Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01581801 |
| Other study ID # |
UCSC-2012-V01 |
| Secondary ID |
2012-bariatric-0 |
| Status |
Completed |
| Phase |
N/A
|
| First received |
April 19, 2012 |
| Last updated |
February 4, 2017 |
| Start date |
October 2012 |
| Est. completion date |
March 2016 |
Study information
| Verified date |
February 2017 |
| Source |
Catholic University of the Sacred Heart |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Bariatric surgery has long been recognized as an effective treatment for grade 3 or grade 2
obesity associated with complications. Among the bariatric surgical procedures, roux-en-y
gastric bypass (RYGB) was shown to account for 41% of all bariatric operations at least in
the United Sates. Sleeve gastrectomy (SG), that was conceived as the first step before
performing a RYGB or a biliopancreatic diversion with duodenal switch in patients who were
super-obese, has recently emerged as a new restrictive bariatric procedure.
Reactive hypoglycemia is a late complication affecting up to 72% of RYGB patients although
it seems to occur also after SG, in about 3% of the cases. However, until now no prospective
studies have investigated the incidence of hypoglycemia after RYGB nor randomized studies
have been undertaken to compare the effect of SG to that of RYGB in terms of incidence of
hypoglycemic episodes.
The primary aim of the present study is to conduct a 1-year randomized trial to compare the
incidence of hypoglycemia after RYGB or SG.
Description:
INTRODUCTION Geltrude Mingrone,Simona Panunzi, Andrea De Gaetano, Caterina Guidone,
Celestino Pio Lombardi, Marco Raffaelli,Rocco Bellantone Departments of Internal Medicine,
Surgery and Biomathematics of the Catholic University of Rome, Italy
The overall prevalence of grade 2 and 3 adult obesity (BMI> 35 kg/m2) derived from the
2009-2010 National Health and Nutrition Examination Survey (NHANES) exceeded 15% and grade 3
obesity (BMI > 40 kg/m2) accounted for 6.3% (1). The dietary approach is modestly
satisfactory in the short term and weight regain is practically the rule in the long run as
a consequence of the scarce compliance to the diet shown by the obese subjects. In fact, in
a recent study (2) where different types of diets were assigned to a population of
overweight and obese subjects (BMI from 25 to 40 kg/m2), an average of 6 kg, corresponding
to 7% of the initial body weight, was lost in the first 6 months, but the weight was
regained after 1 year and at 2 years, only 31-37% of the participants had lost 5% of their
initial weight.
Bariatric surgery has long been recognized as an effective treatment for grade 3 or grade 2
obesity associated with complications (3) and, accordingly, the number of bariatric
operations in the United States is growing over time from ca. 10,000 in the early 1990s to
103,000 in 2003 (4).
Bariatric surgery allows to type 2 diabetes remission (5,6) while improving several other
serious comorbidities (7). Among the bariatric surgical procedures, roux-en-y gastric bypass
(RYGB) was shown to account for 41% of all bariatric operations at least in the United Sates
(8). Sleeve gastrectomy (SG), that was conceived as the first step before performing a RYGB
or a biliopancreatic diversion with duodenal switch in patients who were super-obese (9),
has recently emerged as a new restrictive bariatric procedure (10). It was noticed that SG
determines a weight loss similar to that achieved after RYGB (11) and larger than that
following laparoscopic adjustable gastric banding (12,13).
Reactive hypoglycemia is a late complication of RYGB although it seems to occur also after
SG.
After RYGB insulin secretion is enhanced early after an oral glucose tolerance test (OGTT)
(14) or a meal (15,16) and might explain the later reactive hypoglycemia. An increasing
number of reports highlight the occurrence of severe hypoglycemia after RYGB including
neuroglycopenia that is attributed to nesidioblastosis (17-20). Roslin et al (21) found that
72%, i.e. 26 out of 36 patients operated of RYGB 6 months earlier, had reactive hypoglycemia
at 2 hours after an OGTT (100 g of glucose), which was defined as "an absolute serum glucose
level ≤60 mg/dL, or a drop of 100 mg/dL in serum glucose level in 1 h".
