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GLP-1-mediated Gluco-metabolic Effects of Bile Acid Sequestration (SeveX)

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ClinicalTrials.gov Identifier: NCT03739268
Recruitment Status : Recruiting
First Posted : November 12, 2018
Last Update Posted : November 26, 2018
Sponsor:
Collaborator:
Sanofi
Information provided by (Responsible Party):
Steno Diabetes Center Copenhagen

Brief Summary:
The objective of this study is to investigate the potential GLP-1-mediated contribution to the well-established glucose-lowering effect of sevelamer-induced bile acid sequestration . Exendin9-39 has been demonstrated to act as a potent and specific GLP-1 receptor antagonist with no partial agonistic potential and is considered a useful tool in the assessment of GLP-1 physiology. The aim is to evaluate any contribution of sevelamer-induced GLP-1 secretion to the reduced plasma glucose concentrations observed after treatment with sevelamer. A randomised placebo-controlled cross-over study involving two 17-day treatment periods with sevelamer and placebo, respectively, in metformin-treated patients with type 2 diabetes, will be conducted. The impact of bile acid sequestration on GLP-1 secretion and effect will be examined during two randomised experimental days after 15 and 17 days of treatment with sevelamer (1,600 mg three times a day) and placebo, respectively. During each of these two experimental days, a meal test with concomitant exendin9-39 infusion or placebo will be performed (for evaluation of any GLP-1-mediated effects). Postprandial plasma glucose excursion is the primary endpoint, and secondary endpoints include postprandial plasma/serum excursions of insulin, C-peptide, GLP-1, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-2 (GLP-2), peptide YY (PYY), oxyntomodulin, ghrelin, fibroblast growth factor (FGF)-19, FGF-21, C4 (an intermediate in the de novo synthesis of bile acids), cholecystokinin (CCK), bile acids and plasma lipids. Furthermore, gastric emptying, gallbladder emptying, liver fat content, appetite and ad libitum food intake will be examined.

Condition or disease Intervention/treatment Phase
Type 2 Diabetes Mellitus Drug: Sevelamer Drug: Placebo Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Official Title: GLP-1-mediated Gluco-metabolic Effects of Bile Acid Sequestration
Actual Study Start Date : September 1, 2018
Estimated Primary Completion Date : February 28, 2019
Estimated Study Completion Date : September 1, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Sevelamer

Arm Intervention/treatment
Active Comparator: sevelamer
Patients with type 2 diabetes treated with sevelamer
Drug: Sevelamer
Sevelamer powder dissolved in water 1,600 mg three times a day for 17 days

Placebo Comparator: placebo
Patients with type 2 diabetes treated with placebo
Drug: Placebo
placebo powder dissolved in water 1,600 mg three times a day for 17 days




Primary Outcome Measures :
  1. plasma glucose [ Time Frame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes ]
    Postprandial plasma glucose (PG) excursion (AUC240 min)


Secondary Outcome Measures :
  1. Postprandial responses of glucagon-like peptide-1 (GLP-1) [ Time Frame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes ]
    Meal response of GLP-1

  2. Postprandial responses of glucose-dependent insulinotropic polypeptide (GIP) [ Time Frame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes ]
    Meal response of glucose-dependent insulinotropic polypeptide (GIP)

  3. Postprandial responses of glucagon-like peptide-2 (GLP-2) [ Time Frame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes ]
    Meal response of glucagon-like peptide-2 (GLP-2)

  4. Postprandial responses of Glucagon [ Time Frame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes ]
    Meal response of Glucagon

  5. Postprandial responses of peptide YY (PYY) [ Time Frame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes ]
    Meal response of peptide YY (PYY)

  6. Postprandial responses of Insulin and c-peptide [ Time Frame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes ]
    Meal response of Insulin and c-peptide as a insulin/c-peptide ratio

  7. Postprandial responses of Ghrelin [ Time Frame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes ]
    Meal response of Ghrelin

  8. Postprandial responses of fibroblast growth factor (FGF)-19 [ Time Frame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes ]
    Meal response of fibroblast growth factor (FGF)-19

