Gastric Cancer, Dumping Syndrome
Conditions
Keywords
Dumping syndrome, Gastrectomy, GLP-1, Insulin
Brief summary
Patients who have undergone gastrectomy (removal of the stomach) to treat or prevent cancer are known to have a significantly reduced quality of life. To date, there is very little information on the physiological causes of this. The investigators suspect that overproduction of a hormone (chemical) called glucagon like peptide-1 (GLP-1) released by the lining of the gut may play a role in the reduced appetite, weight loss and low blood sugar symptoms seen in this group. To investigate this, the investigators will study the response of 16 patients who have previously had a gastrectomy to a glucose drink, and a meal, while receiving an infusion of a specific blocker of GLP-1 or placebo. The investigators will examine the levels of sugar and associated hormones in the blood, food consumption and food reward behaviour using standard tools. Participants will be invited to attend the Clinical Research Facility at Addenbrooke's Hospital for a screening visit, and two whole day study visits. The study has been designed to assess the role of overproduction of GLP-1 by completely blocking its actions, rather than assess the use of the blocking compound as a medication, and is therefore regarded as a physiological study, not a clinical trial. The goal of this study is to demonstrate the magnitude of effect of GLP-1 on blood sugar and appetite derangement in patients who have had a gastrectomy. This will guide future work on the development of novel treatment paradigms for the post-gastrectomy patient group.
Interventions
OTHERExendin 9-39
Complete blockade of action of endogenous GLP-1 by Exendin 9-39. Defined as a physiological study, not a clinical trial as such (as advised by the UK MHRA).
OTHERPlacebo
Infusion of 1% human albumin in normal saline
Sponsors
Cambridge University Hospitals NHS Foundation Trust
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* • At least 3 months post completion of treatment for gastric cancer, or prophylactic gastrectomy * Aged at least 18 years * Able to tolerate an oral glucose tolerance test * Able to understand and retain all information regarding the study and give informed consent. * Willing to receive an infusion of human albumin solution
Exclusion criteria
* • Have a diagnosis of diabetes * Have a history of untreated anaemia in the last 3 months * Be aged under 18 years * Have active gastric cancer * Be pregnant or attempting to conceive
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Nadir Blood Glucose | As assessed during a 50g glucose tolerance test while receiving infusion of GLP-1 antagonist. At time 30-120 minutes of infusion of Exendin 9-39. | Lowest blood sugar reading during an oral glucose tolerance test while receiving infusion of GLP-1 antagonist. Please note participants will receive infusion of active compound for a maximum of four hours, with no expected effect of compound persisting for more than 30 minutes post-infusion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Eating Rate During ad Libitum Meal | 150-210 minutes during infusion of Exendin 9-39 or placebo. | As measured by universal eating monitor, total weight of a standardised meal consumed over a measured time in grams per minute. |
| Decreased Hunger and Satiety Ratings During and After ad Libitum Meal | 150-240 minutes during infusion of Exendin 9-39 or placebo and for 4 hours post-cessation of infusion. | Will be measured on visual analogue scale and reported as a score out of 100. Higher value indicated more hunger and more satiety. |
| Altered Food Attention. | 0-240 minutes during infusion of Exendin 9-39 or placebo, assessed on four occasions (baseline or T0, post-OGTT, pre-meal, post-meal) using a validated dot-probe visual response tool and reported in response time (milliseconds). | Food motivation can be measured by response rates to visual cues while being distracted by food related images. Will be measured with and without GLP-1 blockade to investigate effects of GLP-1 on food attention behaviour. Measure is of difference in response time when visual cue is colocated with a food related image vs a non-food related image, indicating degree of bias in attention to food images. Measure is undertaken during infusion at four timepoints - baseline (i.e. fasting), post oral glucose tolerance test (post-OGTT), before a standard meal (pre-meal) and after the meal (post-meal). |
| Total Insulin Secretion | Samples collected at 0, 15, 30, 45 and 60 minutes post oral glucose tolerance test. | 60 minute incremental area under the curve (i.e. total) insulin secretion during 50g oral glucose tolerance test while receiving infusion of GLP-1 antagonist. Please note participants will receive infusion of active compound for a maximum of four hours, with no expected effect of compound persisting for more than 30 minutes post-infusion. |