As compared with RYGB, SG seems to have a much lower occurrence of reactive hypoglycemia,
ca. 3%, i.e. 1 out of 31 patients studied at 6 weeks after the operation (22).
Fortunately, the frequency of severe hypoglycemia or related symptoms requiring
hospitalization after RYGB is pretty low, the adjusted hazard ratios were in fact 2.7 for
hypoglycemia, 2.8 for confusion, 4.9 for syncope, 3.0 for epilepsy and 7.3 for seizures (23)
in a Swedish cohort study based on national registries with 5,040 operated persons (23).
However, until now no prospective studies have investigated the incidence of hypoglycemia
after RYGB nor randomized studies have been undertaken to compare the effect of SG to that
of RYGB in terms of incidence of hypoglycemic episodes.
The primary aim of the present study is to conduct a 1-year randomized trial to compare the
incidence of hypoglycemia after RYGB or SG.
STUDY OBJECTIVE
Primary objective The primary objective of the study is to verify whether SG decrease the
percentage of patients presenting with reactive hypoglycemia with respect to RYGB within 1
years after the bariatric operation.
Secondary objectives
- To quantify the relative contribution of changes in insulin sensitivity and insulin
secretion measured after an OGTT to the glycemic effect of bariatric surgery and to
determine if differences exist between the two surgical treatments.
- To determine whether treatment is associated with body weight, BMI and abdominal
circumference loss and with body composition, as assessed by DEXA, as well as with
lipid profile and cardiovascular system abnormalities.
- To assess the occurrence of severe hypoglycemia or related symptoms (shakiness,
sweating, dizziness or light-headedness, confusion, difficulty speaking, weakness,
confusion, syncope, epilepsy, seizures) within 5 years after the operation and
determine whether SG decrease its incidence.
EXPERIMENTAL DESIGN Study End-points
Primary End-point The Primary Endpoint of the study is the incidence reactive hypoglycemia
at 1 year after the bariatric surgery.
Secondary End-points
- Changes at 1 year of insulin sensitivity and insulin secretion measured after an OGTT.
- Changes at 1 year of body weight, BMI, abdominal circumference, body composition, lipid
profile and cardiovascular system abnormalities.
- the incidence of severe hypoglycemia or related symptoms (shakiness, sweating,
dizziness or light-headedness, confusion, difficulty speaking, weakness, confusion,
syncope, epilepsy, seizures) within 5 years after the operation.
Experimental plan This is a monocentric prospective controlled randomized clinical trial
designed to investigate if the SG reduces the incidence of reactive hypoglycemia with
respect to RYGB within 1 years after the bariatric operation.
At the moment of the Screening visit subjects will be randomized to be undergone either the
SG or the RYGB surgical procedure.
Study Design diagram
The diagram of the study plan is as follows:
Screening Visit (-18 weeks) Baseline Visit (-4 weeks) Follow-up Visit (+1 month) Follow-up
Visit (+3 months) Follow-up Visit (+6 months) Follow-up Visit (+9 months) Follow-up Visit
(+12 months) Written informed consent Demographic Data Medical and surgical history Physical
examination† Height weight, BMI waist and hip circumference DEXA blood pressure and heart
rate ECG laboratory assessments OGTT adverse events recording concomitant medication An
overview of all planned blood samples, including volumes and purpose is provided in Table 2.
Study duration
Subjects will be studied from the time of Screening Visit to 1 year after the surgical
procedure and will undergo four distinct phases:
- Screening visit (week -18)
- Baseline visit (week -4)
- A follow-up period after the surgical treatment (1 year of duration, month 1, 3, 6, 9,
12)
- A further follow-up period after study conclusion (4 years of duration)
Screening Visit At week -18, eligible patients are identified and the Written informed
consent is obtained. Demographic data, anthropometric measures, physical examination and
information about medical history, concomitant medication and variables related to inclusion
criteria are collected.
