Obesity and asthma: Effect of bariatric surgery on lung function, inflammation and quality of life.|
|- candidate number||10665|
|- NTR Number||NTR3204|
|- ISRCTN||ISRCTN wordt niet meer aangevraagd.|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||9-dec-2011|
|- Secondary IDs||NL25637.101.08 CCMO|
|- Public Title||Obesity and asthma: Effect of bariatric surgery on lung function, inflammation and quality of life.|
|- Scientific Title||Obesity and asthma: Effect of bariatric surgery on lung function, inflammation and quality of life.|
|- hypothesis||1. All obese patients have low-grade systemic inflammation characterized by IL-6, TNF-alfa, leptin and adiponectin. Patients with obesity and asthma have higher expression of these mediators and neutrophils in bronchial mucosa than obese patients without asthma;|
2. There is a correlation between these inflammatory mediators in visceral fat tissue, blood and bronchial mucosa in patients with obesity and asthma;
3. Asthma control and bronchial inflammation will improve after bariatric surgery.
|- Healt Condition(s) or Problem(s) studied||Asthma, Obesity|
|- Inclusion criteria||1. For the asthma patients: Physician diagnosed, persistent asthma > 2 years;|
2. Age > 18 and < 50 year;
3. Acceptable operative risk;
4. BMI > 35 kg/m2;
5. Ability to perform a reproducible lung function test;
6. Approval for 2 year follow-up visits.
|- Exclusion criteria||1. Smoking > 10 sig/d or > 10 pack years (PY);|
2. COPD or other pulmonary pathology apart from asthma;
4. Exacerbation in 4 weeks prior to screening;
5. Use of oral steroids;
6. Psychological instability.
|- mec approval received||yes|
|- multicenter trial||no|
|- Type||2 or more arms, non-randomized|
|- planned startdate ||1-sep-2009|
|- planned closingdate||31-dec-2012|
|- Target number of participants||120|
|- Interventions||Bariatric surgery (sleeve resection or gastric bypass).
The study will start in September 2009 and the design will be prospective, observational, longitudinal and controlled. Before the start of the study, approval of the local medical ethics committee and informed consent will be obtained. Pulmonary screening is a procedure that is already incorporated in the work-up of obesity patients in our hospital. Asthma is diagnosed when respiratory symptoms are accompanied by reversible airway obstruction (improvement in FEV1 > 12% after bronchodilator inhalation) and/or increased bronchial hyperreactivity (PC20 methacholine < 8 mg/ml). Patients must have stable disease before operation. Baseline measures will be performed, including spirometry, determination of fractionated nitric oxide in the exhaled air (FeNO), asthma questionnaire (ACQ), asthma control test (ACT), skin prick test and blood samples, diet diary, activity measurement (see overview). Directly after intubation, before bariatric surgery, bronchoscopy will be done with collection of 7 bronchial biopsies. Then a laparoscopic gastric sleeve resection will be performed. During the procedure a visceral fat biopsy will be collected. After the operation, the study subjects will have a follow-up of one year, with a visit every 3 months, including spirometry, methacholine provocation test, FeNO, ACQ, ACT and blood samples. One year after surgery, a second bronchoscopy will be performed (under local anaesthesia). Asthma medication will be tapered with maintenance of asthma control based on the methacholine provocation test. Self management consisting of diet and physical activity will be monitored during the study with diary observation and activity measurement with an activity meter.
Every year 250 new patients with morbid obesity (O) undergo a preoperative screening. According to our own studies and other epidemiologic studies, the prevalence of asthma (A) in this group is > 25%. Annually, we expect to diagnose 60 obese patients with asthma. The group with obesity and no asthma is the internal control group. Twenty patients with obesity and asthma that will not have an intervention serve as an external control group. In total, 100 obese patients will be included in the study: 40 with asthma (O+A) and 40 without asthma (O-A) that undergo operation and 20 with asthma that will have no operation (NO+A). The three groups will be matched for age, gender, BMI, allergy and smoking.
