Gastric botulinum toxin A injection

Botulinum toxin A (BTA) is an acetylcholinesterase inhibitor that functions as a long-acting inhibitor of both voluntary and smooth muscle contraction leading to a reversible paralytic-type effect. Direct injection into the gastric antral smooth muscle offers the potential to delay gastric emptying by moderating the propulsive contraction effect of the antral pump. In theory, pump inhibition leads to impaired gastric emptying, increased satiety, inhibition of ghrelin release, decreased oral intake, and eventual weight loss.

Preclinical animal studies were initially performed in rats. In 2000, a prospective, 3-way parallel, randomized controlled study was performed whereby rats were subjected to laparotomy with gastric BTA injection, sham laparotomy, or control group without laparotomy. At 10-week follow-up, there was significant weight loss in the BTA group versus the sham group (14.0% vs 4.4% [maximum weight loss as a percentage], P <.001). In 2005, a follow-up randomized, sham-controlled study in a specific obese rat population, reiterated findings of significant weight loss in the BTA injection group.

Numerous human pilot studies were subsequently performed. In 2005, an 8-patient observational study demonstrated feasibility and safety of the gastric BTA injection method. During a standard upper endoscopy, BTA was directly injected into the antral mucosa. Compared with baseline patient weights, there was a significant mean weight reduction at 1 month after BTA (121.8 kg vs 124.6 kg, P <.05). Further pilot studies investigated optimal BTA dosing administrations, and BTA effects on gastric emptying; however, the results were generally equivocal.

In 2007, a randomized, sham-controlled study with 6-month follow-up revealed weight reduction that was not statistically significant in the BTA group. Conversely, a randomized controlled trial, performed in 2012, administered BTA injections throughout the stomach including the fundus. The results noted statistically significant weight loss at the interval 12-week follow-up.

In 2007, a randomized, sham-controlled trial revealed significant weight loss (11.0 vs 5.7 kg, P <.001) and body mass index (BMI) reduction (4.00 vs 2.00 kg/m ² , P <.001) in the BTA group during 12-week follow-up. This study was noteworthy for also demonstrating significantly decreased gastric-emptying time in the BTA group (+18.9 vs −2.2, P <.05).

Given the equivocal data regarding mucosal-based gastric BTA injection therapy, studies investigated submucosal BTA injection into the muscularis propria. In 2008, a pilot study was performed via endoscopic ultrasound–guided BTA injections into the antral submucosa. At 16-week follow-up, the average body weight loss was 4.9 (±6.3) kg. A follow-up double-blinded, randomized, sham-controlled trial was conducted in 2013. At 24-week follow-up, there was no significant weight loss; however, significantly delayed gastric emptying was observed in the 300-unit BTA injection cohort.

A 2015 meta-analysis was performed summarizing the 8 gastric BTA studies to date, 5 of which were randomized controlled trials. The results did reveal statistically significant weight loss effects with gastric BTA treatment. A follow-up editorial reviewing the study raised concerns regarding the study methodology, particularly the inclusion of non-randomized controlled trials in statistical subanalysis. As a result, the final meta-analysis conclusions have been cautiously interpreted. Currently, BTA is a US Food and Drug Administration–approved modality; however, its use for obesity remains strictly off-label.

Transpyloric shuttle

Transpyloric shuttle (TPS; Baronova, Goleta, CA) is a non-surgical device that comprises a large spherical proximal silicone bulb attached with a tether to a smaller distal cylindrical bulb. The device is deployed into the stomach via an integrated delivery system that incorporates a flexible introducer sheath through which the TPS device is passed in elongated form. The TPS device assembles at the end of the delivery sheath, consisting of a smooth outer skin into which the internal silicone component coils and is locked. The device is delivered to the stomach, and with normal physiologic peristalsis, the distal cylindrical bulb (about the size of a large olive) advances to the proximal duodenum. The tether traverses the pylorus, and the larger spherical bulb remains positioned in the antrum. The larger bulb intermittently engages the pylorus during peristalsis, leading to transient gastric outlet obstruction, but then falls back into the stomach, allowing for gastric content to pass through the pylorus intermittently, hence the “shuttle” effect. In the clinical trials to date, the device placement is for 6 to 12 months, followed by mandatory removal. Retrieval of the device requires the use of a modified standard esophageal overtube using rat-tooth graspers and a snare to unlock and uncoil the components of the proximal bulb, removing them through the overtube and then grasping the outer skin and removing it from the stomach.

