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Gastrointestinal Motility Among Diabetes Patients

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ClinicalTrials.gov Identifier: NCT02573519
Recruitment Status : Unknown
Verified September 2016 by University of Aarhus.
Recruitment status was:  Recruiting
First Posted : October 9, 2015
Last Update Posted : November 11, 2016
Sponsor:
Collaborators:
Novo Nordisk A/S
Svend Faelding Humanitarian Foundation
Copenhagen University Foundation for Medical Students
Hoejmosegaard Foundation
Holger Rabitz og Hustru Doris Mary foedt Phillipps Mindelegat
Information provided by (Responsible Party):
University of Aarhus

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. 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. 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. 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. 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

Perspectives Detailed information about cholinergic denervation in DM and objective classification of the pathophysiology of diabetic GI dysfunction may allow targeted future treatment of individual patients.


Condition or disease Intervention/treatment Phase
Diabetic Autonomic Neuropathy Gastrointestinal Motility Disorder Diabetes Mellitus Change of Transit or Circulation Radiation: 11C Donepezil PET/CT scan Device: 3D-Transit Drug: 3D-Transit during treatment with Pyridostigmine Device: 3D-Transit after Malone appendicostomy Not Applicable

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Official Title: Gastrointestinal Motility Among Diabetes Patients
Study Start Date : October 2015
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : August 2019

Arm Intervention/treatment
Active Comparator: Diabetic patient

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
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.

Device: 3D-Transit

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
Other Name: MTS-2

Drug: 3D-Transit during treatment with Pyridostigmine
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.
Other Name: MTS-2 with treatment of acetylcholine esterase inhibitor

Device: 3D-Transit after Malone appendicostomy
3D-Transit (as earlier described) is performed after Malone appendicostomy. The patients are suppose use the antegrade edema technic during the 3D-transit examination.
Other Name: MTS-2

Active Comparator: Healthy subjects

The study consists of two different parts:

  1. 11C Donepezil PET/CT scan
  2. 3D-Transit
Radiation: 11C Donepezil PET/CT scan
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.

Device: 3D-Transit

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
Other Name: MTS-2




Primary Outcome Measures :
  1. Difference in Donepezil standard-uptake values (SUV) for the small intestine between diabetic patients and healthy subjects. [ Time Frame: Through study completion, an average of 1 year ]
    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.

  2. Difference in total gastrointestinal transit time between diabetic patients and healthy subjects [ Time Frame: Through study completion, an average of 1 year ]

    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.



Secondary Outcome Measures :
  1. Measurement of gastric amplitudes [ Time Frame: Through study completion, an average of 1 year ]
    If new software for analysis permits more detailed data analysis. Amplitudes of gastric contractions during awake and sleep will be analyzed.

  2. Measurement of fast movements in the small intestine [ Time Frame: Through study completion, an average of 1 year ]
    If new software for analysis permits more detailed data analysis. Number of "fast movements" in the small intestine will be analyzed.

  3. Measurement of mass movements in colorectum [ Time Frame: Through study completion, an average of 1 year ]
    If new software for analysis permits more detailed data analysis. Number and distance covered by "mass-movements" in colorectum will be analyzed.

  4. Difference in total gastrointestinal transit times in diabetic patients´s 3D-transit with and without Pyridostigmine [ Time Frame: Through study completion, an average of 1 year ]
    3D-Transit data from capsule 1 and 2 (only the diabetic patients): By comparing total GI transit times with and without administration of acetylcholine esterase inhibitor mechanistic data will be obtained to determine if neuropathy of acetylcholine containing neurons is the cause of physiological changes in GI transit times. The primary end-point is difference in total gastrointestinal passage time.

  5. Difference in regional intestinal transit times between diabetic patients and healthy subjects [ Time Frame: Through study completion, an average of 1 year ]

    The following parameters are analyzed: Gastric emptying, small intestinal and colorectal transit time (capsule number 1).

    Data from capsule 1 in healthy and patients will be used for: Comparison of regional GI transit times and transit patterns in healthy individuals and diabetic patients.


  6. Difference in regional transit times in diabetic patients´s 3D-transit with and without Pyridostigmine [ Time Frame: Through study completion, an average of 1 year ]

    The following parameters are analyzed: Gastric emptying, small intestinal and colorectal transit time (capsule number 1 and 2, only in diabetic patients).

    Data from capsule 1 and 2 will be used for: Comparison of regional GI transit times and transit patterns in diabetic patients with and without Pyridostigmine


  7. Difference in regional transit times in diabetic patients´s 3D-transit before and after Malone antegrade continence enema [ Time Frame: Through study completion, an average of 1 year ]

    The following parameters are analyzed: Gastric emptying, small intestinal and colorectal transit time (capsule number 1 and 3, only in diabetic patients with Malone Surgery).

    Data from capsule 1 and 3 will be used for: Comparison of regional GI transit times and transit patterns in diabetic patients




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

Inclusion Criteria: (only patients)

  • 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

Exclusion Criteria:

  • 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
  • Allergic reaction to Pyridostigmine and/or intravenously administrated contrast
  • Severe upper gastrointestinal pathology seen by endoscopy
  • Blood glucose below 4 mmol/L or higher than 10 mmol/L right before examination
  • Bile acid malabsorption or malabsorption in general
  • Obstruction of the urinary system
  • Severe renal insufficiency (eGFR < 45)
  • Peritonitis

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): NCT02573519


Contacts
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Contact: Mette W Andersen, Ph.d student +45 22635197 meteader@rm.dk

Locations
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Denmark
Department of Hematology and Gastroenterology, Aarhus University Hospital Recruiting
Aarhus, Denmark, 8000
Contact: Mette Winther Andersen    +45 22635197    meteader@rm.dk   
Contact: Klaus Krogh, Professor    +45 23385937    klaukrog@rm.dk   
Sub-Investigator: Anne-Mette Haase, P.hD.         
Sub-Investigator: Lotte Fynne, P.hD.         
Sponsors and Collaborators
University of Aarhus
Novo Nordisk A/S
Svend Faelding Humanitarian Foundation
Copenhagen University Foundation for Medical Students
Hoejmosegaard Foundation
Holger Rabitz og Hustru Doris Mary foedt Phillipps Mindelegat
Investigators
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Principal Investigator: Klaus Krogh, Professor Department of Hepatology and Gastroenterology, Aarhus University Hospital

Publications:

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Responsible Party: University of Aarhus
ClinicalTrials.gov Identifier: NCT02573519     History of Changes
Other Study ID Numbers: 1-10-72-54-15
First Posted: October 9, 2015    Key Record Dates
Last Update Posted: November 11, 2016
Last Verified: September 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by University of Aarhus:
11C Donepezil PET/CT scan
3D-Transit
Diabetes Mellitus
Gastrointestinal motility disorder
Diabetic autonomic neuropathy
Additional relevant MeSH terms:
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Diabetic Neuropathies
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Nervous System Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Diabetes Complications
Acetylcholine
Donepezil
Pyridostigmine Bromide
Cholinesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Nootropic Agents
Vasodilator Agents
Cholinergic Agonists