Sample size calculation:
The group size is powered on the expected change in FEV1/FVC ratio before and after bariatric surgery. Based on a pilot study and the literature we assume that in obese patients with asthma the FEV1/FVC ratio increases from 72% to 75% (SD ± 6). The increase of 3% represents an effect size of 0.5. This is slightly more than the improvement seen after dietary interventions, but the expected weight reduction after bariatric surgery is greater. Unfortunately, most studies did not include a control group. In our pilot study we have found a FEV1/FVC ratio of 79 ± 5%. We do not expect this ratio to change in this non-asthmatic group. To find a difference in the group with obesity and asthma before and after operation with a error of 5% and a power of 80%, we need at least 27 participants per group. With an expected drop-out of 25% over 2 years follow-up we aim at 40 patients per subgroup.
The effect of laparoscopic gastric sleeve resection on lung function, airway inflammation and asthma control will be studied in patients with morbid obesity. All study patients will undergo two bronchoscopies. There is no difference between the asthmatic patients (O+A) and non-asthmatic control group (O-A) in treatment procedures. The non-intervention group (NO+A) will not undergo bronchoscopy due to expected respiratory problems during the procedure.
Use of co-intervention:
Inhaled corticosteroids will be withdrawn in asthmatic patients 4 weeks prior lung function tests, until surgical intervention. Lung function (with the use of a peakflow meter), symptoms and airway inflammation will be carefully observed to guarantee asthma control. Patients will receive instructions to call the pulmonologist on call in case of:
1. Need for more than 3 puffs of salbutamol per day;
2. More than 3 nightly awakenings per week due to breathlessness;
3. Other complaints that may relate to their asthma control.
In case of loss of asthma control, the patient will receive budesonide 400 mcg b.i.d. Symptoms will be additionally controlled by use of ventolin. After operation steroids will be continued according to the schedule below.
In both asthma groups the use of inhaled corticosteroids will be tapered depending on the PC20 methacholine tests. Four steps in the treatment with controller medication will be:
1. No requirement for corticosteroids;
2. Low-dose inhaled steroids 2 times daily 200 microg budenoside by dry-powder inhaler;
3. Intermediate dose inhales steroids 2 times daily 400 microg;
4. High dose inhaled steroids (2 times daily 800 microg) plus a short course of oral prednisone (30 mg/d for 2 days, with subsequent doses decreasing by 5 mg every 2 days).
A methacholine PC20 less than 0,25 mg/ml requires a treatment step 4. Metacholine PC20 between 0.25 and 1.0 mg/ml requires a treatment step 3. Between 1.0 and 4.0 mg/ml treatment step 2, and higher than 4.0 mg/ml treatment step 1.
All patients that still smoke will be offered a stop-smoking program at our stop-smoking clinic.
For treatment of asthma symptoms: Ventolin 200 mcg Diskus 1-4 dd.
For treatment of allergic rhinitis: Aerius 5 mg 1 dd.
|- Primary outcome||Lung function: FEV1/FVC at 12 months after bariatric surgery.|
|- Secondary outcome||1. Other lung function parameters: FEV1, FIV1, TLC, FRC, reversibility (supine and sitting position). R5, X5 and Fres (FOT);|
2. Airway inflammation: FeNO, bronchial biopsies (during operation), PC20 methacholine;
3. Systemic inflammation (blood): TNF-á, IL-6, eotaxin, high sensitivity CRP, leptin, adiponectin, oestrogen, progesteron, lipid spectrum, glucose, sCD14;
4. Local inflammation (visceral fat tissue and bronchial biopsies): determination of gene expression (TNF-á, IL-6, eotaxin, leptin, adiponectin), polymorphisms of Beta-2 receptor ADRB2, glucocorticoid receptor gen NR3C1 and Toll-like receptors (TLR2, TLR4, TLR6 en TLR10, and IgE. Intima Media Thickness measurement. Determination of structural features in bronchial mucosa (airway remodelling);
5. Asthma symptoms: ACQ, exacerbation frequency, medication use, ACT.
|- Timepoints||1. Before surgery;|
2. 3 months FU;
3. 6 months FU;
4. 9 months FU;
5. 12 months FU.
