Gastrointestinal Motility Among Diabetes Patients

NCT02573519 | Terminated DMC

• 1 other identifier: 1-10-72-54-15
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

Gastrointestinal (GI) symptoms including vomiting, nausea, abdominal pain, constipation or chronic diarrhea affect a large number of patients with diabetes mellitus (DM). Furthermore, abnormal GI transit times restrict correct dosing of medication. Two new methods, in combination only available at Aarhus University Hospital (AUH), allow examination of human whole-gut function with a high degree of detail: PET-scans (positron emission tomography scans) of cholinergic signaling in the bowel wall The most important nerve fibers stimulating GI peristalsis use acetylcholine as neurotransmitter. The novel PET technique, \[11C\] Donepezil PET/CT (Donepezil PET/CT scan based on a carbon isotope), developed at AUH, allows in vivo quantification of cholinergic cells within the bowel wall. 3D-Transit With 3D-Transit electromagnetic capsules are followed during their passage through the GI tract. The novel method provides highly detailed information about regional and whole-gut passage times and contractility patterns. Study protocol 20 healthy subjects and 25 diabetic patients with severe GI symptoms will be included.

1. 1.With \[11C\]donepezil PET/CT, we aim to describe the degree of cholinergic denervation of the intestine in DM patients with GI severe symptoms.
2. 2.Using 3D-Transit in DM patients before and during intervention with acetyl cholinesterase inhibitor we aim to determine how cholinergic denervation of the intestine contributes to abnormal GI transit patterns.
3. 3.Comparing the transit times of DM patients with either vomiting or diarrhea as main symptoms, we aim to provide pilot data on phenotypes of diabetic GI dysfunction.
4. 4.We aim to explore various aspects of "pan-enteric" dysfunction in DM, including prolonged gastric emptying secondary to severe constipation and delayed small intestinal transit in patients with symptoms of gastroparesis with or without delayed gastric emptying

Conditions

Diabetic Autonomic Neuropathy; Gastrointestinal Motility Disorder; Diabetes Mellitus; Change of Transit or Circulation

Keywords

11C Donepezil PET/CT scan; 3D-Transit; Diabetes Mellitus; Gastrointestinal motility disorder; Diabetic autonomic neuropathy

Outcome Measures

Primary Outcomes (2)

• Difference in Donepezil standard-uptake values (SUV) for the small intestine between diabetic patients and healthy subjects.

  The PET signal is measured as standard-uptake values (SUV) in the internal organs. This simple value has earlier been validated as equivalent to more advanced PET kinetic parameters, were an arterial-needle is required. From the CT-scan volume-of-interests of the relevant organs are applied (bowel segments, heart, pancreas) and the SUV-values draw from the PET-scans. SUV in the small intestine are compared between healthy subjects and diabetic patients. SUV is a measure of in vivo quantification of cholinergic cells in the small bowel.

  Through study completion, an average of 1 year

• Difference in total gastrointestinal transit time between diabetic patients and healthy subjects

  The following parameters are analyzed: Total gastrointestinal transit time (capsule number 1). Data from capsule 1 in healthy subjects and diabetic patients will be used for: Comparison of total GI transit times and transit patterns in healthy individuals and diabetic patients.

  Through study completion, an average of 1 year

Secondary Outcomes (7)

• Measurement of gastric amplitudes

  Through study completion, an average of 1 year

• Measurement of fast movements in the small intestine

  Through study completion, an average of 1 year

• Measurement of mass movements in colorectum

  Through study completion, an average of 1 year

• Difference in total gastrointestinal transit times in diabetic patients´s 3D-transit with and without Pyridostigmine

  Through study completion, an average of 1 year

• Difference in regional intestinal transit times between diabetic patients and healthy subjects

  Through study completion, an average of 1 year

Study Arms (2)

Diabetic patient

ACTIVE COMPARATOR

The study consists of four different parts: 1. 11C Donepezil PET/CT scan 2. 3D-Transit 3. 3D-Transit during treatment with pyridostigmine 4. 3D-Transit after Malone appendicostomy (only diabetic patients who had a Malone-surgery for severe obstipation ordered during standard clinical practice)