Basal Visit At week -4 patients at the screening visit will be asked to return for the
baseline visit and they will be asked to give their informed consent to randomization. Study
compliance will be assessed during the screening and baseline periods using attendance at
appointments and completion of questionnaires. Baseline anthropometric measures, body
composition, blood pressure, and biochemical data (levels of fasting plasma glucose,
glycated hemoglobin [HbA1c], C-peptide, and serum insulin, lipid profile and oral glucose
tolerance test) are measured.
Follow-up Period One month after the bariatric surgery and each 3 months until 1 year after
the surgical treatment (month 1, 3, 6, 9, 12) all the collected variables at baseline will
be recorded and an OGTT will be performed. Adverse events will be recorded at each follow-up
visit.
Study conclusion and a further follow-up period At the conclusion of the a study a
conclusion form will be filled in and patients will be followed up to 5 years after the
surgical treatment.
STUDY POPULATION
Sample size The sample size depends on the magnitude of the difference in reactive
hypoglycemia incidence as derived from previous studies (21) and (22). The study is designed
to detect a more conservative absolute difference in the occurrence of hypoglycemia of 50%,
expecting an incidence of 70% in the RYGB group versus an incidence of 20% in the SG group.
A sample size of 19 patients per group would be required for this clinical trial to detect
an improvement data significance level of 0.05 and a power of 0.90. Considering an attrition
rate of 25% over the course of the study a total of 50 subjects (25 for each group) will be
enrolled.
An amendment to enlarge the number of patients to 120, 60 in each arm, was approved by the
Ethical Committee on November 2012. For a more conservative estimate in fact, we have
reduced the percent difference between the two groups from 50% to 30% considering the
incidence of reactive hypoglycemia to be 50% in RYGB and to 20% in SG instead of 70% and 20%
respectively. In this way, the number of patients to be allocated in each arm is 50 with a
power of 90%. Considering an attrition rate of 20% the number of patients in each group will
be 60 and, thus, overall 120. Secondary endpoints for CGM and insulin sensitivity and
secretion are evaluated in a subset of 50 patients, 25 in each Group, but can be also
extended to entire sample.
Selection study population Patients will be recruited from the Outpatient Clinics and Day
Hospital of Obesity of the Catholic University of Rome, Italy. The study will be subject to
revision and approval by the Ethical Committee of the above institution in accordance with
the guidelines of the National Health Ministry and the Helsinki Declaration, as revised in
2000. All participants will provide written informed consent to participate in the study.
Additional written informed consent will be obtained prior to the surgical procedure.
Inclusion Criteria Patients are eligible if aged between 25 and 65 years, have a body mass
index of 35 (in presence of complications as sleep apnea, severe coxarthritis or
gonarthritis, severe hypertension) to 50 kg/m2, and are able to understand and comply with
the study process.
Exclusion Criteria
- History of type 1 diabetes or secondary diabetes;
- Previous bariatric surgery;
- History of medical problems such as mental impairment;
- Major cardiovascular disease;
- Major gastrointestinal disease;
- Major respiratory disease;
- Hormonal disorders;
- Infection;
- History of drug addiction and/or alcohol abuse;
- Internal malignancy;
- Pregnancy;
- Impaired glucose tolerance;
- Suspected or confirmed poor compliance;
- Informed consents; Participants will be excluded if they did not attend at least 2
initial information visits.
TREATMENT
Surgical Program Within 1 month of randomization the patients will undergo RYGB or SG.
Roux-en-Y Gastric Bypass This laparoscopic operation includes the division of the stomach in
two parts. A proximal, smaller pouch (20-25 cc volume), is connected to the rest of the
gastrointestinal tract through a gastro-jejunal anastomosis, whereas the distal gastric
pouch is left behind but excluded from the transit of food.
