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Effect of Reversible Intermittent Intra-abdominal Vagal Nerve
Blockade on Morbid Obesity
The ReCharge Randomized Clinical Trial
Sayeed Ikramuddin, MD; Robin P. Blackstone, MD; Anthony Brancatisano, MD, PhD; James Toouli, MD, PhD; Sajani N. Shah, MD; Bruce M. Wolfe, MD;
Ken Fujioka, MD; James W. Maher, MD; James Swain, MD; Florencia G. Que, MD; John M. Morton, MD; Daniel B. Leslie, MD; Roy Brancatisano, MD;
Lilian Kow, MD, PhD; Robert W. O’Rourke, MD; Clifford Deveney,MD; Mark Takata, MD; Christopher J. Miller,MS; Mark B. Knudson, PhD;
Katherine S. Tweden, PhD; ScottA . Shikora, MD; Michael G. Sarr, MD; Charles J. Billington, MD
IMPORTANCE Although conventional bariatric surgery results in weight loss, it does so with
potential short-term and long-term morbidity.
OBJECTIVE To evaluate the effectiveness and safety of intermittent, reversible vagal nerve
blockade therapy for obesity treatment.
DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, sham-controlled clinical
trial involving 239 participants who had a body mass index of 40 to 45 or 35 to 40 and 1 or
more obesity-related condition was conducted at 10 sites in the United States and Australia
between May and December 2011. The 12-month blinded portion of the 5-year study was
completed in January 2013.
INTERVENTIONS One hundred sixty-two patients received an active vagal nerve block device
and 77 received a sham device. All participants received weight management education.
MAIN OUTCOMES AND MEASURES The coprimary efficacy objectives were to determine
whether the vagal nerve block was superior in mean percentage excess weight loss to sham
by a 10-point margin with at least 55% of patients in the vagal block group achieving a 20%
loss and 45% achieving a 25% loss. The primary safety objective was to determine whether
the rate of serious adverse events related to device, procedure, or therapy in the vagal block
group was less than 15%.
RESULTS In the intent-to-treat analysis, the vagal nerve block group had a mean 24.4%
excess weight loss (9.2% of their initial body weight loss) vs 15.9% excess weight loss (6.0%
initial body weight loss) in the sham group. The mean difference in the percentage of the
excess weight loss between groups was 8.5 percentage points (95% CI, 3.1-13.9), which did
not meet the 10-point target (P= .71), although weight loss was statistically greater in the
vagal nerve block group (P= .002 for treatment difference in a post hoc analysis). At 12
months, 52% of patients in the vagal nerve block group achieved 20% or more excess weight
loss and 38% achieved 25% or more excess weight loss vs 32% in the sham group who
achieved 20% or more loss and 23% who achieved 25% or more loss. The device, procedure,
or therapy–related serious adverse event rate in the vagal nerve block group was 3.7% (95%
CI, 1.4%-7.9%), significantly lower than the 15% goal. The adverse events more frequent in
the vagal nerve block group were heartburn or dyspepsia and abdominal pain attributed to
therapy; all were reported as mild or moderate in severity.
CONCLUSION AND RELEVANCE Among patients with morbid obesity, the use of vagal nerve
block therapy compared with a sham control device did not meet either of the prespecified
coprimary efficacy objectives, although weight loss in the vagal block group was statistically
greater than in the sham device group. The treatment was well tolerated, having met the
primary safety objective.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01327976
JAMA. 2014;312(9):915-922. doi:10.1001/jama.2014.10540
Editorial page 898
Supplemental content at
jama.com
Author Affiliations: Author
affiliations are listed at the end of this
article.
Corresponding Author: Charles J.
Billington, MD, Minneapolis VA
Medical Center, 1 Veterans Dr,
Minneapolis, MN 55417 (billi005
@umn.edu).
Research
Original Investigation
915
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Illness imposed by obesity, especially by morbid obesity,has
inspired an array of treatment options, typically applied in
stepwise fashion. Although changes in food intake and ac-
tivity levels can be effective for some, the mean effect is
modest.
1
The most effective treatment, bariatric surgery, can
produce significant weight loss and improvementin health but
is associated with risks of morbidity and distortion of anatomy
that are unacceptable to some.
2
Medications can be helpful,
but their application is limited by adverse effects and reluc-
tance of insurance companies to cover them.