Radiation: 11C Donepezil PET/CT scan; Device: 3D-Transit; Drug: 3D-Transit during treatment with Pyridostigmine; Device: 3D-Transit after Malone appendicostomy

Healthy subjects

ACTIVE COMPARATOR

The study consists of two different parts: 1. 11C Donepezil PET/CT scan 2. 3D-Transit

Radiation: 11C Donepezil PET/CT scan; Device: 3D-Transit

Interventions

11C Donepezil PET/CT scan RADIATION

Donepezil binds with high affinity to acetylcholine esterase in the cholinergic synapses. The quantity of density of acetylcholine esterase in the abdominal organs including the intestinal wall are demonstrated by 11C Donepezil PET/CT scan. The PET-signal are measured as Standard-uptake values (SUV) in the internal organs. After 6 hours of fast CT- and PET-scans are performed after injection of iv. contrast and about 500MBq (megabecquerel) \[11C\]donepezil. The CT scan is used for anatomical location of the internal organs. The scan-field includes the heart and the abdominal organs. Total scan time is about 60 minutes.

Diabetic patient; Healthy subjects

3D-Transit DEVICE

3D-Transit: 3D-Transit for minimal invasive and ambulant describing of regional transit times and contractions pattern of the bowel. The motility and the passage time is measured by 3D-Transit The description of location and rotation of the capsule is dynamic and very precise. It permits precise detailed description of the gastrointestinal contraction pattern and regional passage time. 3D-transit consist of three different parts: 1. A wireless electromagnetic capsule to be swallowed by the subject 2. A portable detector plate comprising four sensors worn in a belt around the waist 3. Specific software for visualizing and analyzing data

Also known as: MTS-2

Diabetic patient; Healthy subjects

3D-Transit during treatment with Pyridostigmine DRUG

3D-Transit and Pyridostigmine: The motility and the passage time is measured by 3D-Transit (as mentioned above) in diabetic patients during administration of Pyridostigmine 60 mg administrated 4 times with 4 hours between each administration. Pyridostigmine is increasing the amount of cholinergic neurotransmitter and is suggested to have a reversible effect on the cholinergic denervation. The mechanism of action of Pyridostigmine in the human body is well-known and the drug is used as a tool to determine if the disturbance in the guts are reversible in diabetic patients.

Also known as: MTS-2 with treatment of acetylcholine esterase inhibitor

Diabetic patient

3D-Transit after Malone appendicostomy DEVICE

3D-Transit (as earlier described) is performed after Malone appendicostomy. The patients are suppose use the antegrade edema technic during the 3D-transit examination.

Also known as: MTS-2

Diabetic patient

Eligibility Criteria

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

You may qualify if:

• Subject is suffering from diabetes
• Gastrointestinal symptoms including diarrhoea, nausea, vomiting, bloating and abdominal discomfort)
• Subject \> 18 years of age who possess capacity to understand subject information sheet and give informed consent for participation
• Fasted since midnight until morning 8 o´clock

You may not qualify if:

• Dysregulated metabolic disease
• Structuring bowel disease or obvious stenotic symptoms or perforation
• Subject has known swallowing disorders
• Subject has cancer or other life threatening diseases or conditions
• Subject is pregnant or breastfeeding
• Subject has undergone extensive abdominal surgery
• Subject has a abdominal diameter \> 140 cm
• Drug abuse or alcoholism
• Bacterial overgrowth
• Subject has known severe cardiovascular or pulmonary diseases (including artificial pacemaker and/or implantable cardioverter-defibrillator (ICD))
• Central nerve system (CNS) surgery
• Patient have infusion pump or other implantable medical device
• Medication (not possible for pausing for 48 hours) or any other disease affecting motility or/and gastroparesis.
• Subjects having MRI within the next four weeks
• Taking corticosteroids during the last month

Sponsors & Collaborators

• University of Aarhus: lead
• Novo Nordisk A/S: collaborator
• Svend Faelding Humanitarian Foundation: collaborator
• Copenhagen University Foundation for Medical Students: collaborator
• Hoejmosegaard Foundation: collaborator
• Holger Rabitz og Hustru Doris Mary foedt Phillipps Mindelegat: collaborator
• Lundbeck Foundation: collaborator
• Wilhelm Frank og Angelina Franks Mindelegat: collaborator
• Torben og Alice Frimodts Fond: collaborator
• Fonden til Lægevidenskabens Fremme, A.P. Møller Fonden: collaborator