An entero-entero anastomosis, with a Roux-en-Y type of reconstruction, allows the bile and
pancreatic juices to mix with the nutrients at about 100-150 cm from the gastro-jejunal
connection.
Sleeve gastrectomy Laparoscopic SG involves a longitudinal resection of the stomach on the
greater curvature from the antrum starting opposite of the nerve of Latarjet up to the angle
of His The final gastric volume is about 100 mL.
Randomization Process Automatic dynamic allocation of the treatment to the patients will be
performed via a Web-based software. The randomization procedure via Internet is an automatic
and flexible mechanism that on one hand guarantees random allocation and on the other hand
reduces imbalance with respect to the two treatment groups over the two considered
stratification factors: gender and age (18-40 and 40-60). The mechanism may be accessed from
any web-connected computer; it clears the user for data access (userid/password); it
requires the user to specify the screening number of the subject about to be randomized; it
verifies inclusion/exclusion criteria and acquires stratification information; it finally
assigns the subject to a treatment, and delivers the corresponding unique randomization
number. The procedure optimizes the overall balance of treatments among each stratification
cell. The allocation algorithm will be verified by the responsible statistician for the
study, who will have continuing access to the randomization statistics throughout the
duration of the study.
Criteria for discontinuation and/or withdrawal
Criteria for discontinuation:
- Withdrawal of informed consent
- Subject uncooperative
- Safety reasons as judged by principal investigator
- Non-compliance to the protocol
- Incorrect enrolment
- Subjects who could not be operated laparoscopically
- Conditions requiring medication that could interfere with the outcome of the study
except those for intercurrent illnesses or adjustment of anti-hypertensive therapy as
judged by the principal investigator
- Subjects with severe complications due to the surgery as judged by the principal
investigator
- Bleedings related to surgery that make it impossible to draw blood samples
Subjects may be discontinued from the study at any time, at the discretion of the
investigator. Subjects are free to discontinue their participation in the study at any time.
Subjects who discontinue from the study should always be asked about the reason(s) for the
discontinuation. If possible, they should always be seen and assessed by an investigator.
Adverse events will be followed up according to national requirements.
If a subject discontinues participation in the study, then his enrolment number cannot be
issued to another subject.
EFFICACY EVALUATION
In order to evaluate the effect of the sleeve gastrectomy versus the Roux-en-Y Gastric
bypass on the glycemic control the following parameters will be considered:
Primary endpoint Primary Endpoint: incidence of reactive hypoglycemia at 1 year after the
bariatric surgery.
Secondary End-points
- Changes at 1 year of insulin sensitivity and insulin secretion measured by means of an
OGTT.
- Changes at 1 year of body weight, BMI, abdominal circumference, body composition and
lipid profile.
- the incidence of severe hypoglycemia or related symptoms (shakiness, sweating,
dizziness or light-headedness, confusion, difficulty speaking, weakness, confusion,
syncope, epilepsy, seizures) within 5 years after the operation.
Evaluation methods and timing
During the experimental study the following clinical evaluations will be performed:
1. Demographic Data (week -18)
- Date of birth
- Gender
- Ethnicity
2. Medical and Surgical History (week -18, week -4)
3. Anthropometric measurements (week -18, week -4, month 1, 3, 6, 9 and 12)
- Body Weight (will be measured to the nearest 0.1 kg on a balanced beam scale in
the morning before breakfast after a visit to the lavatory in their underwear's).
- Height (will be measured to the nearest 0.5 cm using a stadiometer)
- Waist circumference (will be measured at the part of the trunk midway between the
most caudal part of the lateral costal arch and the iliac crest in the morning
before breakfast, after lavatory visit with the person standing with feet about
25-30 cm apart. The measurer will stand beside the individual and fit the tape
snugly, without compressing any underlying soft tissues. The circumference will be
measured to the nearest 0.5 cm, at the end of a normal expiration.