3
There is great
interest in the development of a device that could be as effec-
tive or nearly as effective as bariatric surgery but that has fewer
risks and that is less invasive. One such possibility is vagal
blockade using electrodes implanted through minimally in-
vasive laparoscopic surgery.
4
The vagus nerve is known to play a key role in satiety, me-
tabolism, and autonomic control in upper gastrointestinal track
function.
5
The EMPOWER
6
study, a recent randomized trial
testing vagal blockade, found substantial weight loss, but the
difference in weight loss between treatmentand control groups
was not significant. However, treatment group participants
who received at least 12 hours of vagal block therapy a day
achieved the level of weight loss anticipated in the design. Fur-
thermore, a significant dose response of weight loss in rela-
tion to hours of device use for both groups coupled with the
possibility that control patients may have received partial va-
gal blockade through low-energy safety or device checks con-
founded the interpretation of the trial’s results.
6
These find-
ings required a new study to determine the efficacy of vagal
nerve block therapy with a treatment device that consis-
tently delivered at least 12 hours of therapy a day and a sham
control device that had no possibility of delivering therapy. The
ReCharge Study, a multicenter,randomized, double-blind trial
that addressed these design limitations, is the focus of this ar-
ticle.
Methods
Participants
Participants at 2 sites in Australia and 8 sites in the UnitedStates
were eligible for inclusion in the study if their body mass in-
dex (BMI, calculated as weight in kilograms divided by height
in meters squared) was 40 to 45 (class III obesity) or 35 to 40
(class II obesity) and had 1 or more obesity-related comorbid
conditions, including type 2 diabetes, hypertension (systolic
blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm
Hg), dyslipidemia (total cholesterol ≥200 mg/dL or low-
density lipoprotein [LDL] ≥130 mg/dL), sleep apnea syn-
drome, or obesity-related cardiomyopathy. The participation
of those with type 2 diabetes was limited so that potential
weight loss limiting effects of diabetes and its treatment did
not affect the study outcomes. A detailed description of in-
clusion and exclusion criteria can be found in Supplement 1.
All participants provided written informed consent, and the
institutional review boards at each study site approvedall study
protocols. (To convert LDL from mg/dL to mmol/L, multiply
by 0.0259.)
Study Design
This multicenter, randomized, double-blind trial compared
active vagal nerve blocking with an implanted sham device.
The randomization allocation was 2:1 for active vagal nerve
block to sham devices in permuted block sizes of 3 or 6,
stratified by study site and type 2 diabetes status (Figure 1).
To ensure comparability between groups with respect to
potential weight loss, participants with type 2 diabetes were
limited to 10% of enrollment at each site; their randomiza-
tion was not stratified by site. Randomization to active or
sham group occurred once patients were admitted to the
hospital. The participant, sponsor, and follow-up staff at the
clinical site were blinded to treatment assignment. The sur-
geons and surgery support staff could not be blinded, so
their interaction with participants after placing the device
was limited.
Implanting vagal nerve block therapy electrodes requires
standard laparoscopic techniques and general anesthesia.
4
The
anterior and posterior vagus nerves were identified and dis-
sected free at the gastroesophageal junction. Customized elec-
trodes were placed around the nerves and then secured with
sutures.
4
These electrodes were connected to a transcutane-
ously rechargeable neuroregulator placed in a subcutaneous
pocket on the thoracic side wall. Both treatment and control
devices were 8.6 cm in diameter, 7.1 cm in width, and 1.6 cm
thick.
Participants in the sham group were implanted similarly
but with a neuroregulator that dissipated charges intoan elec-
tronic circuit within the device without leads. Their proce-
dure consisted of the same number of skin incisions as vagal
nerve block participants without peritoneal penetration.
Neuroregulators were programmed to deliver a charge
for at least 12 hours daily. An external programming device
allowed the investigator to increase the amplitude in both
active and sham devices at scheduled intervals during
follow-up visits in accordance with the protocol to the
desired amplitude of 6 to 8 mA, depending on patient toler-
ance. The active or sham neuroregulator battery required
recharging at least twice a week for approximately 30 min-
utes to 90 minutes using an external charging device. Each
charging session was recorded by the device and data were
monitored by the clinic staff for safety and recharging
adherence.
