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Hyularonic acid at the gastroesophageal junction

Endoscopic Injection of Hyaluronic Acid at the Gastro Esophageal Junction as an adjuvant to obesity treatments. An ongoing clinical trial.

In 2012, the treatment of morbid obesity entails several surgical procedures, most of them being performed laparoscopically. In order to gain wider acceptance, research for non-invasive techniques is mandatory in this field. The protocol we introduce here has compared a simple and cheap injection device to a bariatric technique, the intra-gastric balloon.

We suggested creating a moderate food restriction through endoscopic channels as a treatment for severe or morbid obesity. This restriction is mediated by the circular sub-mucosal injection of a bio-compatible material, hyaluronic acid, within a pre-identified anatomical area that matches the surgical anatomy when a laparoscopic gastric banding is placed. 

The first part of the study has permitted the evaluation of the sleeve gastrectomy combined with hyaluronic acid injection (4 patients), comparing their results with a control group (4 patients).

The second stage of the trial – OBENDO 2, a prospective, single-blinded, randomised and controlled multi-centre study – has compared the effects of hyaluronic acid injection, balloon, and the combination of both in a sequential mode (98 patients, 2010-2012). 

It has involved three groups: group 1 (balloon alone), group 2 (balloon followed by injection at the time of removal, i.e. 6 months), group 3 (injection, and balloon placement at 6 months). 

Preliminary results indicate that a third stage (OBENDO 3) should follow up on the results of group 3, with a three- to six-month interval between injection and balloon placement.

OBENDO 2 Protocol

At a preliminary stage, cadaver studies (2006) and animal protocols (2007) were carried out Then hyaluronic acid injections were combined with sleeve gastrectomy (OBENDO 1 trial).

OBENDO 2 has consisted of an open and randomised non-inferiority trial, comparing intra-gastric balloon and hyaluronic acid injection. Four French centres have included 98 patients from April 2010 to April 2012.

The allocation to each different group was effective from the start (hyaluronic acid versus intra-gastric balloon). A second endoscopy was scheduled six months later: balloon removal for control, hyaluronic acid injection for group 2, and balloon insertion in patients for group 3.

Patients from the control group were offered an injection later on, but only one has taken it so far. 

We gave priority to the intra-gastric balloon, owing to its simplicity and the opportunity to easily launch a prospective multi-centre randomised trial while rapidly enrolling the necessary number of patients. It was easier to assess the benefits in terms of weight-loss, since weight-loss maintenance is an obvious weakness of the intra-gastric balloon approach. 

The insertion of the intra-gastric balloon is a rapid and simple technique, taking ten minutes. Both operations are performed as an outpatient procedure. 

The effect of the hyaluronic acid injection definitely does not last longer than the duration of an intra-gastric balloon.  

Preliminary results have been transmitted to the Ethics Committee and National Health Authorities in April 2012.

Let us keep in mind the literature data regarding the balloon:

Weight loss at six months 14.4kg (12-17)
Percentage weight loss 10%-14%
BMI loss 5.7 (4.4-6.9)
Difference with placebo 6.7kg/17.6% EWL

Weight-regain after balloon explantation is about 40% after one year; the combination that has been tested could improve this result.

The primary objective of the study was to assess the benefit of hyaluronic acid injection in comparison with intra-gastric balloon, and demonstrate a superior effect to placebo. Among secondary objectives, the most important was to assess the benefit of the combination hyaluronic acid injection/balloon and vice-versa.

98 patients have been included. To show non-inferiority of hyaluronic acid injection to intra-gastric balloon, 138 patients would have been necessary. Although encouraging, our preliminary results are yet not in favour of such a hypothesis, i.e. a hyaluronic acid injection as a stand-alone strategy. 

This primary objective is not to be considered out of reach, owing to the progress that can be made regarding the bulking effect of filling agents at the GE junction. On the other hand, the numbers were quite enough to evaluate the secondary objectives: the relevance of the balloon-injection combination in the mid-term (key-periods of 12 and 18 months).

