The Impact of Lixisenatide on Postprandial Glucose Tolerance in Pancreatectomised Subjects (Px-Lixi)

• ClinicalTrials.gov Identifier: NCT02640118
• Recruitment Status: Completed
• First Posted: December 28, 2015
• Last Update Posted: May 7, 2020
• Sponsor: University Hospital, Gentofte, Copenhagen
• Collaborator: MCM Vaccines B.V.
• Information provided by (Responsible Party): Filip Krag Knop, University Hospital, Gentofte, Copenhagen

Study Description

Brief Summary:

Postprandial glucose (PPG) excursions are not only determined by insulin-mediated glucose disposal and endogenous glucose production (regulated by insulin and glucagon); also the rate of gastric emptying constitutes an important determinant of PPG levels 1. The short-acting glucagon-like peptide-1 (GLP-1) receptor agonist lixisenatide is used in the treatment of type 2 diabetes. It increases glucose-dependent insulin secretion, suppresses glucagon secretion and reduces gastric emptying of meals 2. These three mechanisms most likely constitute the weightiest mechanisms behind the potent impact of lixisenatide on exaggerated PPG excursions in patients with type 2 diabetes - which often are normalised during lixisenatide treatment 3. However, the separate impact of lixisenatide-induced reduction of gastric emptying (independently of the pancreatic effects) has been difficult to determine. Importantly, treatment with lixisenatide also decreases appetite and food intake and may, like native GLP-1, increase energy expenditure 4. So far an exact demarcation of the pancreatic and extrapancreatic effects of lixisenatide in humans remains to be established.

The present project serves to determine whether effects of lixisenatide on gastric emptying, appetite, food intake and resting energy expenditure are dependent on the endocrine pancreas.

The study is a randomised, placebo-controlled, double-blinded, cross-over study.

12 healthy persons and 12 pancreatectomized patients (i.e. patients who have had their pancreata removed due to pancreatic cancer or severe chronic pancreatitis) will be subjected to two experimental days on which they will undergo a liquid meal test followed by a fasting period and finished off with an ad libitum meal with lixisenatide and placebo, respectively.

Condition or disease	Intervention/treatment	Phase
Diabetes After Total Pancreatectomy	Drug: Lixisenatide; Drug: Lixisenatide-Placebo; Other: Standardized liquid meal	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Basic Science
• Official Title: The Impact of Lixisenatide on Postprandial Glucose Tolerance in Pancreatectomised Subjects -a Delineation of Extrapancreatic Effects
• Study Start Date: August 2015
• Actual Primary Completion Date: July 2016
• Actual Study Completion Date: July 2016

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Pancreatectomised + Lixisenatide; During the experimental day the patient will ingest a standardized liquid meal (200 ml containing 1,650 kJ (394 kcal): carbohydrate 50%, protein 15%, fat 35%, consisting of glucose (48.4 g + 1.6 g [U-13C6]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol). Before the meal a Lixisenatide-injection will be given subcutaneously	Drug: Lixisenatide; single injection of 20 µg lixisenatide subcutaneously; Other Name: Lyxumia; Other: Standardized liquid meal; standardized liquid meal (200 ml containing 1,650 kJ (394 kcal): carbohydrate 50%, protein 15%, fat 35%, consisting of glucose (48.4 g + 1.6 g [U-13C6]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol).
Placebo Comparator: Pancreatectomized + lixisenatide-placebo; During the experimental day the patient will ingest a standardized liquid meal (200 ml containing 1,650 kJ (394 kcal): carbohydrate 50%, protein 15%, fat 35%, consisting of glucose (48.4 g + 1.6 g [U-13C6]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol). Before the meal a placebo-injection will be given subcutaneously.	Drug: Lixisenatide-Placebo; Other: Standardized liquid meal; standardized liquid meal (200 ml containing 1,650 kJ (394 kcal): carbohydrate 50%, protein 15%, fat 35%, consisting of glucose (48.4 g + 1.6 g [U-13C6]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol).
Active Comparator: Healthy + Lixisenatide; During the experimental day the subject will ingest a standardized liquid meal (200 ml containing 1,650 kJ (394 kcal): carbohydrate 50%, protein 15%, fat 35%, consisting of glucose (48.4 g + 1.6 g [U-13C6]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol). Before the meal a Lixisenatide-injection will be given subcutaneously	Drug: Lixisenatide; single injection of 20 µg lixisenatide subcutaneously; Other Name: Lyxumia; Other: Standardized liquid meal; standardized liquid meal (200 ml containing 1,650 kJ (394 kcal): carbohydrate 50%, protein 15%, fat 35%, consisting of glucose (48.4 g + 1.6 g [U-13C6]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol).
Placebo Comparator: Healthy + lixisenatide-placebo; During the experimental day the subject will ingest a standardized liquid meal (200 ml containing 1,650 kJ (394 kcal): carbohydrate 50%, protein 15%, fat 35%, consisting of glucose (48.4 g + 1.6 g [U-13C6]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol). Before the meal a placebo-injection will be given subcutaneously	Drug: Lixisenatide-Placebo; Other: Standardized liquid meal; standardized liquid meal (200 ml containing 1,650 kJ (394 kcal): carbohydrate 50%, protein 15%, fat 35%, consisting of glucose (48.4 g + 1.6 g [U-13C6]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol).