Data Collection and Study Conduct
Data collected prior to randomization included height, weight,
medical histories, and medication usage. Follow-up visits
following randomization were weekly for the first month,
then every 2 weeks between weeks 4 and 12, and monthly
thereafter from 3 to 12 months to collect primary and second-
ary measures including weight and adverse events. All par-
ticipants attended a weight management program, consist-
ing of 17 face-to-face educational counseling sessions that
ranged from 15 minutes to 45 minutes and discussed such top-
ics as healthful food choices, physical fitness, and social sup-
port. No diet or exercise regimen was prescribed.
Coprimary efficacy objectives for the study were based on
the percentage excess weight loss, which is calculated using
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the formula: percent of excess weight loss = 100% × [weight
loss/excess body weight at implant placement]. Excess body
weight was defined as the difference between weight at im-
plantation and the ideal body weight to achieve a BMI of 25.
The first efficacy objective was based on a mean percent ex-
cess weight loss comparison between groups at a superiority
margin of 10% (super-superiority). The second efficacy objec-
tive was to demonstrate that 55% of patientsin the vagal ner ve
block group would achieve 20% excessweight loss and that 45%
would achieve 25% excess weight loss.
Safety data were monitored by an independent data and
safety monitoring board that was chartered to meet atleast an-
nually and adjudicated all serious adverse events. No interim
analyses or early stopping boundaries were used during this
study. Serious adverse events were defined as any untoward
event that led to death or serious deterioration in the health
of the participant, including prolonged hospitalization. The pri-
mary safety objective was to demonstrate that the serious ad-
verse event rate related tothe dev ice, the implantor rev ision,
or the therapy was less than 15% in the vagal nerve block group.
This single-group comparison with a performance criterion was
chosen in consultation with the US Food and Drug Adminis-
tration (FDA) to demonstrate a lowerserious adverse event rate
than studies used to support FDA approval for the laparo-
scopic adjustable gastric band. The site investigator deter-
mined the severity and attribution of adverse eventsthat were
not serious.
Statistical Analysis
The assumptions of the trial were that, on average, patients
in the vagal nerve block group would achieve 25% excess
weight loss and the sham group would achieve 5% excess
weight loss at 12 months. These estimates were based on
experience with the dose-response effect observed in the
EMPOWER trial and the 12-month weight loss observed in
the VBLOC DM2 study among participants with type 2
diabetes.
6,7
In EMPOWER, participants with fewer than 6
hours of device use per day in the first 12 months achieved a
mean 5% excess weight loss, and those who received at least
12 hours of therapy per day achieved a mean 29% of excess
weight loss.
6
In the observational VBLOC DM2 study, par-
ticipants achieved an average of 25% of excess weight loss.
7
Therefore, it was determined that a minimum of 233 partici-
pants (allocated 2:1) would be required to achieve 85% sta-
tistical power to detect a 20-point mean difference between
groups with a superiority margin of 10 points at 12 months,
accounting for up to 15% attrition.
Data were analyzed according to the intention-to-treat
(ITT) principle, in which all participants were analyzed as ran-
domized. Per protocol, missing 12-month values for the per-
centage of excess weight lost were imputed using the last-
observation-carried-forward method. We also conducted a post
hoc multiple imputation analysis with 50 imputation data sets
using multivariate normal regression for 26 missing 12-
month values for the percentage of excess weight loss using
Figure 1. CONSORT Diagram of Participants in the ReCharge Study
420 Patients assessed for eligibility
181 Excluded
30 BMI criteria not met
25 Failed psychiatric evaluation
12 Medical condition making
subject unfit for surgery
10 Unable to complete study visits
9Has history of hiatal hernia
7Diabetes inclusion not met
88 Refused participation/other
239 Randomized
162 Included in the primary analysis 77 Included in the primary analysis
147 Had 12-month data
10 Did not have 12-mo data
7Missed follow-up visit
2Lost to follow-up
1Withdrew (adverse event)
66 Had 12-month data
10 Did not have 12-mo data
4Missed follow-up visit
3Withdrew (because of subject decision)
3Withdrew (adverse event)
162 Randomly assigned to weight
management program and active vagal
nerve block device
157 Received intervention as
randomized
5Not implanted because of
intraoperative exclusion and
withdrawn
77 Randomly assigned to weight
management program and sham
control device
75 Received intervention as
randomized
2Did not receive the sham device
as randomized
1Received active vagal nerve
block device
1Not implanted for subject decision
and withdrawn
BMI indicates body mass index.
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treatment group, age, sex, race, diabetic status, weight at im-
plantation, and site as predictors.
