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SAFEGUARD: Pleiotropic Effects of Incretin Based Therapies

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01744236
Recruitment Status : Completed
First Posted : December 6, 2012
Last Update Posted : December 9, 2015
Sponsor:
Collaborator:
EU FP7: SAFEGUARD consortium
Information provided by (Responsible Party):
M.H.H. Kramer, VU University Medical Center

Tracking Information
First Submitted Date  ICMJE December 4, 2012
First Posted Date  ICMJE December 6, 2012
Last Update Posted Date December 9, 2015
Study Start Date  ICMJE April 2013
Actual Primary Completion Date August 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 4, 2012)
  • Changes from baseline following infusion of GLP-1RA (acute effects) and the changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on resting heart rate variability, as derived from electrocardiographic measurements. [ Time Frame: 12 weeks ]
  • Changes from baseline following infusion of GLP-1RA (acute effects) and the changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on Glomerular Filtration Rate, measured by the inulin-clearance technique. [ Time Frame: 12 weeks ]
  • Changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on pancreatic exocrine function, measured as fecal Elastase-1. [ Time Frame: 12 weeks ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 20, 2014)
  • Changes from baseline following infusion of GLP-1RA (acute effects) and the changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on the following cardiovascular parameters: [ Time Frame: 12 weeks ]
    • Blood pressure and heart rate
    • Hemodynamic variables (blood pressure, heart rate, stroke volume, cardiac output/-index/-contractility, systemic vascular resistance) derived from non-invasive beat-to-beat finger blood pressure measurements
    • Cardiac autonomic nervous system function
    • Microvascular function and vasomotion
    • Arterial stiffness
    • Lipid spectrum
    • Glycemic variables (HbA1c, fasting and postprandial glucose)
    • Body anthropometrics: body weight, height, BMI and waist circumference
    • Body fat content
  • Changes from baseline following infusion of GLP-1RA (acute effects) and the changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on the following renal parameters: [ Time Frame: 12 weeks ]
    • Effective renal plasma flow (ERPF)
    • Renal tubular function
    • Renal damage, measured by urine biomarkers
  • Changes from baseline following infusion of GLP-1RA (acute effects*) and changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on the following gastrointestinal parameters: [ Time Frame: 12 weeks ]
    • Pancreatic exocrine function (* In the acute intervention only exocrine pancreatic function is assessed)
    • Pancreatic structure
    • Pancreatic enzymes
    • Gallbladder emptying speed
    • Liver enzymes
    • Hepatic structure/steatosis
    • Gastric emptying
Original Secondary Outcome Measures  ICMJE
 (submitted: December 4, 2012)
  • Changes from baseline following infusion of GLP-1RA (acute effects) and the changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on the following cardiovascular parameters: [ Time Frame: 12 weeks ]
    • Blood pressure and heart rate
    • Hemodynamic variables (blood pressure, heart rate, stroke volume, cardiac output/-index/-contractility, systemic vascular resistance) derived from non-invasive beat-to-beat finger blood pressure measurements
    • Cardiac autonomic nervous system function
    • Microvascular function and vasomotion
    • Arterial stiffness
    • Lipid spectrum
    • Glycemic variables (HbA1c, fasting and postprandial glucose)
    • Body anthropometrics: body weight, height, BMI and waist circumference
    • Body fat content
  • Changes from baseline following infusion of GLP-1RA (acute effects) and the changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on the following renal parameters: [ Time Frame: 12 weeks ]
    • Effective renal plasma flow (ERPF)
    • Renal tubular function
    • Renal damage, measured by urine biomarkers
  • Changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on the following gastrointestinal parameters: [ Time Frame: 12 weeks ]
    • Pancreatic exocrine function
    • Pancreatic structure
    • Pancreatic enzymes
    • Gallbladder emptying speed
    • Liver enzymes
    • Hepatic structure/steatosis
    • Gastric emptying
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE SAFEGUARD: Pleiotropic Effects of Incretin Based Therapies
Official Title  ICMJE A Phase IV, Randomized, Double-blind, Placebo-controlled, Parallel-group Trial to Assess the Effect of 12-week Treatment With the Glucagon-like Peptide-1 Receptor Agonist (GLP-1RA) Liraglutide or Dipeptidyl Peptidase-4 Inhibitor (DPP-4i) Sitagliptin on the Cardiovascular, Renal and Gastrointestinal System in Insulin-naïve Patients With Type 2 Diabetes (T2DM).
Brief Summary The aim of this study is to detail the (mechanisms underlying the) actions of the GLP-1 receptor agonists and DPP-4 inhibitors on the cardiovascular, renal and gastrointestinal systems in patients with Type 2 Diabetes Mellitus.
Detailed Description