  9. Postprandial responses of fibroblast growth factor (FGF)-21 [ Time Frame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes ]
    Meal response of fibroblast growth factor (FGF)-21

  10. Postprandial responses of Bile acids [ Time Frame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes ]
    Meal response of Bile acids

  11. Postprandial responses of cholecystokinin (CCK) [ Time Frame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes ]
    Meal response of cholecystokinin (CCK)

  12. Postprandial responses of plasma lipids [ Time Frame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes ]
    Meal response of plasma lipids

  13. Postprandial responses of Amino acids [ Time Frame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes ]
    Meal response of Amino acids

  14. Gastric emptying [ Time Frame: -30 minutes to 240 minutes with ingestion of a meal and paracetamol at 0 minutes ]
    Gastric emptying measured by paracetamol absorption test. Paracetamol is ingested along with meal, the appearance in blood will be calculated as a measure of gastric emptying.

  15. Rate of gall bladder emptying [ Time Frame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes ]
    Gall bladder volumen measured by ultrasound over time after a meal (see time frame below). The rate of gall bladder emptying will be calculated

  16. Liver stiffness and fat [ Time Frame: At initiation and after 15 days of treatment with sevelamer/placebo ]
    Liver stiffness and fat content measured by fibroscan

  17. Appetite measured by visual analog scale [ Time Frame: -30 minutes to 240 minutes with ingestion of a meal at 0 minutes ]
    We assessed appetite parameters (hunger, satiety, fullness, prospective food consumption) and well-being, nausea, and thirst by visual analogue scales. Overall appetite score (OAS) will be calculated as (satiety + fullness + (100 - hunger) + (100 - prospective food consumption)



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Ages Eligible for Study:   40 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Type 2 diabetes for at least 3 months (diagnosed according to the criteria of the World Health Organization (WHO))
  • Men and postmenopausal women
  • Metformin applied as the only glucose-lowering drug
  • Caucasian ethnicity
  • Normal haemoglobin
  • Age above 40 years and below 75 years
  • BMI >23 kg/m2 and <35 kg/m2
  • Informed and written consent

Exclusion Criteria:

  • Liver disease (alanine aminotransferase (ALAT) and/or serum aspartate aminotransferase (ASAT) >2 times normal values) or history of hepatobiliary disorder
  • Gastrointestinal disease, previous intestinal resection, cholecystectomy or any major intra-abdominal surgery
  • Nephropathy (serum creatinine >150 µM and/or albuminuria)
  • Hypo- or hyperthyroidism
  • Hypo- or hypercalcaemia
  • Hypo- or hyperphosphataemia
  • Active or recent malignant disease
  • Treatment with medicine that cannot be paused for 12 hours
  • Treatment with oral anticoagulants
  • Any treatment or condition requiring acute or sub-acute medical or surgical intervention
  • Any condition considered incompatible with participation by the investigators

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): NCT03739268


Contacts
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Contact: Henriette H Nerild, M.D. +45 3867 4264 henriette.holst.nerild@regionh.dk
Contact: Filip K Knop, M.D. PhD +45 3867 4266 filip.krag.knop.01@regionh.dk

Locations
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Denmark
Steno Diabetes Center Copenhagen, Gentofte Hospital Recruiting
Hellerup, Denmark, 2900
Contact: Henriette H Nerild, M.D.    +45 3867 4264    henriette.holst.nerild@regionh.dk   
Sponsors and Collaborators
Steno Diabetes Center Copenhagen
Sanofi
Investigators
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Study Director: Filip K Knop, M.D. PhD Steno Diabetes Center Copenhagen
Principal Investigator: Henriette H Nerild, M.D. Steno Diabetes Center Copenhagen

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Responsible Party: Steno Diabetes Center Copenhagen
ClinicalTrials.gov Identifier: NCT03739268     History of Changes
Other Study ID Numbers: SeveX2018
First Posted: November 12, 2018    Key Record Dates
Last Update Posted: November 26, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Steno Diabetes Center Copenhagen:
bile acid

Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Sevelamer
Bile Acids and Salts
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action
Gastrointestinal Agents