The primary safety objective was analyzed using a 1-sided
exact binomial test at the 0.025 significance level. Superior-
ity of the mean percentage of excess weight lost was com-
pared between groups using a 1-sided ttest at the 0.025 sig-
nificance level with a 10-point superiority margin. Post hoc
testing with a 2-sided ttest was used to compare weight loss
between groups with no superiority margin. In addition, the
odds ratio comparing the percentage of excess weight loss
thresholds by treatment group are presented as post hoc ex-
ploratory analyses. Statistical analyses were conducted using
SAS version 9.3 (SAS Institute Inc).
Results
Baseline Characteristics
The screening and randomization procedure is summarized in
Figure 1. Of the 239 participants, 162 to were randomized from
May 16 to December 27, 2011, to receive the vagal nerve block
and 77 to receive the sham device. Twelve-month visits were
completed by January 4, 2013. Participant characteristics at
baseline are summarized in Table 1.
Participant Disposition
Seven participants did not receive the implants as random-
ized. One participant randomized to the sham control group
changed his/her mind immediately before the procedure and
withdrew. Another participant in the sham group was anes-
thetized in the operating room, but because no sham kits were
available, an active device was implanted. Five participants in
the vagal nerve block group did not receive the implant due
to intraoperative exclusions (ie, hiatal hernia >5 cm, previous
Nissen fundoplication, food in stomach, cirrhosis or hepatitis
C, and inability to locate anterior vagal nerve) and were with-
drawn.
Followingimplantation, 6 patients in the sham group with-
drew (3 for patient decision, 3 for adverse events) as did 3 pa-
tients in the vagal nerve block group (2 lost to follow-up, 1 for
an adverse event). The completion rate of the 12-month visit
was 91% in the vagal nerve block group and 86% in the sham
control group.
During the 12-month blinded study period, 8 patients
(4.9%) in the vagal nerve block group had undergone a revi-
sion procedure to reposition or replace the neuroregulator; no
revisions were required in the sham group. Five participants
(3.1%) in the vagal nerve block group and 8 (10.4%) in the sham
group had the device removed by 12 months. Two patients in
the vagal nerve block did so because 1 had experienced pain
at the neuroregulator site and the other, heartburn. Of the 4
patients in the sham group, 1 had pain at the neuroregulator
site, 1 needed to undergo magnetic resonance imaging to in-
vestigate causes for shoulder pain, 1 had worsening of irri-
table bowel syndrome symptoms, and 1 had breast cancer.
Three patients in the vagal nerve block group and 4 in the sham
group asked to have the devices removed.
Efficacy
At 12 months in the ITT population (Table 2), the mean per-
centages of excess weight loss was 24.4% in the vagal nerve
block group and 15.9% in the sham group with a mean differ-
ence of 8.5 percentage points (95% CI, 3.1-13.9). This differ-
ence did not meet the primary efficacy objective of achieving
superiority with a 10 percentage-point margin (P=.71), al-
though weight loss was statistically greater in the vagal nerve
block group (P= .002 for treatment difference in post hoc test-
ing). When analyzed using multiple imputation analysis, the
mean percentage of excess weight loss was 26.1% in the vagal
nerve block group and 16.9% in the sham group with a mean
difference of 9.2 percentage points (95% CI, 2.7-15.6). Figure 2
illustrates the percentage of excess weight loss as observed
through 12 months. The mean percentage of initial body weight
loss at 12 months in the ITT population was 9.2% in the vagal
nerve block group and 6.0% in the sham group for a mean dif-
ference of 3.2 percentage points (95% CI, 1.1-5.2).
At 12 months, 52% of participants in the vagal nerve block
group achieved at least 20%; and 38%, at least 25% of excess
weight loss (Table 2), which did not meet the primary effi-
cacy objective performance goals of at least 55% of partici-
pants achieving a 20% excess weight loss and 45% achieving
a 25% excess weight loss. Table 2 presents the percentage of
participants reaching weight loss thresholds from 20% to 50%
as well as the post hoc exploratory odds ratios showing higher
odds of participants in the vagal nerve block group achieving
those thresholds than participants in the sham group.