The TPS has several key mechanisms of action that promote weight loss. The large bulb, although not sized as much as the water- or gas-filled balloons, represents a space-occupying device, similar to IGBs, which partially reduces functional gastric volume. During antral contractions, the large bulb repeatedly engages the pylorus, causing intermittent obstruction. This action delays gastric emptying, prolongs gastric accommodation, and increases satiety. It is possible that the distal bulb is interacting with duodenal mucosa and incretin signaling, although this remains to be elucidated.

In 2014, a prospective, nonrandomized single-center clinical trial reported the feasibility, safety, and efficacy of the TPS device. A total of 20 patients were enrolled, all of which had a BMI between 30 and 50 kg/m ² . Proton pump inhibitors were administered for all patients during the length of the study. The device was safely deployed and removed in all 20 patients. At 3- and 6-month follow-up, 25.1% and 44.0% excess weight loss (EWL) were observed, respectively. Ninety percent of study patients revealed maximum weight loss at the time of device removal, which suggested the possibility of longer-term weight loss potential. Two patients required early device removal due to gastric ulceration.

Following strong pilot data, the pivotal ENDObesity II study was initiated in the United States, which represents a multicenter, randomized, sham-controlled clinical trial. The target study population (n = 270, 2:1 randomization for the device) includes patients who have failed lifestyle changes or medical therapy, with a BMI of 30.0 to 40.0. The study has completed subject enrollment, with early observation being highly encouraging for safely producing weight loss.

The TPS device is designed for temporary placement and does not fundamentally alter the gastrointestinal anatomy. Similar to IGBs, the indications for TPS placement may be both for primary obesity management and as a bridge to bariatric surgery. This device may also prove to be useful for the pediatric population. In addition to defining the weight loss potential, translational research studies investigating the corresponding neurohormonal signaling are warranted to better characterize the antiobesity effects of the TPS device.

Endoscopic sclerotherapy

As prefaced in the article dedicated to endoscopic revision of Roux-en-Y gastric bypass (RYGB), weight regain after bariatric surgery is a common complication. Acquired anatomic defects can contribute to weight regain, including gastric-gastric fistula and dilated gastrojejunal (GJ) anastomosis. GJ aperture reduction has been shown to curb weight regain and promote weight loss by potentially delaying gastric emptying and increasing satiety.

An option to alter compliance of the postbypass stoma and thereby effect weight loss by altering the kinetics of emptying may be accomplished with the use of endoscopic sclerotherapy. Endoscopic sclerotherapy involves the injection of a sclerosant such as sodium morrhuate into the GJ aperture, thereby creating submucosal blebs, which reduce stomal diameter, initially through edema and later by fibrosis following inflammation. In 2003, 20 patients with a dilated GJ stoma underwent sclerotherapy with sodium morrhuate. The study demonstrated a good safety profile, technical feasibility, and results, noting GJ stomal reduction to 9 to 10 mm after an average of 1.3 sessions. Twelve-month follow-up data revealed that 91.6% of patients achieved persistent weight loss or weight stabilization after sclerotherapy. Subsequent observational studies have reiterated persistent weight loss or weight regain stabilization after endoscopic sclerotherapy. A 2012 large retrospective study, summarizing 231 patients, revealed that 78% of study patients experienced weight-regain stabilization at 12 months after the procedure.

Although there may be more effective methods of managing after-RYGB weight gain, endoscopic sclerotherapy is a straightforward, cost-effective, minimally invasive, technically facile procedure that can be used by the general gastroenterologist or surgeon. Given the positive outcomes in the literature related to after-RYGB stomal sclerotherapy, this would seem a legitimate therapeutic option to ameliorate after-RYGB weight regain.

