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Bariatric clinical trials

Imperial College undertakes obesity/metabolism clinical trials

Studies looking at the limb length during RYGB, whether Liraglutide can substantially reduce blood glucose in patients who have had either RYGB or VSG and if duodenal mucosal resurfacing treatment can increase insulin sensitivity in women with PCOS

Imperial College London has provided an update on three important clinical trials that are assessing various aspects of bariatric and metabolic procedures. The three unique studies are looking at the importance of the biliopancreatic  limb length during Roux-en-Y gastric bypass (RYGB); whether the administration of Liraglutide can substantially reduce blood glucose and weight in patients who have had either RYGB or vertical sleeve gastrectomy (VSG); and if duodenal mucosal resurfacing treatment can increase insulin sensitivity and whether it can help women of reproductive age start menstruating in women with polycystic ovarian syndrome (PCOS).

LONG LIMB Trial

Steve Bloom

Researchers at Imperial College London and King’s College London, UK, are comparing long-limb RYGB vs. the standard-limb RYGB. In this a prospective, double-blinded, randomised, controlled clinical trial, 50 patients are being recruited and randomised to either the long-limb (150cm biliopancreatic limb with a 100cm Roux limb) or the standard-limb (50cm biliopancreatic limb with a 100cm Roux limb) RYGB surgery. Clinical assessments and mechanistic studies are taking place before and after surgery.

Francesco Rubino

The long-limb RYGB has been devised as a hybrid operation that combines design of the standard-limb RYGB, but with a longer biliopancreatic limb (150cm).

It is believed that procedure improves glucose-lowering efficacy of the standard RYGB, whilst avoiding the high risk of complications with the biliopancreatic diversion with duodenal switch (BPD/DS) procedure.

Ahmed Ahmed

The LONG LIMB Trial, funded by the National Institute for Health Research (UK), is led by Professors Sir Steve Bloom and Francesco Rubino, run by Mr Ahmed R Ahmed and Miss Anna Kamocka, and will follow patients for one year after surgery. The trial outcomes are expected to be reported in 2018.

The study entitled, ‘Are gut hormone changes the reason why the long-limb gastric bypass is more effective than the standard limb gastric bypass in improving type 2 diabetes mellitus? A randomised controlled trial,’ will investigate the mechanisms of both procedures and the underlying differences by:

  • Comparing the clinical efficacy of the two procedures on obese patients with T2DM
  • Measuring insulin and gut hormone secretion following a standardised mixed meal tolerance test
  • Measuring insulin sensitivity (hepatic and peripheral) using the two-phase euglycaemic-hyperinsulinaemic clamp
  • Exploring the role of changes in plasma bile acid levels, gut bacteria diversity and their metabolites in the glycaemic improvements observed after these procedures

GRAVITAS trial

In the study, ‘The GRAVITAS trial: GLP­1 Receptor Agonist interVentIon for poor responders afTer bariAtric Surgery’, researchers are exploring whether the administration of Liraglutide to poor responders after RYGB and vertical sleeve gastrectomy (VSG), to examine whether Liraglutide can substantially reduce blood glucose, body weight and food intake, change eating behaviour, and prove to be a novel, effective and safe therapy for this cohort of patients.

According to the researchers, in diabetic patients undergoing bariatric surgery the remission or improvement of diabetes at 12 months is achieved in around 80% of those undergoing a RYGB and 55% in VSG. However, at five-year follow-up, around 20-40% of patients maintain T2DM remission. Similar pattern is seen with weight. During the first-year post surgery there is an important weight loss of approximately 20-30% of total body weight. However, after 12 months, there is a progressively weight regain of around 50% of the initial weight loss and this may be one of the predominant factors leading to the decrease in diabetes remission rates overtime. Therefore, despite high success rates, a proportion of patients fails to achieve sustained control of diabesity following surgery.

It is also known that pre-operative use of anorexigenic gut hormone analogues, such as the gut hormone glucagon like peptide (GLP) 1, is effective not only for glycaemic control but also for moderate weight loss in the absence or presence of T2DM by suppressing appetite, food intake and potentially by changing food preferences. Several retrospective observational studies have shown its benefits in poor responders after bariatric surgery, but no previous clinical trials have been performed.

Tricia Tan

The GRAVITAS Trial, led by Professor Sir Steve Bloom and Professor Tricia Tan, and run by Dr Belen Pevida, is a prospective double-blinded randomised, placebo-controlled clinical trial. The trial has recruited 80 patients who have undergone RYGB or VSG surgery at least 12 months before randomisation and have sub-optimally controlled T2DM. Patients were randomised to either treatment with the GLP-1 receptor agonist liraglutide or placebo and treated for six months. Clinical assessments and mechanistic studies are taking place before and after treatment.

