|
Welcome
|
|
23 May 2012
|
|
|
| home | my details | ISRCTN Register | mRCT | links | information | press |
|
||||
|
||||
|
||||
|
||||
|
||||
|
||||
|
||||
|
||||
|
||||
|
||||
|
||||
|
||||
|
||||
|
||||
| [ Print-friendly version ] |
| Prevalence of metabolic obesity in patients with Barrett's Oesophagus and its potential role in carcinogenesis |
| ISRCTN | ISRCTN99001055 |
| ClinicalTrials.gov identifier | |
| Public title | Prevalence of metabolic obesity in patients with Barrett's Oesophagus and its potential role in carcinogenesis |
| Scientific title | Prevalence of metabolic obesity in patients with Barrett's Oesophagus and its potential role in carcinogenesis: a single centre non-randomised controlled trial |
| Acronym | N/A |
| Serial number at source | v.2 06/01/2011 |
| Study hypothesis |
In the last few decades there has been a clear increase in the detection of oesophageal lesions at endoscopy, with an increasing prevalence of reflux oesophagitis and hiatus hernia. Moreover, an increasing incidence of oesophageal adenocarcinoma has been reported throughout North America and Europe at a rate exceeding that of any other human solid tumour, the underlying reasons for which are unclear. Oesophageal cancer is the sixth most common cause of cancer death and accounts for around 5% of all cancer deaths in UK.
Barrett's Oesophagus is the strongest recognised risk factor for the development of oesophageal adenocarcinoma: the overwhelming majority of patients with Barrett's Oesophagus however will not develop this cancer. The British Society of Gastroenterology defines Barrett's Oesophagus as "an endoscopically apparent area above the gastro-oesophageal junction that is suggestive of Barrett's Oesophagus (salmon-coloured mucosa) which is supported by the finding of columnar lined oesophagus on histology". Surveillance endoscopic programmes have been endorsed in order to prevent development of oesophageal cancer. To date, in clinical practice dysplasia remains the only factor useful for identifying patients that need to be treated in order to avoid development of oesophageal adenocarcinoma. In parallel, obesity [defined as body mass index (BMI) > 30] has risen to epidemic proportions in USA, Europe and Asia over the last two decades. Although other factors such as genetic predisposition may be contributors, in general increased food intake and decreased physical activity have been cited as primary causes for the observed trends. Recent studies have clearly implicated chronic gastro-oesophageal reflux disease and several lifestyle risk factors, including tobacco consumption, diet and particularly obesity to be associated with increased risk of oesophageal adenocarcinoma, though the mechanism for this is unclear. A pathway from reflux to inflammation through metaplasia and dysplasia is the dominant hypothesis. Abdominal fat seems to play a crucial role for developing oesophageal diseases but it is unclear if it is exclusively due to the chronic increase in intra-abdominal pressure or is mainly related to the presence of the adipose mass which represents an important source of pro-inflammatory cytokines. Additionally there is debate as to whether or not patients with morbid obesity have a dysfunction of the lower oesophageal sphincter and/or altered oesophageal motility, even when they are asymptomatic for gastro-oesophageal reflux disease (GORD) symptoms. Reports describing that obesity per se predisposes to GORD and Barrett's Oesophagus have brought conflicting results. A minority of patients with hiatus hernia will develop GORD and only a minority of them will develop Barrett's oesophagus. Data show a more pronounced association between oesophageal adenocarcinoma and obesity. The parallel increase of incidence of both obesity and oesophageal cancer has outlined the epidemiological evidence that the increase in obesity prevalence occurring over the past 30 years would explain the increase in incidence of oesophageal adenocarcinoma. Other risk factors that modulate reflux-related inflammatory and neoplastic effects on oesophageal epithelium have been hypothesized. Alterations in serum leptin and adiponectin, obesity-related cytokines, have been postulated as potential mediators of obesity-related carcinogenesis. Adiponectin is a peptide secreted by adipocytes, and its plasma levels are inversely associated with obesity. Leptin is synthesized in adipocytes as a 16 kDa molecule and the circulating level is directly proportional to the total amount of fat in the body. Data show that while a high serum leptin is associated with an increased risk of Barrett's oesophagus in men but not women, a high level of low molecular weight adiponectin is associated with a decreased risk of Barrett's Oesophagus. Obesity has been found to be associated with upregulated leptin-receptor and adiponectin receptor 2 expression in oesophageal adenocarcinoma suggesting that pathways involving adipocytokines affect tumour biology. Recently a new category of patients has been identified, with normal weight and body mass index but whose fat mass is >30% of their total body weight and whose risk of developing obesity-related diseases is likely increased. These individuals are considered "metabolically" obese and at risk of developing obesity-related diseases. For the sake of clarity we have called this metabolic obesity throughout this protocol. In obese