Study Sites (1)

Department of Hepatology and Gastroenterology, Aarhus University Hospital

Aarhus, 8000, Denmark

Location

Related Publications (19)

• Rao SS, Camilleri M, Hasler WL, Maurer AH, Parkman HP, Saad R, Scott MS, Simren M, Soffer E, Szarka L. Evaluation of gastrointestinal transit in clinical practice: position paper of the American and European Neurogastroenterology and Motility Societies. Neurogastroenterol Motil. 2011 Jan;23(1):8-23. doi: 10.1111/j.1365-2982.2010.01612.x.

  PMID: 21138500 BACKGROUND

• Bytzer P, Talley NJ, Leemon M, Young LJ, Jones MP, Horowitz M. Prevalence of gastrointestinal symptoms associated with diabetes mellitus: a population-based survey of 15,000 adults. Arch Intern Med. 2001 Sep 10;161(16):1989-96. doi: 10.1001/archinte.161.16.1989.

  PMID: 11525701 BACKGROUND

• Maleki D, Locke GR 3rd, Camilleri M, Zinsmeister AR, Yawn BP, Leibson C, Melton LJ 3rd. Gastrointestinal tract symptoms among persons with diabetes mellitus in the community. Arch Intern Med. 2000 Oct 9;160(18):2808-16. doi: 10.1001/archinte.160.18.2808.

  PMID: 11025791 BACKGROUND

• Vanormelingen C, Tack J, Andrews CN. Diabetic gastroparesis. Br Med Bull. 2013;105:213-30. doi: 10.1093/bmb/ldt003. Epub 2013 Jan 29.

  PMID: 23363458 BACKGROUND

• Jones KL, Russo A, Stevens JE, Wishart JM, Berry MK, Horowitz M. Predictors of delayed gastric emptying in diabetes. Diabetes Care. 2001 Jul;24(7):1264-9. doi: 10.2337/diacare.24.7.1264.

  PMID: 11423513 BACKGROUND

• Sarosiek I, Selover KH, Katz LA, Semler JR, Wilding GE, Lackner JM, Sitrin MD, Kuo B, Chey WD, Hasler WL, Koch KL, Parkman HP, Sarosiek J, McCallum RW. The assessment of regional gut transit times in healthy controls and patients with gastroparesis using wireless motility technology. Aliment Pharmacol Ther. 2010 Jan 15;31(2):313-22. doi: 10.1111/j.1365-2036.2009.04162.x. Epub 2009 Oct 8.

  PMID: 19814743 BACKGROUND

• Kloetzer L, Chey WD, McCallum RW, Koch KL, Wo JM, Sitrin M, Katz LA, Lackner JM, Parkman HP, Wilding GE, Semler JR, Hasler WL, Kuo B. Motility of the antroduodenum in healthy and gastroparetics characterized by wireless motility capsule. Neurogastroenterol Motil. 2010 May;22(5):527-33, e117. doi: 10.1111/j.1365-2982.2010.01468.x. Epub 2010 Jan 29.

  PMID: 20122128 BACKGROUND

• Olausson EA, Brock C, Drewes AM, Grundin H, Isaksson M, Stotzer P, Abrahamsson H, Attvall S, Simren M. Measurement of gastric emptying by radiopaque markers in patients with diabetes: correlation with scintigraphy and upper gastrointestinal symptoms. Neurogastroenterol Motil. 2013 Mar;25(3):e224-32. doi: 10.1111/nmo.12075. Epub 2013 Jan 15.

  PMID: 23316944 BACKGROUND

• Rosa-e-Silva L, Troncon LE, Oliveira RB, Foss MC, Braga FJ, Gallo Junior L. Rapid distal small bowel transit associated with sympathetic denervation in type I diabetes mellitus. Gut. 1996 Nov;39(5):748-56. doi: 10.1136/gut.39.5.748.

  PMID: 9014777 BACKGROUND

• Sellin JH, Hart R. Glucose malabsorption associated with rapid intestinal transit. Am J Gastroenterol. 1992 May;87(5):584-9.