|- Trial web site||N/A|
|- status||inclusion stopped: follow-up|
|- CONTACT FOR PUBLIC QUERIES||Dr. G.J. Braunstahl|
|- CONTACT for SCIENTIFIC QUERIES||Dr. G.J. Braunstahl|
|- Sponsor/Initiator ||Sint Franciscus Gasthuis (SFG) |
(Source(s) of Monetary or Material Support)
|GlaxoSmithKline, AstraZeneca, Novartis, Stichting Onderzoek en Ontwikkeling Interne Specialismen SFG|
|- Brief summary||Rationale: |
The prevalence of obesity has dramatically increased in the Netherlands over the last years. In 7 years, 10% of the population will be obese (BMI > 30). Epidemiological studies have shown that obesity increases the risk of asthma and is related to the severity of asthma. Several mechanisms have been mentioned. In obesity, a reduction in lung volume takes place which also has consequences for airway resistance. In obesity, systemic inflammation is present with a possible effect on the airways. Also gastro-oesophageal reflux symptoms are often prevalent in obesity and could be a possible cause of airway pathology. Finally, links between obesity and asthma could partly be explained by a common genetic background. Bariatric surgery has a proven beneficial effect on symptoms and lung function in obese patients with asthma. The problem with previous intervention studies is the relative small size and the lack of control groups. In addition, it is unclear whether the observed effect of weight reduction on asthma symptoms is the result of improvement of pathophysiological parameters or a reduction of systemic inflammation, or both.
The aims of the study are:
1. To determine the inflammatory pattern in bronchial mucosa of obese asthmatics;
2. To relate the assumed bronchial inflammation in obese asthmatics with low-grade systemic inflammation known to be present in obesity;
3. To evaluate the effect of weight reduction by bariatric surgery on asthma symptoms, lung function and bronchial inflammation.
Eighty morbid obese patients (40 with asthma and 40 without asthma) will prior to and every 3 months after bariatric surgery visit the pulmonary department and undergo spirometry, symptom scores, nitric oxide measurement (FeNO). Blood sampling will be preformed half-yearly. During surgery, bronchial and visceral fat biopsies will be taken from the subjects. Expression of inflammatory mediators, such as tumor necrosis factor alpha (TNF-α), IL-6, leptin en adiponectin will be assessed in biopsy material and blood. Bronchoscopy will be repeated 1 year after surgery. The total follow-up of the study will be one year after surgery. A non-intervention group of 20 obese asthmatics will serve as controls. They will follow the same procedures as the intervention group except for bronchoscopy.
Patients have a BMI > 35 kg/m2 and are between 18 and 50 years old. Asthma diagnosis is based on the presence of symptoms and reversible airway obstruction or bronchial hyperresponsiveness.
Main study parameters/endpoints:
The group size is powered on the expected change in FEV1/FVC ratio 12 months after bariatric surgery. Based on our pilot study and the results in the literature we assume that in obese patients with asthma the FEV1/FVC ratio increases from 72% to 75% (SD ± 6). Secondary endpoints are symptom score, FeNO levels and inflammatory parameters (see study design).
Nature and extent of the burden and risks associated with participation, benefit and group relatedness:
Patients will have no personal benefit from the study. The study comprises seven visits (see study design paragraph). The first visit is already standard practice. Most procedures are non-invasive (e.g. spirometry, FeNO measurement, symptom score and quality of life assessment). Two procedures are invasive and may be potential harmful. First, during the visits blood samples will be taken on three occasions (60 ml). This may lead to bruises, which will resolve spontaneously. Second, two bronchoscopies will be performed (visit 3 and 7). This is regarded as a safe procedure. During the first bronchoscopy the patients are deeply sedated, so they will not be aware of the procedure. The second bronchoscopy will take place 1 year after bariatric surgery. By that time, the expected weight reduction will be 30 %, resulting in a substantially lower chance of complications. Several bronchial biopsies (max. 7) will be taken from the central bronchial mucosa. This may cause some minor bleeding, which will often stop spontaneously or may need intervention by cold water installation or xylomethazoline. The risk of major bleeding or pneumothorax after taking central bronchial biopsies is extremely low. Visceral fat biopsies will be collected during laparascopy and are not considered to add additional risk to the operation.
|- Main changes (audit trail)|
|- RECORD||9-dec-2011 - 29-dec-2011|
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