| Number of Participants With Infusion Related Adverse Events as Assessed by CTCAE v4 | 24 hours from onset of infusion. | — |
| Total Meal Consumption | 150-210 minutes during infusion of Exendin 9-39 or placebo | Total consumption amount of a standard meal during study intervention, measured in grams using a universal eating monitor. |
| Altered Food Motivation | 0-240 minutes during infusion of Exendin 9-39 or placebo (baseline or T0, post-OGTT, pre-m, assessed on four occasions using a validated grip strength surrogate of food motivation and measured as the area under the curve of a grip force monitoring curve. | Participant motivation to view particular food based cues is assessed by grip strength exerted to maintain those cues. Measure is undertaken during infusion at four timepoints - baseline (i.e. fasting), post oral glucose tolerance test (post-OGTT), before a standard meal (pre-meal) and after the meal (post-meal). |
Countries
United Kingdom
Participant flow
Recruitment details
Five participants recruited from Hereditary Diffuse Gastric Cancer patient population
Participants by arm
| Arm | Count |
|---|---|
| All Participants All participants were randomised to reveal both interventions, so baseline characteristics are reported for the whole study population. | 5 |
| Total | 5 |
Baseline characteristics
| Characteristic | All Participants | — |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 0 Participants | — |
| Age, Categorical Between 18 and 65 years | 5 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United Kingdom | 5 participants | — |
| Sex: Female, Male Female | 1 Participants | — |
| Sex: Female, Male Male | 4 Participants | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 5 |
| other Total, other adverse events | 0 / 5 | 0 / 5 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 |
Outcome results
Primary
Nadir Blood Glucose
Lowest blood sugar reading during an oral glucose tolerance test while receiving infusion of GLP-1 antagonist. Please note participants will receive infusion of active compound for a maximum of four hours, with no expected effect of compound persisting for more than 30 minutes post-infusion.
Time frame: As assessed during a 50g glucose tolerance test while receiving infusion of GLP-1 antagonist. At time 30-120 minutes of infusion of Exendin 9-39.
Population: Crossover study - analysis by paired T test
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Nadir Blood Glucose | 3 mmol/l | Standard Error 0.3 |
| Exendin | Nadir Blood Glucose | 4.4 mmol/l | Standard Error 0.3 |
p-value: 0.008t-test, 2 sided
Secondary
Altered Food Attention.
Food motivation can be measured by response rates to visual cues while being distracted by food related images. Will be measured with and without GLP-1 blockade to investigate effects of GLP-1 on food attention behaviour. Measure is of difference in response time when visual cue is colocated with a food related image vs a non-food related image, indicating degree of bias in attention to food images. Measure is undertaken during infusion at four timepoints - baseline (i.e. fasting), post oral glucose tolerance test (post-OGTT), before a standard meal (pre-meal) and after the meal (post-meal).
Time frame: 0-240 minutes during infusion of Exendin 9-39 or placebo, assessed on four occasions (baseline or T0, post-OGTT, pre-meal, post-meal) using a validated dot-probe visual response tool and reported in response time (milliseconds).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Altered Food Attention. | Pre-meal | 24.8 milliseconds | Standard Error 10.8 |
| Placebo | Altered Food Attention. | Time 0 | 17.9 milliseconds | Standard Error 8.6 |
| Placebo | Altered Food Attention. | Post-meal | 25.7 milliseconds | Standard Error 10.8 |
| Placebo | Altered Food Attention. | Post OGTT | 18.2 milliseconds | Standard Error 4.1 |
| Exendin | Altered Food Attention. | Post-meal | 10.7 milliseconds | Standard Error 3 |
| Exendin | Altered Food Attention. | Time 0 | 11.1 milliseconds | Standard Error 7.1 |
| Exendin | Altered Food Attention. | Pre-meal | 17.9 milliseconds | Standard Error 8.9 |
| Exendin | Altered Food Attention. | Post OGTT | 12.0 milliseconds | Standard Error 9 |
Comparison: Baselinep-value: 0.2t-test, 2 sided
Comparison: Post-OGTTp-value: 0.58t-test, 2 sided
Comparison: Pre-mealp-value: 0.39t-test, 2 sided
Comparison: Post-mealp-value: 0.2t-test, 2 sided
Secondary
Altered Food Motivation
Participant motivation to view particular food based cues is assessed by grip strength exerted to maintain those cues. Measure is undertaken during infusion at four timepoints - baseline (i.e. fasting), post oral glucose tolerance test (post-OGTT), before a standard meal (pre-meal) and after the meal (post-meal).