  PMID: 1595644 BACKGROUND

• Guy RJ, Dawson JL, Garrett JR, Laws JW, Thomas PK, Sharma AK, Watkins PJ. Diabetic gastroparesis from autonomic neuropathy: surgical considerations and changes in vagus nerve morphology. J Neurol Neurosurg Psychiatry. 1984 Jul;47(7):686-91. doi: 10.1136/jnnp.47.7.686.

  PMID: 6747645 BACKGROUND

• Guo C, Quobatari A, Shangguan Y, Hong S, Wiley JW. Diabetic autonomic neuropathy: evidence for apoptosis in situ in the rat. Neurogastroenterol Motil. 2004 Jun;16(3):335-45. doi: 10.1111/j.1365-2982.2004.00524.x.

  PMID: 15198656 BACKGROUND

• Tay SS, Wong WC. Short- and long-term effects of streptozotocin-induced diabetes on the dorsal motor nucleus of the vagus nerve in the rat. Acta Anat (Basel). 1994;150(4):274-81. doi: 10.1159/000147630.

  PMID: 7839795 BACKGROUND

• Clouse RE, Lustman PJ. Gastrointestinal symptoms in diabetic patients: lack of association with neuropathy. Am J Gastroenterol. 1989 Aug;84(8):868-72.

  PMID: 2756978 BACKGROUND

• Horvath VJ, Vittal H, Lorincz A, Chen H, Almeida-Porada G, Redelman D, Ordog T. Reduced stem cell factor links smooth myopathy and loss of interstitial cells of cajal in murine diabetic gastroparesis. Gastroenterology. 2006 Mar;130(3):759-70. doi: 10.1053/j.gastro.2005.12.027.

  PMID: 16530517 BACKGROUND

• Punkkinen J, Farkkila M, Matzke S, Korppi-Tommola T, Sane T, Piirila P, Koskenpato J. Upper abdominal symptoms in patients with Type 1 diabetes: unrelated to impairment in gastric emptying caused by autonomic neuropathy. Diabet Med. 2008 May;25(5):570-7. doi: 10.1111/j.1464-5491.2008.02428.x.

  PMID: 18445170 BACKGROUND

• Hopkins DA, Bieger D, deVente J, Steinbusch WM. Vagal efferent projections: viscerotopy, neurochemistry and effects of vagotomy. Prog Brain Res. 1996;107:79-96. doi: 10.1016/s0079-6123(08)61859-2. No abstract available.

  PMID: 8782514 BACKGROUND

• Haase AM, Gregersen T, Schlageter V, Scott MS, Demierre M, Kucera P, Dahlerup JF, Krogh K. Pilot study trialling a new ambulatory method for the clinical assessment of regional gastrointestinal transit using multiple electromagnetic capsules. Neurogastroenterol Motil. 2014 Dec;26(12):1783-91. doi: 10.1111/nmo.12461. Epub 2014 Oct 27.

  PMID: 25348504 BACKGROUND

• Fynne L, Worsoe J, Gregersen T, Schlageter V, Laurberg S, Krogh K. Gastric and small intestinal dysfunction in spinal cord injury patients. Acta Neurol Scand. 2012 Feb;125(2):123-8. doi: 10.1111/j.1600-0404.2011.01508.x. Epub 2011 Mar 24.

  PMID: 21428967 BACKGROUND

MeSH Terms

Conditions

Diabetic Neuropathies; Diabetes Mellitus

Interventions

Pyridostigmine Bromide; Cyclin-Dependent Kinase Inhibitor p15

Condition Hierarchy (Ancestors)

Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases; Diabetes Complications; Endocrine System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Pyridinium Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Cyclin-Dependent Kinase Inhibitor Proteins; Intracellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Cell Cycle Proteins; Proteins; Tumor Suppressor Proteins; Neoplasm Proteins

Study Officials

• Klaus Krogh, Professor

  Department of Hepatology and Gastroenterology, Aarhus University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 5, 2015
• First Posted: October 9, 2015
• Study Start: October 1, 2015
• Primary Completion: February 11, 2019
• Study Completion: February 11, 2019
• Last Updated: January 8, 2021

Record last verified: 2018-08

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)