Table 1. Baseline Characteristics byTreatment Group
Vagal Nerve Block
(n=162)
Sham
(n=77)
Demographics
Women, No. (%) 141 (87) 62 (81)
Age, mean (SD), y 47 (10) 47 (9)
Race, No. (%)
White 149 (92) 73 (95)
Black 8 (5) 3 (4)
American Indian 2 (1) 1 (1)
Asian 1 (1) 1 (1)
Hawaiian/Pacific Islander 1 (1) 0
Body size measures when device
placed, mean (SD)
Height, cm 166 (8) 168 (9)
Weight, kg 113 (13) 116 (14)
Body mass index 41 (3) 41 (3)
Excess weight, kg
a
44 (9) 45 (10)
Waist circumference, cm 121 (12) 123 (11)
Type 2 diabetes mellitus, No. (%) 9 (6) 6 (8)
Hypertension, No. (%) 63 (39) 32 (42)
Dyslipidemia, No. (%) 91 (56) 46 (60)
Obstructive sleep apnea, No. (%) 33 (20) 23 (30)
a
Excess weight was calculated as the difference between the weight at the time
of implantation and the ideal body weight corresponding to a body mass index
of 25, which is calculated as weight in kilograms divided by height in meters
squared.
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Safety
The primary safety end point, the rate of serious adverse events
that were related directly to the device, implantation or revi-
sion, or therapy in the vagal nerve block group, was 3.7% (95%
CI, 1.4%-7.9%); therefore, the primary safety objective was met
(P<.001). Two serious adverse events were for neuroregula-
tor malfunction requiring replacement and 1 was pain at the
neuroregulator site following a large weight loss (80% of ex-
cess weight loss), which required repositioning; these partici-
pants were hospitalized overnight and discharged. One par-
ticipant developed atelectasis, which prolonged hospitalization
by 2 days. One patient developed emesis and needed a hiatus
hernia repair and was discharged 2 days following repair. One
participant had gallbladder disease, which was determined to
be possibly related to therapy due to weight loss.
Nine serious adverse events were related to general intra-
abdominal surgery. Six were for nausea resulting in pro-
longed hospitalization of at least 1 daylonger than what is typi-
cal for the procedure. One was for intraoperative oozing, which
resulted in overnight hospitalizationand hemodynamic moni-
toring. A participant who had not received an implant due to
an intraoperative exclusion for cirrhosis was hospitalized be-
cause of a complicated liver biopsy.One partic ipanthad a mod-
erate ileus of the stomach, was treated with pain medica-
tions, and was discharged on the second postoperative day.
Combining the serious adverse events thatwere related to intra-
abdominal surgery with those related to vagal nerve block, the
rate was 8.6% (95% CI, 4.8% to 14.1%). eTable 1 in Supplement
2 lists all serious adverse events by the adjudicated cause of
the event.
The most common adverse events related to treatment are
reported in Table 3. Pain at the neuroregulatorsite was the most
common event in both groups. Ninety-six percent of these
events in the vagal nerve block group were deemed to be mild
or moderate, although a revision was performed in 3 cases and
an explant in 1 due to pain. Heartburn and dyspepsia, abdomi-
nal pain, other or nonspecific pain, dysphagia, and eructa-
tion or belching were reported more frequently by partici-
pants in the vagal nerve block group and were attributed by
investigators to be primarily related totherapy. All events were
Figure 2. Weight Loss From Baseline as ObservedWithout Imputation
0
–5
–10
–15
–20
–25
–30
0
–2
–4
–6
–8
–10
–12
Mean Percentage of Excess
Weight Loss, BMI Method
Mean Percentage of Initial
Body Weight Loss
Visit Month
0
162
77
3
151
71
6
149
69
9
135
60
12
147
66
No. of patients
Vagal nerve block
Vagal nerve block
Sham
Sham Error bars indicate 95% CIs. BMI
indicates body mass index.
Table 2. Twelve-Month Percentage Excess Weight Loss
Mean (95% CI)
Difference (95% CI)
Vagal Nerve Block
(n=162)
Sham
(n=77)
Continuous outcomes
Percentage of excess weight loss
LOCF 24.4 (20.8-28.1) 15.9 (11.9-19.9) 8.5 (3.1-13.9)
Multiple Imputation 26.1 (22.2-29.9) 16.9 (11.6-22.2) 9.2 (2.7-15.6)
Categorical Outcomes No. (%) of Patients Odds Ratio (95% CI)
Percentage of excess weight loss
threshold, LOCF
20 85 (52) 25 (32) 2.3 (1.3-4.1)
25 62 (38) 18 (23) 2.0 (1.1-3.8)
30 49 (30) 14 (18) 2.0 (1.0-3.8)
35 42 (26) 7 (9) 3.5 (1.5-8.2)
40 35 (22) 4 (5) 5.0 (1.7-14.7)
45 30 (19) 3 (4) 5.6 (1.7-19.0)
50 24 (15) 1 (1) 13.2 (1.8-99.6) Abbreviation: LOCF, last observation
carried forward.
