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Gastrointestinal Nutrient Transit and Enteroendocrine Function After Upper Gastrointestinal Surgery (EndoGut)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03734627
Recruitment Status : Completed
First Posted : November 8, 2018
Last Update Posted : August 16, 2021
Sponsor:
Information provided by (Responsible Party):
Dr Jessie A Elliott, St. James's Hospital, Ireland

Study Description
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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.


Condition or disease Intervention/treatment
Esophageal Cancer Nutrition Disorders Appetite Disorders Dumping Syndrome Delayed Gastric Emptying Surgery Drug: Octreotide Acetate Drug: Saline Solution Drug: Paracetamol Drug: Sulfasalazine Diagnostic Test: Duodenal biopsy

Study Design
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Study Type : Observational
Actual Enrollment : 40 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Gastrointestinal Nutrient Transit and Enteroendocrine Function After Upper Gastrointestinal Surgery
Actual Study Start Date : July 1, 2016
Actual Primary Completion Date : July 1, 2021
Actual Study Completion Date : July 1, 2021

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Group/Cohort Intervention/treatment
Upper Gastrointestinal Surgery - Transit Drug: Octreotide Acetate
50mcg octreotide acetate by subcutaneous injection 10 minutes prior to a 400kcal mixed meal challenge

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

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

Drug: Sulfasalazine
1g sulfasalazine by mouth consumed with a 400kcal mixed meal challenge
Control - Transit Drug: Octreotide Acetate
50mcg octreotide acetate by subcutaneous injection 10 minutes prior to a 400kcal mixed meal challenge

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

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

Drug: Sulfasalazine
1g sulfasalazine by mouth consumed with a 400kcal mixed meal challenge
Upper Gastrointestinal Surgery - Gut Function Diagnostic Test: Duodenal biopsy
Biopsy from the second part of the duodenum taken at routine endoscopic surveillance, undertaken for another clinical indication.
Control - Gut Function Diagnostic Test: Duodenal biopsy
Biopsy from the second part of the duodenum taken at routine endoscopic surveillance, undertaken for another clinical indication.


Outcome Measures
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Primary Outcome Measures :
  1. Area under the curve for paracetamol at 30 minutes after a 400kcal mixed meal stimulus [ Time Frame: 30 minutes post meal ]

Secondary Outcome Measures :
  1. Peak paracetamol level [ Time Frame: Within 300 minutes post meal ]
  2. GLP-1 area under the curve over 300 minutes after a 400kcal mixed meal stimulus [ Time Frame: Within 300 minutes post meal ]
  3. Glucose area under the curve over 300 minutes after a 400kcal mixed meal stimulus [ Time Frame: Within 300 minutes post meal ]
  4. Insulin area under the curve over 300 minutes after a 400kcal mixed meal stimulus [ Time Frame: Within 300 minutes post meal ]
  5. Visual analogue scales [ Time Frame: Within 300 minutes post meal ]
  6. EORTC health related quality of life [ Time Frame: At one year post surgery, on the day of assessment ]

Other Outcome Measures:
  1. Duodenal enteroendocrine cell density [ Time Frame: At one year post surgery, on the day of assessment ]
  2. Duodenal enteroendocrine L-cell density [ Time Frame: At one year post surgery, on the day of assessment ]
  3. Duodenal enteroendocrine cell mRNA expression profile [ Time Frame: At one year post surgery, on the day of assessment ]

Biospecimen Retention:   Samples With DNA
  • Plasma
  • Serum
  • Duodenal biopsies

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.
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.

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03734627


Locations
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Ireland
Department of Surgery, St. James's Hospital
Dublin, Ireland, D4
Wellcome Trust-Health Research Board Clinical Research Facility, St. James's Hospital
Dublin, Ireland, D8
Sponsors and Collaborators
St. James's Hospital, Ireland
Investigators
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Principal Investigator: 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
More Information
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Publications:

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Responsible Party: Dr Jessie A Elliott, Clinical Research Fellow, St. James's Hospital, Ireland
ClinicalTrials.gov Identifier: NCT03734627    
Other Study ID Numbers: CRFSJ075 and 0095
2016-02-CA(9) ( Other Identifier: SJH/AMNCH Research Ethics Committee )
2016-03-11(1) ( Other Identifier: SJH/AMNCH Research Ethics Committee )
First Posted: November 8, 2018    Key Record Dates
Last Update Posted: August 16, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Dr Jessie A Elliott, St. James's Hospital, Ireland:
Gut hormones
GLP-1
Enteroendocrine L-cell
Early satiety
Dumping syndrome
 Gastrointestinal transit
Insulin
Octreotide
Somatostatin
Esophagectomy
Additional relevant MeSH terms:
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Gastroparesis
Dumping Syndrome
Nutrition Disorders
Disease
Feeding and Eating Disorders
Pathologic Processes
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Paralysis
Neurologic Manifestations
Postgastrectomy Syndromes
Postoperative Complications
Mental Disorders
Acetaminophen
 Sulfasalazine
Octreotide
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Antipyretics
Gastrointestinal Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Anti-Infective Agents
Anti-Inflammatory Agents, Non-Steroidal
Anti-Inflammatory Agents
Antirheumatic Agents