- Hip circumference (will be measured as the maximal circumference over the
buttocks)
- BMI (will be computed as weight (kg) / height (m2))
4. Physical examination (week -18, week -4, month 1, 3, 6, 9 and 12)
- General appearance
- Skin
- Head and neck
- Lymph nodes
- Thyroid
- Cardiovascular system
- Respiratory systems
- Abdomen
- Other
5. Cardiovascular Parameters (week -18, week -4, month 1, 3, 6, 9 and 12)
- Blood pressure
- Heart rate (blood pressure and heart rate will be measured in sitting position in
duplicate after 15 min rest)
- ECG (recorded under resting condition. It will be performed according to standard
routine at bariatric surgery)
6. Biochemical analysis (week -18, week -4, month 1, 3, 6, 9 and 12)
- Fasting plasma glucose
- Fasting plasma insulin
- Fasting plasma C-peptide
- HbA1c
- Total cholesterol
- HDL-cholesterol
- Triglycerides
- Hematology profile
- Chemistry panel
7. Oral Glucose Tolerance Test (OGTT) (week -18, month 1, 3, 6, 9 and 12) At 8:00-9:00
a.m., after a 12-h overnight fast, an intravenous catheter is placed in one antecubital
vein to draw blood samples. An OGTT (75 g of glucose) is performed in 10 minutes
maximum and blood samples obtained at −20, -5, 5, 10, 20, 30, 40, 60, 80, 100, 120,
140, 160 and 180 min relative to the start of the OGTT. Samples are placed in chilled
tubes, and plasma is separated within 20 min and stored at −70°C.
Analytical Methods Plasma glucose will be measured by the glucose-oxidase method
(Beckman, Fullerton, CA). Plasma insulin will be assayed by microparticle-enzyme
immunoassay (Abbott, Pasadena, CA) with a sensitivity of 1 μU/ml and an intra-assay CV
of 6.6%.
C-peptide will be assayed by radioimmunoassay (MYRIA; Technogenetics, Milan, Italy):
minimal detectable concentration =17 pmol/l and inter- and intra-assay CVs of 3.3-5.7
and 4.6 -5.3, respectively.
Mathematical modeling: to be detailed.
8. DEXA variables (week -4, month 6, 9 and 12) (Body composition is measured by DEXA
(Lunar Prodigy), which provides results on total and regional (trunk, arms, legs,
pelvis) fat mass, fat free mass, and bone mass)
- Total body bone mineral density
- Lean body mass
- Fat mass
- Percent weight body fat
9. Concomitant medication (week -18, week -4, month 1, 3, 6, 9 and 12)
SAFETY AND TOLERANCE EVALUATION AND ASSESSMENT The safety of the surgical procedures
will be evaluated at the end of the study analyzing all the information recorded in the
Case Report Form suitably designed for the study, according to the timing and
modalities described in other sections of the present protocol.
Information to assess the safety will include: objective exam, patient's symptoms
related to the operation, occurrence of adverse events.
Safety parameters Adverse Events
The clinical tolerability will be evaluated by recording of the occurrence of adverse
events as reported by the patient or observed by the medical investigator. Any adverse
event occurred after the surgical treatment will have to be recorded in the Case Report
Form.
Definitions
An adverse event (AE) is any untoward medical occurrence in a patient or clinical
investigation subject undergone a treatment and which does not necessarily have a
causal relationship with this treatment. An AE can therefore be any unfavorable and
unintended sign, symptom, or disease temporally associated with the use of a medicinal
product, or related to the surgical procedure. Pre-existing events, which increase in
frequency or severity, or change in nature during or as a consequence of use of a drug
in human clinical trials, will also be considered as AEs.