Time frame: 0-240 minutes during infusion of Exendin 9-39 or placebo (baseline or T0, post-OGTT, pre-m, assessed on four occasions using a validated grip strength surrogate of food motivation and measured as the area under the curve of a grip force monitoring curve.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Altered Food Motivation | T0 / Baseline | 508 Newton seconds | Standard Error 182 |
| Placebo | Altered Food Motivation | Post-OGTT | 139 Newton seconds | Standard Error 63 |
| Placebo | Altered Food Motivation | Pre-meal | 328 Newton seconds | Standard Error 82 |
| Placebo | Altered Food Motivation | Post-meal | 207 Newton seconds | Standard Error 82 |
| Exendin | Altered Food Motivation | Post-meal | 227 Newton seconds | Standard Error 116 |
| Exendin | Altered Food Motivation | T0 / Baseline | 219 Newton seconds | Standard Error 69 |
| Exendin | Altered Food Motivation | Pre-meal | 339 Newton seconds | Standard Error 116 |
| Exendin | Altered Food Motivation | Post-OGTT | 274 Newton seconds | Standard Error 56 |
Comparison: Baselinep-value: 0.26t-test, 2 sided
Comparison: Post-OGTTp-value: 0.06t-test, 2 sided
Comparison: Pre-mealp-value: 0.95t-test, 2 sided
Comparison: Post-mealp-value: 0.88t-test, 2 sided
Secondary
Decreased Hunger and Satiety Ratings During and After ad Libitum Meal
Will be measured on visual analogue scale and reported as a score out of 100. Higher value indicated more hunger and more satiety.
Time frame: 150-240 minutes during infusion of Exendin 9-39 or placebo and for 4 hours post-cessation of infusion.
Population: Unfortunately it proved impossible to collect data on hunger and fullness during the ad libitum meal, due to the cognitive effects of the gastrectomy which all of this group had undergone, meaning participants were unwilling to accurately record these sensations while eating. This data is therefore meaningless and was not analysed.
Secondary
Eating Rate During ad Libitum Meal
As measured by universal eating monitor, total weight of a standardised meal consumed over a measured time in grams per minute.
Time frame: 150-210 minutes during infusion of Exendin 9-39 or placebo.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Eating Rate During ad Libitum Meal | 0.62 grams/minute | Standard Error 0.12 |
| Exendin | Eating Rate During ad Libitum Meal | 0.66 grams/minute | Standard Error 0.07 |
Comparison: For meal consumption ratep-value: 0.79t-test, 2 sided
Secondary
Number of Participants With Infusion Related Adverse Events as Assessed by CTCAE v4
Time frame: 24 hours from onset of infusion.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Infusion Related Adverse Events as Assessed by CTCAE v4 | 0 participants |
| Exendin | Number of Participants With Infusion Related Adverse Events as Assessed by CTCAE v4 | 0 participants |
p-value: 1Other
Secondary
Total Insulin Secretion
60 minute incremental area under the curve (i.e. total) insulin secretion during 50g oral glucose tolerance test while receiving infusion of GLP-1 antagonist. Please note participants will receive infusion of active compound for a maximum of four hours, with no expected effect of compound persisting for more than 30 minutes post-infusion.
Time frame: Samples collected at 0, 15, 30, 45 and 60 minutes post oral glucose tolerance test.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Total Insulin Secretion | 41000 pmol*minute/l | Standard Error 10400 |
| Exendin | Total Insulin Secretion | 14500 pmol*minute/l | Standard Error 2600 |
p-value: 0.03t-test, 2 sided
Secondary
Total Meal Consumption
Total consumption amount of a standard meal during study intervention, measured in grams using a universal eating monitor.
Time frame: 150-210 minutes during infusion of Exendin 9-39 or placebo
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Total Meal Consumption | 422 grams | Standard Error 45 |
| Exendin | Total Meal Consumption | 434 grams | Standard Error 162 |
p-value: 0.84t-test, 2 sided