and overweight subjects a waist/ hip ratio > 1.0 in men or 0.9 in women allows diagnosis of central (visceral or abdominal) obesity which is strongly related to insulin-resistance. Visceral obesity has been associated with oesophageal and junctional adenocarcinomas. Establishing a causal link between obesity and Barrett's Oesophagus is of major public health importance because of their present epidemic proportions. Barrett's Oesophagus might represent a component of the disease spectrum of the metabolic syndrome. If the promotion of GORD and Barrett's Oesophagus is not simply due to a pressure mechanism, the effects of visceral and metabolic obesity on the risk of Barrett's Oesophagus might be mediated by leptin and/or other circulating factors. Therefore the identification of sub-categories of patients with an increased risk of developing Barrett's Oesophagus may lead to new prevention and treatment strategies, with consequent impact on the strongest risk factor for oesophageal cancer as well as delay or even prevention of cancer onset. Positive results from this initial study would lead to larger trials to confirm the findings and to examine potential interventions to prevent progression. |
| Lay summary | Lay summary under review |
| Ethics approval |
East Central London Research Ethics Committee, 09 February 2011, ref: 10/H0721/83
|
| Study design | Single centre non-randomised controlled trial |
| Countries of recruitment | United Kingdom |
| Disease/condition/study domain | Barrett's Oesophagus and metabolic obesity |
| Participants - inclusion criteria |
1. Able to understand the nature and requirements of the study and to provide written informed consent
2. Aged 18 - 79 years 3. Booked to undergo routine oesophagogastroduodenoscopy |
| Participants - exclusion criteria |
1. Weight loss of more than 10% in the last year
2. Known decompensated liver disease 3. Coeliac disease 4. Inflammatory bowel disease 5. Previous upper gastrointestinal tract surgery 6. Known malignancy or undergoing treatment for previously resected malignancy 7. Inability to provide informed consent |
| Anticipated start date | 01/05/2011 |
| Anticipated end date | 30/04/2012 |
| Status of trial | Completed |
| Patient information material | Not available in web format, please use the contact details below to request a patient information sheet |
| Target number of participants | A total of 460 subjects will be recruited: 230 with known Barrett's Oesophagus and 230 without Barrett's Oesophagus |
| Interventions |
The study will be divided in 2 phases (total duration 12 months):
Phase 1: Recruitment, collection of data, endoscopy (OGD) biopsy and histology, blood tests (duration 8 months). 1. Subjects with known Barrett’s Oesophagus will be recruited from patients booked to have an OGD on a list dedicated to a Barrett’s oesophagus surveillance programme undertaken at University College Hospital, UK. 2. The control group will be recruited from patients booked to have an elective OGD for other gastrointestinal indications (negative at endoscopy for Barrett’s Oesophagus). Phase 2: Gata collection and analysis (duration 4 months) 1. Data will be entered into a database 2. Data analysis The prevalence of obesity, overweight and metabolic obesity will be determined. Anthropometric measurements and body composition (bioimpedance) and biochemical indices of metabolic syndrome will be measured. In those subjects with Barrett's Oesophagus histological presence of metaplasia/dysplasia will also be assessed. |
| Primary outcome measure(s) |
Prevalence of overweight, obesity, and metabolic obesity in subjects with Barrett's Oesophagus as compared to subjects without Barrett's Oesophagus (standardised for age and sex).
All the measures will be done only once at baseline, when patients attend their endoscopy test as part of their clinical management. No follow-up is required. |
| Secondary outcome measure(s) |
1. The characteristics of body composition, metabolic parameters and serum level of adiponectin/leptin in obese, overweight and metabolic obese subjects compared to those of normal weight.
2. The prevalence of abdominal obesity (in obese and overweight subjects) and metabolic obesity in subjects with dysplastic Barrett's oesophagus compared to those without dysplasia. All the measures will be done only once at baseline, when patients attend their endoscopy test as part of their clinical management. No follow-up is required. |
| Sources of funding | University College London Hospital (UCLH) Charities - Clinical Research and Development Committee (CRDC) (UK) ref: GCT/2011/MB-Po |
| Trial website | |
| Publications | |
| Contact name | Dr Matthew Banks |
| Address |
University College London Hospital
250 Euston Road |
| City/town | London |
| Zip/Postcode | NW1 2BU |
| Country | United Kingdom |
| Tel | +44 (0)20 7380 9419 |
| matthew.banks@uclh.nhs.uk | |
| Sponsor | University College London Hospital [UCLH] (UK) |
| Address |
c/o Dr Philip Diamond
Research and Development Department Rosenheim Building 25 Grafton Way |
| City/town | London |
| Zip/Postcode | WC1E 6DB |
| Country | United Kingdom |
| Tel | +44 (0)20 7380 9833 |
| philip.diamond@uclh.nhs.uk | |
| Sponsor website: | http://www.uclh.org/ |
| Date applied | 12/07/2011 |
| Last edited | 10/01/2012 |
| Date ISRCTN assigned | 05/01/2012 |
|
|
|
|
|
| © 2012 ISRCTN unless otherwise stated. | |
|
|
|
|