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adjudicated as mild or moderate in severity, and most were re-
solved with alteration to the therapy algorithm. Nausea was
reported more frequently by participants in the vagal nerve
block group, which was expected given that sham implantpro -
cedures had no peritoneal penetration. Eighty-six percent of
nausea events were mild or moderate.
Discussion
In this study of patients with morbid obesity, the percentage
of excess weight loss among participants treated with vagal
block did not meet either of the coprimary efficacy objec-
tives, although weight loss in the intervention group was sta-
tistically greater than in the sham group. The vagal nerve block
group nearly achieved the 25% mean excess weight loss re-
sponse predicted in the trial design, but the sham group re-
sponse was 3 times greater than predicted. Fifty-two percent
of participants in the vagal nerve block group achieved 20%
and 38% achieved 25% excessweight loss; however, those were
lower percentages than the study’s objective of 55% achiev-
ing a 20% loss and 45% achieving a 25% loss. Weight loss was
achieved with a low rate of serious adverse events related to
device implantation or function, and most adverse events were
mild or moderate in severity.
This is 1 of 3 reported trials testing devices to treat obe-
sity in which a randomized, sham-control method was used.
6-8
To our knowledge, it is the first to report a statistically greater
weight loss among treated patients than among those in the
control group. Previous trials with an earlier version of the va-
gal nerve block device
6
and with an implantable gastric
stimulator
8
did not produce statistically different treatment
effects. Randomized placebo controlled trials have been the
standard in obesity trials involving medication and lifestyle in-
tervention, but up to this time, obesity device trials, such as
those for laparoscopic adjustable gastric band, have rarely in-
cluded a sham comparator or a 10%-point superiority mar-
gin. Consequently, the trial used an unusually strong design
to study this obesity-treatment device.
It is likely that the sham group weight loss was due to a
placebo effect of surgery, daily self-monitoring reinforced by
interaction with the sham device to recharge the battery, and
participation in the weight management program. Placebo con-
trol groups in recent obesity medication studies have shown
1% to 2% initial body weight loss.
9-11
Lifestyle counseling with-
out medication or meal replacements produced a 3.5% initial
body weight loss at 12 months in a controlled trial.
12
The 6%
initial body weight loss seen in the sham group in this study
is similar to the sham effect in the previous vagal nerve block
trial (EMPOWER)
6
and to the control group in the recent SHAPE
trial of an implantable gastric stimulator.
8
At the time this trial
was designed, weight loss in the previous vagal nerve block
sham treatment was thought to be due to inadvertent active
treatment. In the EMPOWER study, there was a relationship
between hours of use and weight loss, regardless of assign-
ment to active or control groups.
6
Sham surgeries are known to have substantial placebo ef-
fects in other contexts, such as arthroscopic knee surgery,
13,14
vertebroplasty for back pain,
15,16
and internal mammary ar-
tery ligation for angina.
17
The sham effect was sufficient in each
of these cases to result in a conclusion of ineffectiveness for
the intervention. A recent review article highlights the large
sham effects observed with surgical interventions.
18
Further-
more, the structure of a clinical weight loss trial imposes more
than usual behavioral changes, notably in the form of self-
monitoring of behavior and weight, which may have impor-
tant effects.
19
The results in the ReCharge trial are therefore
of heightened interest because the post hoc analysis showed
greater weight loss in the active group despite a robust sham
effect.