For the first two weeks of the study, all participants were taught how to use the injector pen device and asked to inject themselves with a dummy (placebo) every day. At the end of the two weeks, the devices are measured in order to find out how well each participant stuck to the regime. Participants are then randomly allocated to one of two groups.

Participants in the first group are given pens containing liraglutide to use every day. For one week, a dose of 0.6mg/day is taken, then 1.2mg/day for the next week and then 1.8mg/day for the following week. After this, participants are given the opportunity to adjust the dose if they are experiencing a lot of side effects. Participants in the second group are given pens containing a dummy (placebo) to use every day at the same doses as the first group. At the start of the study and then again after 26 weeks, participants in both groups attended follow up appointments so that their weight and blood sugar levels (in a blood test) were measured.

Participants in both groups benefited from being under the care of a specialist team which they would not normally have access to. The patients taking the liraglutide may also benefit from improvements to their diabetes management and weight loss. The clinical research team provided patients with a capillary glucose meter, inform them of possible side effects of liraglutide (e.g. nausea, vomiting, constipation or diarrhoea, hypoglycaemia and possible dehydration), and advised them as to how to deal with them. Patients were also informed of the rare complication of pancreatitis and were specifically instructed to urgently report any symptoms of abdominal pain to the clinical research team.

This trial was funded by the J P Moulton Charitable Foundation and the medications kindly provided by Novo Nordisk. The trial outcomes are expected to be reported in 2018.

DOMINO Trial

The DOMINO Trial, led by Dr Alex Miras, Senior Lecturer in Endocrinology at Imperial College London, is a prospective double-blinded randomised controlled trial investigating whether the Fractyl Revita System, can increase insulin sensitivity and whether it can help women of reproductive age start menstruating in women with PCOS.

Alex Miras

Polycystic ovarian syndrome is the most common endocrine disorder affecting women. In addition to hyperandrogenism, dysregulated menstrual cycles and subfertility, women with PCOS have an increased rate of obesity and insulin resistance. This constellation leads to a number of co-morbid conditions including metabolic syndrome, hypertension, dyslipidaemia, glucose intolerance and type 2 diabetes.

According to Miss Vasha Kaur that runs the trial weight loss is the most effective therapy for restoring fertility in women with PCOS. Reduction in weight as little as 5% can restore regular menses and improve response to pro-ovulatory and fertility medication. However, lifestyle interventions only work in the short term and is difficult to maintain. Pharmacological and invasive treatments have significant side effects with limited efficacy and patient acceptability. As a consequence, a large number of these women remain infertile and this can have a devastating impact on their psychological health.

In the study, ‘Investigation of the metabolic effects of duodenal resurfacing on insulin resistant women with polycystic ovarian syndrome’, patients will receive either Fractyl Revita duodenal mucosal resurfacing treatment or a sham procedure. Patients will be followed for six months post-procedure and both the intervention and control groups will be given intensive NHS Tier 3 lifestyle advice for weight loss, therefore the control group is also expected to benefit from the trial.

Duodenal mucosal resurfacing is a novel endoscopic technique which ablates the duodenal mucosal from an area distal to the papilla up to the ligament of Treitz. It that has been used effectively in patients with Type 2 diabetes resulting in rapid reduction in blood glucose, Duodenal mucosal resurfacing is thought to cause its effect by increasing insulin sensitivities, which is the predominant mechanism in both Type 2 diabetes and PCOS.

The intervention involves an endoscopic procedure under general anaesthesia, generally as a day-case procedure. A balloon attached to a sterile, single-use catheter is inserted endoscopically. Saline is injected into the submucosa of the duodenum to create a thermal barrier and through the use of hot water inside a balloon thermally ablates ~10cm of the duodenal mucosa at a time from an area distal to the papilla up to the ligament of Treitz. Limited fluoroscopy is used during catheter placement and location certification during treatment. A lead apron will be placed on the abdomen and pelvis during the procedure to protect the reproductive organs. The total procedure time is approximately 70 minutes.

The sham procedure will consist of placing the DMR Catheter into the duodenum under general anaesthesia and leaving it in place for a minimum of 45 minutes and then removing it from the patient.

All participants will be followed up for six months during which they will be invited for blood tests, body composition studies and OGTT at 2 weeks post procedure and at 12 weeks post procedure. At 12 weeks post-procedure they will also have a euglycaemic hyperinsulinaemic clamp. From weeks 12 to 22, participants will be invited to attend for a reproductive blood tests and a pelvic ultrasound scan. At six months, participants will be invited for their final visit and will undergo blood tests and a body composition study.

The study, funded by Fractyl Laboratories, started in January 2018 and is expected to finish in June 2019.

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