GLP-1 receptors are present in most organ systems of the human body, and pharmacological interventions enhancing GLP-1 activity may influence the function of these organs. The use of GLP-1 receptor agonists (GLP-1RA) and DPP-4 inhibitors (DPP-4i) has been associated with an increased heart rate, acute pancreatitis and acute renal failure. To date, studies in humans detailing the effects of these drugs on these organ systems, biological processes and underlying mechanisms, which could explain these associations, are lacking.

Therefore, as part of the EU-FP7 SAFEGUARD program, the present study will aim to detail the (mechanisms underlying the) actions of GLP-1RA and DPP-4i on the cardiovascular, renal and gastrointestinal system in healthy obese subjects and patients with T2DM.

In the main study, sixty patients with type 2 diabetes will undergo two interventions within the same protocol in order to assess changes in the outcome parameters:

  • acute study = acute infusion with exenatide or placebo (to assess the cardiovascular and renal effects)
  • long-term study = 12 weeks of treatment with liraglutide, sitagliptin or placebo (to assess the cardiovascular, renal and gastrointestinal effects)

In a substudy (termed 'acute MRI study'), twelve patients with type 2 diabetes will undergo an additional acute intervention study with exenatide (to assess the pancreatic effects)

In a substudy (termed 'pilot-study'), ten healthy obese subjects will undergo a similar acute study like the patients with type 2 diabetes (to assess the cardiovascular and renal effects). Moreover, in these healthy subjects, the effects of exenatide during L-NMMA infusion will be assessed.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Type 2 Diabetes
Intervention  ICMJE
  • Drug: Liraglutide
    Liraglutide will be started with a titration period of 2 weeks (week 1: 0.6mg once daily and week 2: 1.2mg once daily). If liraglutide is well tolerated it will be continued for 10 more weeks in a dosage of 1.8mg once daily.
  • Drug: Sitagliptin
    Sitagliptin 100mg will be given once daily for 12 weeks.
  • Drug: Exenatide
    Exenatide will be administered intravenously with a loading dose of 50ng/min for 30 minutes, followed by a maintenance dose of 25ng/min during the rest of the tests
  • Drug: Liraglutide placebo
    Liraglutide-placebo will be started with a titration period of 2 weeks (week 1: 0.6mg once daily and week 2: 1.2mg once daily). It will be continued for 10 more weeks in a dosage of 1.8mg once daily.
  • Drug: Sitagliptin placebo
    Sitagliptin-placebo be given once daily for 12 weeks.
  • Drug: Exenatide placebo
    Exenatide-placebo (saline) will be administered intravenously
  • Drug: L-NMMA
Study Arms  ICMJE
  • Experimental: Liraglutide (main study, long-term intervention)
    This arm (n=20) will receive liraglutide 1.8mg and sitagliptin-placebo during 12 weeks
    Interventions:
    • Drug: Liraglutide
    • Drug: Sitagliptin placebo
  • Experimental: Sitagliptin (main study, long-term intervention)
    This arm (n=20) will receive sitagliptin 100mg and liraglutide-placebo during 12 weeks
    Interventions:
    • Drug: Sitagliptin
    • Drug: Liraglutide placebo
  • Placebo Comparator: Placebo (main study, long-term intervention)
    This arm (n=20) will receive liraglutide-placebo and sitagliptin-placebo during 12 weeks
    Interventions:
    • Drug: Liraglutide placebo
    • Drug: Sitagliptin placebo
  • Experimental: Exenatide (main study, acute intervention)
    Prior to the 12-week intervention study, a GLP-1 receptor agonist (exenatide) will be administered intravenously (n=30).
    Intervention: Drug: Exenatide
  • Placebo Comparator: Placebo (main study, acute intervention)
    Prior to the 12-week intervention study, placebo will be administered intravenously (n=30).
    Intervention: Drug: Exenatide placebo
  • Acute MRI intervention study
    In a subset of 12 patients with type 2 diabetes, a crossover trial with acute infusion of exenatide and placebo is performed. This is done prior to the 12-week intervention study.
    Interventions:
    • Drug: Exenatide
    • Drug: Exenatide placebo
  • Pilot-study
    In 10 healthy obese subjects, a crossover trial with acute infusion of exenatide, placebo and L-NMMA is performed.
    Interventions:
    • Drug: Exenatide
    • Drug: Exenatide placebo
    • Drug: L-NMMA
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 20, 2014)
70
Original Estimated Enrollment  ICMJE
 (submitted: December 4, 2012)
68
Actual Study Completion Date  ICMJE August 2015
Actual Primary Completion Date August 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age between 35 and 75 years.
  • Females must be post-menopausal (no menses >1 year).
  • Type 2 diabetes (HbA1c 6.5-9% DCCT or 48-75 mmol/mol IFCC), who are being treated with a stable dose of oral antihyperglycemic agents (either metformin alone, SU alone or a combination of metformin and SU) for at least 3 months prior to inclusion.
  • BMI 25 - 40 kg/m2
  • Caucasian
  • Signed informed consent