Adverse events in this trial were less severe than those as-
sociated with conventional bariatric surgical procedures, pri-
Table 3. AdverseEvents Related to Treatment Through 12 Months
Adverse Event
Vagal Nerve Block
(n=162)
Sham
(n=77)
No. (%) Patients No. Events No. (%) Patients No. Events
Pain, neuroregulator site 61 (38) 73 32 (42) 35
Heartburn/dyspepsia 38 (23) 42 3 (4) 3
Pain, other 37 (23) 42 0 0
Pain, abdominal 20 (12) 26 2 (3) 2
Nausea 11 (7) 14 1 (1) 1
Dysphagia 13 (8) 13 0 0
Eructation/belching 13 (8) 13 0 0
Incision pain 12 (7) 13 7 (9) 7
Chest pain 9 (6) 9 2 (3) 2
Cramps, abdominal 7 (4) 7 0 0
Wound redness or irritation 7 (4) 7 5 (6) 5
Appetite increased 5 (3) 6 2 (3) 3
Constipation 6 (4) 6 7 (9) 8
Emesis/vomiting 5 (3) 6 2 (3) 2
Bloating, abdominal 5 (3) 5 1 (1) 2
Headache 5 (3) 5 2 (3) 2
Only adverse events attributed by the
investigator to the device, procedure,
or therapy that occurred in at least
3% of vagal nerve block group
participants are displayed.
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marily mild or moderate events related to therapy. Recent re-
ports of uncontrolled clinical trials and registry data provide
comparative safety data on laparoscopic adjustable gastric
band.
20-22
Overall, the rate of device-related adverse eventsin
the Helping Evaluate Reduction in Obesity (HERO)registr y ap-
pears to be 4.7%.
20
Phillips et al
21
reported adverse events that
included dysphagia (9.4%), gastroesophageal reflux (19.2%),
and vomiting (40.6%) and a reoperation rate of 15.2%.
Cobourn et al
20
reported a low rate of band-related complica-
tions, but a reoperation rate of 15.2%. Late complications for
laparoscopic adjustable gastric band include band slippage and
pouch dilation, which occurs in up to 20% of patients, and band
erosion occurring in up to 4% of patients.
23
However, adverse
events of vagal nerve block have not yet been reportedfollow-
ing widespread use. Rates of adverse events often increase
when therapies are used in general populations.
This study has limitations including the demographics of
the study participants, which were primarily white women, so
inference to other groups must be made with care. Further-
more, the study population had a low rate of diabetes, a com-
mon comorbidity of significant obesity, and a low rate of other
metabolic complications such as hypertension and dyslipid-
emia. The study focused on obesity in the BMI range of 35 to
45, so application of the treatment to individuals with higher
BMI will need careful consideration.
Conclusions
Among patients with morbid obesity, the use of vagal nerve
block therapy compared with a sham control device did not
meet either of the coprimary prespecified efficacy objec-
tives, although the intervention group had statistically greater
weight loss than the sham control group. The treatment met
the primary safety objective and was well tolerated. Addi-
tional studies are needed to compare effectiveness of vagal
nerve block with other obesity treatments and to assess long-
term durability of weight loss and safety.
ARTICLE INFORMATION
Author Affiliations: Department of Surgery,
University of Minnesota, Minneapolis (Ikramuddin,
Leslie); University of Minnesota, Minneapolis;
Scottsdale Healthcare Bariatric Center, Scottsdale,
Arizona (Blackstone, Swain); Institute of Weight
Control, Sydney, Australia (A. Brancatisano,
R. Brancatisano); Adelaide Bariatric Centre,
Adelaide, Australia (Toouli,Kow); Department of
Surgery, Tufts Medical Center, Boston,
Massachusetts (Shah); Department of Surgery,
Oregon Health & Science University,Portland
(Wolfe, Deveney); Scripps Clinic, San Diego,
California (Fujioka, Takata); Division of General
Surgery, Virginia Commonwealth University,
Richmond (Maher); Department of
Gastroenterologic and General Surgery,Mayo Clinic
Rochester,Rochester, Minnesota (Que, Sarr);
Division of General Surgery, StanfordUniversity
School of Medicine, Stanford, California (Morton);
Department of Surgery, University of Michigan and
Ann Arbor VA Hospital (O’Rourke);North American
Science Associates, Minneapolis, Minnesota
(Miller); EnteroMedics Inc, St Paul, Minnesota
(Knudson, Tweden, Shikora);Division of General
and Gastrointestinal Surgery,Brigham and Women’s
Hospital, Boston, Massachusetts (Shikora); Division
of Endocrinology and Diabetes, Minneapolis VA
Medical Center and University of Minnesota,
Minneapolis (Billington).
Author Contributions: Drs. Billington and Sarr had
full access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Toouli,Kow, Knudson,
Tweden, Shikora,Sarr, Billington.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Miller,Knudson,
Tweden, Shikora,Sarr, Billington.