The demographics were as follows:

Sex 18 female, 15 male
Age 38.9 (19-64)
Weight 90.5kg (70-148)
Excess weight 33.2kg (16-67)
BMI 33.8 (27-43.7)

12-month results:

Weight loss (kg) % weight loss BMI loss % BMI loss %EWL % excess BMI loss
Group 1 (N=15) 6.1 6.5 2.4 6.7 16.9 25.2
Group 2 (N=14) 7.1 8.2 2.6 7.9 23 36.6
Group 3 (N=14) 11 12.4 4.8 13.2 33.5 43

12-month results of OBENDO 2 (20/07/2012)

Preliminary conclusions

Hyaluronic acid injection has been safe and reproducible, whether in combination with a sleeve gastrectomy or as a stand-alone procedure and/or combined with an intra-gastric balloon removal in OBENDO 2.

No side-effect, even minor, has been observed during injections or afterwards, whether it took place in a “virgin” stomach or after balloon removal (despite some reservation in this situation as explained hereafter). 

In group 3 patients, operative pictures attest that the GE junction was fully restored at the time of balloon placement (six months). 

Side-effects and complications of intra-gastric balloon were similar to those described in the literature: 30% vomiting and abdominal pain with possible reflux; this rate was not different among primary intra-gastric balloon (group 1 and 2) or secondary intra-gastric balloon (group 3). The balloon-injection combination, or vice-versa, did not have any particular effect.

Weight loss and statistical analysis

Given the relatively modest weight-loss provided by such non-invasive procedures, details concerning the expression of weight-loss were mandatory. 

Percentage weight loss at six months has been 8.8% in groups 1 and 2 (balloon) versus 7.4% in group 3 (hyaluronic acid injection); that is, a 19% difference. In the hypothesis of equivalence, a difference of less than 17% was necessary.

Percentage excess BMI loss were respectively 25.8% and 18.6%. The difference between balloon and placebo in the literature stands around 50%.

Results at 12 and 18 months are important because we know from the literature that 40% of the weight that has been lost with a balloon is regained within a year after explantation. 

Whatever the group, taking care of the patients with a supposedly active device over a one-year period of time instead of six months seemed to have a real impact. Moreover, many current endoscopic devices claim longer duration of action, beyond six months, and some new balloons are even implanted for 12-18 months. It is yet obvious that a single device fails to stay efficient over the time, hence the interest of a non aggressive therapeutic sequence.

Combination with intra-gastric balloon

The group 3 strategy, inserting a balloon six months after injection, currently appears to be the most relevant, owing both to the technique and to the results that have been obtained so far. 

Group 2 represents an interesting and attractive concept, but pending further results, we are not satisfied with the technical feasibility of the method: the status of the GE junction at the time of removal was most often inflammatory, leading to an uneasy injection, most likely poorly efficient. Moreover, it had to be postponed three times because of food residues barring the access to the junction.

Efficacy of the injection at the GE junction

It has to be further tested, but the hyaluronic acid injection could be a preliminary step to non-invasive bariatric techniques. New trials could be performed with different concentrations of hyaluronic acid, although there is no clear relationship between the rapidity of hyaluronic acid absorption and its viscosity (reflecting its molecular weight and concentration). A dedicated needle reinforcing the injection capacity could be designed. 

There is a theoretical possibility that injections could become a stand-alone bariatric procedure, replacing the intra-gastric balloon, but such a claim is very premature. When we look at the number of patients who can be considered “non responders” - less than five kg weight loss at six months - the rate is higher in group 3 (8/17: 47%) than in groups 1 and 2 (10/38: 26%), which is no prejudice to further weight-loss (at 12 and 18 months). This could also indicate that the amount of hyaluronic acid has not been sufficient.

Differences between our series and the literature

Our average BMI was fairly low, and diminished after further application to the Ethics Committee in April 2011 (authorisation to include patients between 30 and 35). It is noted that intra-gastric balloon procedures are not reimbursed in France, whereas bariatric surgery is fully reimbursed for eligible patients after application. 