Endoscopic radiofrequency ablation

Radiofrequency ablation (RFA) therapy represents direct thermal energy administration to gastrointestinal mucosal tissue. Serial RFA ablation of the after-RYGB gastric pouch and GJ aperture may alter pouch compliance, aperture diameter, and gastric wall compliance, which could produce early satiety and subsequent weight loss. A 2016 prospective multicentered pilot study was performed to further qualify the weight loss potential of the RFA device. Twenty-five subjects with documented weight regain after RYGB were enrolled in the trial. These subjects had to have lost 40% of their excess weight postoperatively and then regained 25% back. At 12-month follow-up, and after up to 3 treatment sessions done at 4-month intervals, the mean post-RFA excess body weight loss was reported at 30.4%. Adverse events were reported in 40% of patients, with complaints often related to abdominal pain and vomiting. The initial results are encouraging, albeit with significant transient postprocedural discomfort. Larger studies, including sham-controlled ones, will be required to fully characterize the benefits of the RFA device for post–gastric bypass weight regain and to define the mechanism of effect, such as altered gastric wall compliance, signaling, stomal emptying, or other treatment result.

Transoral endoscopic restrictive implant system device

The transoral endoscopic restrictive implant system (TERIS) device (BaroSense, Redwood, CA) consisted of an endoscopically placed restrictive silicone diaphragm with a 10-mm orifice that was anchored in the gastric cardia with transmural plications. The gastric plications were performed by a novel independently functional endoscopic stapling device. The TERIS system created a luminal stenosis just distal to the gastroesophageal (GE) junction in the gastric cardia. The acquired anatomy after the procedure essentially mimics the laparoscopic-assisted gastric banding (LAGB) surgery.

The device was developed and refined with the use of the canine animal model. Canine gastric tissue was thought to best approximate human gastric tissue and aided in the device-testing process of the tissue plication technology. More than 200 canines were used for device development, with no reported severe adverse events.

The TERIS procedure was initiated with a 5-mm gastroscope and stapling device, both of which were advanced simultaneously via an overtube. The stapler is directed to the gastric cardia mucosa roughly 3 cm distal to the GE junction. The stapler has a suction port that helps to acquire, compress, and facilitate full-thickness transmural plication. Five total transmural plications are performed. Through a series of complex maneuvers, respective silicone membranes were deployed at the plication sites with corresponding anchors. The silicone diaphragm implant was then fastened to the gastric cardia anchors to complete device placement. Follow-up diaphragm removal was performed with the assistance of a gastroscope. The anchor heads were endoscopically visualized, and an internal cutting snare was used to cut each anchor. The diaphragm was subsequently removed via the overtube.

A large phase I observational human clinical trial was performed to further investigate the device. During enrollment, there were 3 complications within the first 7 patients, including 2 cases of pneumoperitoneum and one case of gastric perforation. Procedural adjustments were made including switching from air insufflation to carbon dioxide and performing staple plications 1 cm distal to the original plication sites. Thirteen patients ultimately enrolled, and following procedural adjustments, major adverse events were eliminated. Three-month follow-up revealed a mean EWL of 28%. The observed weight loss response is similar to the cited 3-month after-LAGB follow-up outcome data.

A 2016 follow-up study of the aforementioned patient cohort was performed. The study population consisted of 18 patients, and the mean EWL was 30.1% at 6 months. The results demonstrate that the TERIS system had significant weight loss potential. However, at 6-month follow-up endoscopy, the anchors remained intact in only 62.5% of patients, which raised concerns regarding device durability. Ultimately, the initial complications, procedural complexity, and the lack of device durability led to cessation of the clinical trial and abandonment of further TERIS device development.

Articulating circular endoscopic stapler

The articulating circular endoscopic (ACE) stapler (Boston Scientific Corporation, Natick, MA) is a full-thickness stapling device system with the flexibility of 360° stapling. This stapler device was originally used in the now defunct TERIS system and now acquired by Boston Scientific.

From a procedural standpoint, the ACE stapler has the ability to retroflex, to use a suctioning port to acquire tissue, and to deploy full-thickness tissue staples to plicate redundant gastric tissue. Serial plications throughout the stomach lead to restricted gastric volume, which in theory should promote weight loss. Preclinical animal model data demonstrated a good safety profile without adverse events.

A phase I observational human pilot study was performed in the Netherlands. The 17-patient study revealed a mean 34.9% EWL at 12-month follow-up. On average, 8 staples were placed in the fundus, and 2 staples in the antrum. Upper endoscopy at the end of the study revealed 6 to 9 plications in place with preserved reduced gastric volume in all 17 patients. Transient self-resolving abdominal pain, nausea, and vomiting were reported after the procedure. This pilot study demonstrates procedural feasibility with a good safety profile in both the short and the long term. A 24-month follow-up study is currently underway.

