Clinical trial NCT03734627: Gastrointestinal Nutrient Transit and Enteroendocrine Function After Upper Gastrointestinal Surgery
Official title: Gastrointestinal Nutrient Transit and Enteroendocrine Function After Upper Gastrointestinal Surgery
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Esophageal Cancer
Nutrition Disorders
Appetite Disorders
Dumping Syndrome
Delayed Gastric Emptying
Surgery
Keywords: Gut hormones
GLP-1
Enteroendocrine L-cell
Early satiety
Dumping syndrome
Gastrointestinal transit
Insulin
Octreotide
Somatostatin
Esophagectomy
Lead sponsor: St. James's Hospital, Ireland
Sponsor class: OTHER
First posted: 2018-11-08
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients at least 9 months post upper gastrointestinal surgery and age-, weight- and sex-matched control subjects with gastroesophageal reflux disease or non-dysplastic Barrett's oeosophagus.

Brief summary: The incidence of oesophagogastric cancer has increased by 400% since the 1970s in Ireland and the United Kingdom. In addition, refinement of perioperative management and the now widespread use of multimodal protocols for patients with locally advanced disease have significantly improved outcomes for patients with oesophagogastric cancer treatable with curative intent. Despite significant advances in chemoradiotherapy, surgical resection remains the primary curative option.

Unintentional weight loss and nutritional complications represent serious concerns for patients after radical resection, even among those who remain free from recurrent disease in the long-term. A study from the Swedish Esophageal and Cardia Cancer Registry reported a mean three year weight loss of 10.8% among disease-free patients, with 33.8% of this cohort demonstrating malnutrition at three years post-oesophagectomy.

Mechanisms contributing to weight loss for disease-free patients after upper gastrointestinal surgery are poorly understood, however an association between increasing magnitude of weight loss and the presence of increased satiety is described. Our recent studies at SJH have demonstrated four fold elevated postprandial satiety gut hormone concentrations after oesophagectomy, compared with baseline preoperative values. Postprandial gut hormone levels correlate significantly with postprandial symptoms and altered appetite at 3 months postoperatively, and with body weight loss at 2 years postoperatively. However, the mechanism leading to exaggerated postprandial gut hormone production after upper gastrointestinal surgery is poorly understood, limiting targeted therapeutic options.

In this study, we aim to characterise the role of altered nutrient transit and enteroendocrine cell function in the pathophysiology of excessive post-prandial gut hormone responses after upper gastrointestinal surgery. To do this, we will measure the gut hormone response to a standardised 400 kcal meal, as per previous studies, while concurrently assessing gastrointestinal transit time, and enteroendocrine cell morphology and function. In this way, we will determine whether the magnitude of the postprandial gut hormone response correlates with the rate of nutrient transit into the enteroendocrine L-cell rich small intestine, and whether enteroendocrine cell adaptation occurs after oesophagectomy.

Furthermore, we have previously observed that gut hormone suppression using octreotide is associated with increased ad libitum among subjects after upper gastrointestinal cancer surgery (Elliott JA et al, Annals of Surgery, 2015). The mechanism of action of octreotide may relate to SSTR-5-mediated negative feedback to the enteroendocrine L-cell, but this medication may additionally reduce enteroendocrine L-cell responses through its inhibitory effect on gastrointestinal motility - reducing the rapidity with which nutrients are delivered to the small intestine - and small intestinal nutrient sensing via inhibition of the Na+-dependent glucose transporter SGLT-18-10. Through conduction of this double-blind, randomised, placebo-controlled crossover study, we aim to establish the mechanism of action of octreotide-mediated increased food intake in patients after gastrointestinal surgery. This may inform the design of future targeted interventions for this patient group.


Eligibility criteria: Inclusion Criteria:

Patient group:

1. History of upper gastrointestinal surgery at least 9 months previously

Control group:

1. Patients with suspected or confirmed non-dysplastic Barrett's oesophagus or reflux who are age, weight and gender matched to the patient cohort

Exclusion Criteria:

1. Pregnancy, breastfeeding
2. Recurrent disease after surgery
3. Other active malignancy
4. Significant psychiatric disorder or cognitive decline or communication impairment limiting capacity to provide informed consent
5. Other disease or medication which may impact gut hormone physiology
6. Previous upper gastrointestinal resection
7. Certain allergies or dietary intolerances
8. Anticoagulants

Patients with contraindications to the study medications (as per www.medicines.ie) will not be automatically excluded, but will be invited to participate in an attenuated protocol where that agent is not given. It is not anticipated that this will be a frequent occurrence, however this strategy will minimise unnecessary participant exclusion.

Primary outcomes:
measure: Area under the curve for paracetamol at 30 minutes after a 400kcal mixed meal stimulus
timeFrame: 30 minutes post meal
Secondary outcomes:
measure: Peak paracetamol level
timeFrame: Within 300 minutes post meal
measure: GLP-1 area under the curve over 300 minutes after a 400kcal mixed meal stimulus
timeFrame: Within 300 minutes post meal
measure: Glucose area under the curve over 300 minutes after a 400kcal mixed meal stimulus
timeFrame: Within 300 minutes post meal
measure: Insulin area under the curve over 300 minutes after a 400kcal mixed meal stimulus
timeFrame: Within 300 minutes post meal
measure: Visual analogue scales
timeFrame: Within 300 minutes post meal
measure: EORTC health related quality of life
timeFrame: At one year post surgery, on the day of assessment
Other outcomes:
measure: Duodenal enteroendocrine cell density
timeFrame: At one year post surgery, on the day of assessment
measure: Duodenal enteroendocrine L-cell density
timeFrame: At one year post surgery, on the day of assessment
measure: Duodenal enteroendocrine cell mRNA expression profile
timeFrame: At one year post surgery, on the day of assessment
Locations:
city: Dublin
country: Ireland
facility: Department of Surgery, St. James's Hospital
city: Dublin
country: Ireland
facility: Wellcome Trust-Health Research Board Clinical Research Facility, St. James's Hospital
Study officials:
affiliation: St. James's Hospital, Dublin, Ireland
name: John V Reynolds, MD FRCS
role: PRINCIPAL_INVESTIGATOR
affiliation: Conway Institute of Biomolecular and Biomedical Research
name: Carel W le Roux, FRCP FRCPath PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Elliott JA, Docherty NG, Eckhardt HG, Doyle SL, Guinan EM, Ravi N, Reynolds JV, Roux CWL. Weight Loss, Satiety, and the Postprandial Gut Hormone Response After Esophagectomy: A Prospective Study. Ann Surg. 2017 Jul;266(1):82-90. doi: 10.1097/SLA.0000000000001918.
citation: Elliott JA, Jackson S, King S, McHugh R, Docherty NG, Reynolds JV, le Roux CW. Gut Hormone Suppression Increases Food Intake After Esophagectomy With Gastric Conduit Reconstruction. Ann Surg. 2015 Nov;262(5):824-29; discussion 829-30. doi: 10.1097/SLA.0000000000001465.