Outcome Measures

Primary Outcome Measures :

1. PPG excursions measured as incremental area under curve (iAUC) [ Time Frame: -120,-45,-30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes ]

Secondary Outcome Measures :

1. differences in gastric emptying, measurement of s-paracetamol [ Time Frame: -30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes ]
   measurement of time to peak and incremental area under the curve (iAUC)
2. food intake and appetite [ Time Frame: at time 0,30,60,90,120,150,180 minutes ]
   assessed by a visual analogue scale (VAS)
3. resting energy expenditure (REE) [ Time Frame: -90,30,150 minutes ]
   measured by calorimetry
4. p-glucose mmol/L [ Time Frame: -30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes ]
5. p-C-peptide pmol/l [ Time Frame: -30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes ]
6. glucagon, gastrin, cholecystokinin, GIP, GLP-1, oxyntomodulin [ Time Frame: -30,-15,0,5,10,15,20,25,30,40,50,60,70,80,90,105,120,135,150,180 minutes ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion criteria Pancreatectomised patients

• Caucasians above 18 years of age who have undergone total pancreatectomy
• Normal haemoglobin
• Informed consent Healthy subjects
• Normal fasting plasma glucose (FPG) and normal HbA1C (according to the World Health Organization (WHO) criteria)
• Normal haemoglobin
• Age above 18 years
• Informed consent

Exclusion criteria Pancreatectomised patients

• Inflammatory bowel disease
• Operation within the last 3 months
• Ongoing chemotherapy or chemotherapy within the last 3 months
• Ostomy
• Nephropathy (serum creatinine >150 µM and/or albuminuria)
• Severe liver disease (serum alanine aminotransferase (ALAT) and/or serum aspartate aminotransferase (ASAT) >3×normal values)
• Pregnancy and/or breastfeeding
• Age above 80 years
• Any condition that the investigator feels would interfere with trial participation Healthy subjects
• Diabetes mellitus (DM)
• Prediabetes (impaired glucose tolerance and/or impaired FPG)
• First degree relatives with DM
• Inflammatory bowel disease
• Intestinal resection and/or ostomy
• Nephropathy (serum creatinine >150 µM and/or albuminuria
• Liver disease (ALAT and/or serum ASAT >2×normal values)
• Pregnancy and/or breastfeeding
• Age above 80 years
• Any condition that the investigator feels would interfere with trial participation

Contacts and Locations

Sponsors and Collaborators

University Hospital, Gentofte, Copenhagen

MCM Vaccines B.V.

Investigators

• Principal Investigator: Filip K Knop, Assoc. Prof.; Center for Diabetes Research, Gentofte Hospital, Kildegaardsvej 28, 2900 Hellerup, Denmark

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Juel CTB, Lund A, Andersen MM, Hansen CP, Storkholm JH, Rehfeld JF, van Hall G, Hartmann B, Wewer Albrechtsen NJ, Holst JJ, Vilsbøll T, Knop FK. The GLP-1 receptor agonist lixisenatide reduces postprandial glucose in patients with diabetes secondary to total pancreatectomy: a randomised, placebo-controlled, double-blinded crossover trial. Diabetologia. 2020 May 11. doi: 10.1007/s00125-020-05158-9. [Epub ahead of print]

• Responsible Party: Filip Krag Knop, Associated Professor, MD, P.h.D., University Hospital, Gentofte, Copenhagen
• ClinicalTrials.gov Identifier: NCT02640118
• Other Study ID Numbers: H-15004078
• First Posted: December 28, 2015
• Last Update Posted: May 7, 2020
• Last Verified: May 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Additional relevant MeSH terms:

Lixisenatide; Hypoglycemic Agents; Physiological Effects of Drugs