A 2013 DDW (Digestive Disease Week) abstract evaluated gastric physiology after ACE stapling. Results noted that at 1-month follow-up, there was evidence of significant weight loss, reduced caloric intake, and increased patient reported satiety. There were no significant changes in gastric emptying as evidenced by follow-up emptying scans.

FullSense device

The FullSense device (Sentinel Group, Grand Rapids, MI) is a stent-type device consisting of a proximal esophageal component linked to a distal gastric one, which puts pressure on these areas. There was resultant production of satiety and weight loss in a pilot trial conducted in Mexico with implant duration of 6 weeks. Subjects safely lost weight until the devices were removed, with resultant weight regain with devices removed. No publications are available for review of clinical experience.

Gelesis100 hydrogel capsule

Gelesis100 (Gelesis, Boston, MA) is a swallowable capsule that contains thousands of tiny hydrogel particles and is designed to follow the natural food cycle. The particles consist of modified cellulose strands crosslinked to one another by citric acid. The resultant composition is a hydrophilic lattice network that absorbs water and rapidly expands. Water absorption increases each particle size by 100-fold, and the external particle layer continues to maintain inherent structural integrity and elasticity, which precludes coalescence with extraneous food particles.

Capsule ingestion occurs prior to a meal and is accompanied by water. Upon entering the stomach, the capsule dissolves, allowing hydrogel particles to interact with water and expand. The expanded particles essentially create a temporary space occupying “device”, thereby reducing gastric volume for caloric intake. As the Gelesis100 particles advance into the duodenum, the luminal contents are more viscous. The particles provide a pseudo-barrier that impairs total glucose absorption and may in theory improve glycemic control. Gelesis100 particles eventually breaks down in the large intestine with colonic water resorption leading to hydrogel excretion.

A 2014 study investigated the therapeutic utility of the Gelesis100 device in a double-blinded randomized placebo controlled study in human subjects. One hundred twenty-eight nondiabetic overweight patients were randomized to a 3-arm study, including Gelesis 2.25 g twice daily versus Gelesis 3.75 g twice daily versus placebo over a 12-week period. The intention-to-treat analysis revealed statistically significant weight loss in the 2.25-g treatment arm compared with placebo (6.1 vs 4.1% weight reduction, P = .026). The investigators suggest that tolerability and compliance issues with the 3.75-g treatment arm may have led to the surprisingly lower observed weight loss. The device demonstrated a good safety profile with no major adverse events. Given the strong study design, the results are encouraging. However, longer-term data are needed to further validate this technology.

Magnetically weight loss capsule

IGBs, depending on the type, are often placed and removed endoscopically. These requirements increase general health costs as well as patient morbidity related to sedation and endoscopy. A novel IGB known as the magnetically weight loss capsule (MWLC) is delivered as a swallowable capsule and uses magnet technology to activate balloon inflation and deflation. The device currently is in the developmental stage and has been trialed ex vivo in the porcine stomach. The magnetic capsule balloon is ingested with a glass of water. Once the capsule reaches the stomach, a properly oriented magnet is externally placed on the subject’s stomach, which activates balloon inflation. Reversing the external magnet orientation causes balloon deflation. Once deflated, the balloon can safely pass, in theory, per rectum. The major potential benefits relate to the elimination of endoscopy for capsule placement and removal.

The capsule consists of 2 chambers containing citric acid and potassium bicarbonate, respectively, separated by an inflation valve and 2 internal magnets. The extracorporeal magnet can orient the capsule to open the inflation valve and promote acid-base mixture, resulting in carbon dioxide gas production and balloon inflation. Conversely, reversing external magnet polarity will preclude mixing and allow balloon gas extrusion. At this time, the designed prototype capsule is a latex balloon, which is a material prone to rupture. The balloon size is 170 mL, which is considerably smaller than current commercial balloons. Revised magnet actuated capsule development will undoubtedly be necessary. However, as a proof of concept study, the MWLC represents an exciting first step, and a potentially promising future antiobesity device.