surgery to establish base-line. All patients will fill-out this questionnaire on their weekly visits to the site and the data analysis will compare their weekly visit responses to the baseline.

Upon conclusion of the trials, the aim is to demonstrate that LAGB improves quality of life patients and is a much more safer and effective device than the current standard of care (LRYGB) for morbid obesity.

Monteiro M, Monteiro D, Aguas A, Cardoso H. A rat model of restrictive bariatric surgery with gastric banding. Obesity Surgery. 2006;16:48-15.

Monteiro M, Moteiro D, Aguas A, Cardoso H. Rats submitted to gastric banding are leaner and show distinctive feeding patterns. Obesity Surgery. 2006;16:597-602.

Monteiro M, Moteiro D, Aguas A, Cardoso H. Rats submitted to gastric banding are leaner and show distinctive feeding patterns. Obesity Surgery. 2006;16:597-602.

Kampe J, Brown W, Stefanidis A, Dixon J, Oldfield B. A rodent model of adjustable gastric band surgery - implications for the understanding of underlying mechanisms. Obesity Surgery. 2009;19:635-631