Gastrointestinal Nutrient Transit and Enteroendocrine Function After Upper Gastrointestinal Surgery

NCT03734627 | Completed

• 3 other identifiers: CRFSJ075 and 00952016-02-CA(9)2016-03-11(1)
• Study Type: observational
• Target: 40
• Locations: 1 country
• Sites: 2

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.

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

Outcome Measures

Primary Outcomes (1)

• Area under the curve for paracetamol at 30 minutes after a 400kcal mixed meal stimulus

  30 minutes post meal

Secondary Outcomes (6)

• Peak paracetamol level

  Within 300 minutes post meal

• GLP-1 area under the curve over 300 minutes after a 400kcal mixed meal stimulus

  Within 300 minutes post meal

• Glucose area under the curve over 300 minutes after a 400kcal mixed meal stimulus

  Within 300 minutes post meal

• Insulin area under the curve over 300 minutes after a 400kcal mixed meal stimulus

  Within 300 minutes post meal

• Visual analogue scales

  Within 300 minutes post meal

Other Outcomes (3)

• Duodenal enteroendocrine cell density

  At one year post surgery, on the day of assessment

• Duodenal enteroendocrine L-cell density

  At one year post surgery, on the day of assessment

• Duodenal enteroendocrine cell mRNA expression profile

  At one year post surgery, on the day of assessment

Study Arms (4)

Upper Gastrointestinal Surgery - Transit

Drug: Octreotide Acetate; Drug: Saline Solution; Drug: Paracetamol; Drug: Sulfasalazine

Control - Transit

Drug: Octreotide Acetate; Drug: Saline Solution; Drug: Paracetamol; Drug: Sulfasalazine

Upper Gastrointestinal Surgery - Gut Function

Diagnostic Test: Duodenal biopsy

Control - Gut Function

Diagnostic Test: Duodenal biopsy

Interventions

Octreotide Acetate DRUG

50mcg octreotide acetate by subcutaneous injection 10 minutes prior to a 400kcal mixed meal challenge

Control - Transit; Upper Gastrointestinal Surgery - Transit

Saline Solution DRUG

Equivalent volume of 0.9% saline by subcutaneous injection 10 minutes prior to a 400kcal mixed meal challenge

Control - Transit; Upper Gastrointestinal Surgery - Transit

Paracetamol DRUG

Paracetamol 1g by mouth consumed with a 400kcal mixed meal challenge

Control - Transit; Upper Gastrointestinal Surgery - Transit

Sulfasalazine DRUG

1g sulfasalazine by mouth consumed with a 400kcal mixed meal challenge

Control - Transit; Upper Gastrointestinal Surgery - Transit

Duodenal biopsy DIAGNOSTIC_TEST

Biopsy from the second part of the duodenum taken at routine endoscopic surveillance, undertaken for another clinical indication.

Control - Gut Function; Upper Gastrointestinal Surgery - Gut Function

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• Patient group:
• \. History of upper gastrointestinal surgery at least 9 months previously
• Control group:
• \. Patients with suspected or confirmed non-dysplastic Barrett's oesophagus or reflux who are age, weight and gender matched to the patient cohort

You may not qualify if:

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

Sponsors & Collaborators

• St. James's Hospital, Ireland: lead

Study Sites (2)

Department of Surgery, St. James's Hospital

Dublin, D4, Ireland

Location

Wellcome Trust-Health Research Board Clinical Research Facility, St. James's Hospital

Dublin, D8, Ireland

Location

Related Publications (2)

• 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.

  PMID: 27455150 BACKGROUND

• 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.

  PMID: 26583672 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

* Plasma * Serum * Duodenal biopsies

MeSH Terms

Conditions

Esophageal Neoplasms; Nutrition Disorders; Feeding and Eating Disorders; Dumping Syndrome; Gastroparesis; Insulin Resistance

Interventions

Octreotide; Saline Solution; Acetaminophen; Sulfasalazine

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Head and Neck Neoplasms; Digestive System Diseases; Esophageal Diseases; Gastrointestinal Diseases; Nutritional and Metabolic Diseases; Signs and Symptoms, Digestive; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Mental Disorders; Postgastrectomy Syndromes; Stomach Diseases; Postoperative Complications; Pathologic Processes; Paralysis; Neurologic Manifestations; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases

Intervention Hierarchy (Ancestors)

Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations; Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Sulfonamides; Sulfones; Sulfur Compounds

Study Officials

• John V Reynolds, MD FRCS

  St. James's Hospital, Dublin, Ireland

  PRINCIPAL INVESTIGATOR

• Carel W le Roux, FRCP FRCPath PhD

  Conway Institute of Biomolecular and Biomedical Research

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Research Fellow

Study Record Dates

• First Submitted: November 6, 2018
• First Posted: November 8, 2018
• Study Start: July 1, 2016
• Primary Completion: July 1, 2021
• Study Completion: July 1, 2021
• Last Updated: August 16, 2021

Record last verified: 2021-08

Data Sharing

• IPD Sharing: Will not share

Locations

IE (2)