A serious adverse event (SAE) is defined as any adverse event regardless of causality
that
led to a death, led to a serious deterioration in the health of the subject that
resulted in a life-threatening illness or injury, resulted in a permanent impairment of
a body structure or a body function, required in-patient hospitalization or
prolongation of existing hospitalization, results in medical or surgical intervention
to prevent permanent impairment to body structure or a body function.
led to fatal distress or fatal death.
A serious adverse device effect (ADE) is a serious adverse event related to the adopted
device (in the specific case the surgical procedures) that results in any of the
consequences characteristic of a serious adverse event or that might led to any of
these consequences if suitable action is not taken or intervention is not made or if
circumstances are less opportune.
Adverse Event and adverse device effect Reporting Procedures If the investigator
identifies the occurrence of an AE, SAE or of an ADE report form must be completed and
sent by fax to the Coordinating Investigator within 24 hours of the investigator's
knowledge of the event. This form will be part of the study documentation. Any fatal or
life-threatening event should be reported immediately to Coordinating Investigator by
telephone. These preliminary reports will be followed within 24 hours by detailed
descriptions that will include a completed SAE/ADE form, copies of hospital case
reports, autopsy reports, and other documents, when requested and applicable.
Minimal information should include:
An identifiable subject or patient The type of surgical treatment the patient was
undergone An identifiable reporting source All related adverse events All medications
used Follow-up of SAE/ADEs that occur during the study will continue until satisfactory
resolution or stabilization, with a maximum of six months, upon judgment of the
investigator. The coordinating investigator may request that certain adverse events to
be followed until resolution.
If/ when supplementary information is available, a follow-up SAE/ADE Report Form must
be completed by the investigator and delivered within 24 hours to the coordinating
investigator.
Once faxed, the SAE/ADE form and accompanying documentation should be placed in the
SAE/ADE section of the investigator's file. If supplementary information on a SAE/ADE
has to be sent, the SAE/ADE form has to be used marked as "follow-up report".
The coordinating investigator must inform the Ethics Committee if the serious adverse
event is likely to affect the safety of the subjects or the conduct of the study.
Moreover will be responsibility of the Coordinating Investigator of informing in
writing all clinical investigators about all serious adverse events and all serious
adverse device effects occurring during the study. This information shall be sent to
the clinical investigators based on perceived risk.
DIRECT ACCESS TO ORIGINAL DOCUMENTATION The Investigator will have to allow the
national Regulatory Authority, and the staff designed by the Independent Ethical
Committee or by coordinating investigator direct access to the complete original
documentation - and its verification - including informed consent, signed by the
enrolled patients or by their Legal Representatives, and the clinical records or
outpatient registers. People who have direct access to this documentation will have to
take all reasonable precautions in order to maintain the patient identity and all
information which is property of the Coordinating Investigator, in compliance with
applicable laws.
QUALITY ASSURANCE PROCEDURES The Organization, Monitoring and Quality Assurance of the
present study will be under the responsibility of the Coordinating Investigator.
Clinical Monitoring The clinical monitoring will be carried out by qualified persons
assigned by the Coordinating Investigator and will be conducted according to the
guidelines of the ISO Standard 14155-1. Additionally the monitoring activities will
include the verification of the correct filling of the CRFs and, when applicable, the
consistence between source documents and the electronic stored data used for the
randomization procedures. The coordinating investigator will ensure the practical
training for the personal involved in the study on the surgical and medical techniques
and on filling the CRFs.
Data Review and Audits Data Review and Audits will be carried out by qualified persons
assigned by the Coordinating Investigator.
The CRFs will be periodically reviewed. Financing of the study No financial aspect must
be taken into account because no funding is foreseen for the present study.
Table 1 Variables recorded during the Physical examination and included in DEXA
PHYSICAL EXAMINATION Appearence general Skin Head and neck Lymph nodes Thyroid
Cardiovascular system Respiratory systems Abdomen Concomitant medication Other DEXA
Total body bone mineral density Lean body mass Fat mass Percent weight body fat