Critical revision of the manuscript for important
intellectual content: Ikramuddin, Blackstone, A
Brancatisano, Toouli,Wolfe, Fujioka, Maher, Swain,
Que, Morton, Leslie, R Brancatisano, Kow,
O’Rourke, Deveney, Takata,Miller, Knudson,
Tweden, Shikora,Sarr, Billington.
Statistical analysis: Miller.
Obtained funding: Knudson.
Administrative, technical, or material support: All
authors.
Study supervision: Ikramuddin, Blackstone, A
Brancatisano, Toouli,Shah, Wolfe, Fujioka, Maher,
Swain, Que, Morton, Tweden,Shikora, Sarr,
Billington.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr
Ikramuddin reported that he serves on the advisory
board for Novo Nordisk Inc and Medica; has served
as a consultant for Metamodix Inc and on an expert
panel for OptumHealth; and has received grant
support from USGI Medical Inc, ReShape Medical,
and Covidien. Dr Brancatisano reported that he is a
consultant for EnteroMedics. Mr Miller reports
consulting support from EnteroMedics, Inc. Dr
Fujioka reported receiving personal fees from
EnteroMedics for help and consulting with
European device approval. Dr Swain reports
personal fees from surgical proctoring for
Enteromedics. Dr Knudson reported that he is the
chief executive officer of EnteroMedics and
codeveloped the patented vagal nerve blockade
device, which is owned by EnteroMedics. Dr
Tweden reported that she is an employee of
EnteroMedics and codeveloped the patented vagal
nerve blockade device, which is owned by
EnteroMedics. Dr Sarr reported that he is a
consultant for EnteroMedics. Dr Billington reported
that he is a consultant for EnteroMedics and
NovoNordisk and has received pgrant support from
Covidien.
Funding/Support: The ReCharge Study was
supported by EnteroMedics Inc, St Paul, Minnesota.
Role of the Funder/Sponsor:EnteroMedics Inc
was involved in the design and conduct of the
study,site selec tion, database management. The
sponsor provided funding to the clinical sites for
patient enrollment, core laboratory analyses,
clinical events adjudications, and database entry.
The sponsor provided fees to North American
Science Associates for independent statistical
analyses. Two sponsor representatives (Knudson
and Tweden) were allowedto review and
participate in the critical revision of the manuscript
prior to submission.
National Primary Investigators: Michael G. Sarr,
MD, and Charles J. Billington, MD.
Study and Weight Management Coordinators:
University of Minnesota: Bridget Slusarek, Elsie
Waddick, Shannon Johnson, and Nikolaus Rasmus;
Scottsdale Bariatric Center: Melisa Celaya, Heather
Lane, Samantha Easterly,Cassie Truran, Arrin
Larson, Dorrie Wilson, Katherine Emershad,
Jennifer Childress, and Angelia Seitz; Institute of
Weight Control, Sydney: RadhikaButala, Gre tel
Young, Ruth Hutchinson, Kerry McCurley, and
Geane Sharman; Adelaide Bariatric Centre,
Adelaide: Jane Collins and Fiona McDonald; Tufts
Medical Center: Ann Marie Melanson, Meghan
Ariagno, Danielle DeMarco, and Jillian Regan;
OHSU: Wencesly Paez, Chad Sorenson, Shannon
Rentz, Gloria Scalzo, and Tracy Severson; Scripps
Clinic: Jennifer Wagner,Mary Collard, Sandy Grad,
Cindy Galm, and Melissa Susak; VCU: Donna
Neatrour, Jill Meador, Sakita Sistrun, Melanie
Wiggins, Carly Sopko, and Leah Loomis; Mayo
Clinic: Amy Reynolds, Joe Hockert, Sue Starkson,
Margaret Gall, and Debbie Dixon; and Stanford:
Dana Schroeder and Kristine Birge.
Data and Safety Monitoring Board and Clinical
Events Committee Members: James Freston,MD,
(chair) Department of Medicine, University of
Connecticut School of Medicine, Farmington; Daniel
Bessesen, MD, Division of Endocrinology,University
of Colorado Denver,Denver; Miguel Herrera, MD,
Division of General Surgery, UniversidadNacional
Autónoma de México at Instituto Nacional de la
Nutrición Salvador Zubirán, Mexico City; Melissa
Martinson, PhD, Division of Health Policy and
Management, School of Public Health, University of
Minnesota, Minneapolis; Frank Moody, MD,
Department of Surgery, University of Texas Health
Science Center, San Antonio.
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