We have favoured a “real life” experimentation, instead of imposing a strict follow-up with a low calorie diet (e.g. 1,500-1,800 calories a day). We delivered diet counselling without mandatory appointments, and encouraged physical exercise without schedule. These factors may explain a lesser weight-loss than commonly reported in the literature.

Quality of life and adverse effects

Final results will be analysed in detail when available. We hypothesise a clear difference between injection and balloon in terms of digestive tolerance (ROME III questionnaire). 

Short-term food tolerance after balloon is at best mediocre, as reported most often in the literature, with patients demonstrating vomiting and reflux. Four patients have been re-hospitalised for 24 to 96 hours during the first post-op week for rehydration, and five balloons had to be removed by six months (two to nine weeks post-op) for early and utter intolerance, as well as one balloon after the second part of the protocol (group 3, 4 months). 

In some cases, placement or removal of the balloon has been anticipated from several weeks, most of the time for the personal convenience of the patients. Two patients with insufficient weight-loss had a bariatric operation before the end of the study (one sleeve gastrectomy, one banding, one year after inclusion). 

There has been no case of food intolerance with the injection, which, combined with the absence of any side-effect and the integrity of the GE junction at six months, makes it possible to consider stronger injections, with a higher concentration or a greater quantity of hyaluronic acid. Quality of life questionnaires (SF-36) have reflected a general improvement owing to weight-loss.

Suggestions for subsequent trials

1. A hyaluronic acid with a stronger viscosity could be tested; meanwhile, we suggest increasing the amount of the injection by 30%, in order to obtain a better filling effect. It seems that the speed of absorbtion of hyaluronic acid is not connected to its concentration, so a larger volume could be useful. 

2. A combination of hyaluronic acid injection with other bariatric methods, such as intra-luminal techniques (endo-stapling, endo-plication, etc.), or gastric neuro-stimulation. Continuing with the intra gastric balloon, we have implemented a study following group 3, with a variable delay between injection and balloon placement, from three months in non-responsive patients to 6-8 months if the patient is complying with the program. 

This approach is justified by a recent publication by Farina, Baratta, Nigro et al, which says that modern strategies including non-invasive devices should aim at prolonging its duration of action and/or its duration of implant. 

Farina et al's study aimed to compare in obese patients the effect on weight loss and metabolic changes of lifestyle modifications associated with either intra-gastric balloon or sibutramine or the two treatments in sequence as a maintenance strategy for weight loss. 

At six months, patients treated with a balloon lost significantly (P<0.05) more weight (percent of initial weight lost, %IWL=14.5±1.2; percent of excess BMI lost, %EBL=37.7±3.2) than patients who received pharmacological treatment (%IWL=9.1±1.5, %EBL=25.3±4.1). 

At one year, the weight lost was significantly (P<0.05) greater in patients treated with either balloon/pharmacotherapy (%IWL=15.8±2.3%, %EBL=41.3±6.7%) or balloon/lifestyle (%IWL= 14.3±2.7, %EBL=34.9±6.5%) in respect to the pharmacotherapy group (%IWL=8.0±1.4%, %EBL=22.1±3.9%). 

This therapeutic model consists in prolonging the effects of a non invasive option; that is, what we intended to reproduce with the OBENDO 2 patients. However, our group 3 results suggest that we should probably seek a “trigger action” rather than a prolonging action to that effect, at least dealing with non pharmaceutical methods.

Hence, OBENDO 3 results from the preliminary conclusions of OBENDO 2, while continuing it. While group 1 was considered a control group, group 2 is so far unsatisfactory, and group 3 displayed the best results. The goal of the OBENDO 3 study will be to reinforce the results of OBENDO 2 (that are still incomplete). 

It appears for the time being that injection alone is likely insufficient, but that the sequential mode with a preparation by injection before implanting the balloon could be valuable. Other methods (endoscopic or not) may be combined with injections.