Exclusion Criteria:

  • GFR < 60 mL/min/1.73m2
  • Current / chronic use of the following medication: thiazolidinediones, GLP-1RA, DPP-4i, glucocorticoids, NSAIDs, insulin, antimicrobial agents, chemotherapeutics or immune suppressants. Subjects on diuretics will only be excluded when these drugs (e.g. hydrochlorothiazide) cannot be stopped for the duration of the study.
  • History of or actual pancreatic disease or impaired pancreatic exocrine function
  • Active liver disease
  • History of or actual malignancy (with the exception of basal cell carcinoma)
  • Current urinary tract infection and active nephritis
  • Recent (<6 months) history of cardiovascular disease, including acute coronary syndrome, stroke, transient ischemic neurologic disorder or chronic heart failure (New York Heart Association grade II-IV)
  • Current atrial fibrillation
  • Chronic infectious or auto-immune disease
  • Substance and/or alcohol abuse
  • History of allergy/hypersensitivity to any of the test agents
  • Complaints compatible with or established gastroparesis and/or neurogenic bladder
  • Any condition that has been recognized as a contra-indication for the use of GLP-1RA and DPP-4i, as listed in the respective SPCs
  • History of or actual (severe) mental illness
  • Inability to understand the study protocol and/or inability to give informed consent
  • History of claustrophobia or presence of metal objects/implants (because of MRI protocol)

For the preceding Pilot study, we will include:

  • Males
  • Age between 18 and 50 years
  • BMI 25 - 40 kg/m2
  • Caucasian

The exclusion criteria for the preceding pilot study are similar to the exclusion criteria of the main study, with the additions of:

  • Subjects with a fasting plasma glucose ≥5.6 mmol/L, a 2-hour glucose of ≥7.8 mmol/L after a 75-grams oral glucose tolerance test, or a HbA1c of ≥6.5%
  • Subjects using any kind of medication
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 35 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01744236
Other Study ID Numbers  ICMJE DC2012SAFE001
U1111-1130-8248 ( Other Identifier: WHO Universal Trial Number )
2012-003256-36 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party M.H.H. Kramer, VU University Medical Center
Study Sponsor  ICMJE VU University Medical Center
Collaborators  ICMJE EU FP7: SAFEGUARD consortium
Investigators  ICMJE
Principal Investigator: M.H.H. Kramer, MD PhD VU University Medical Center
PRS Account VU University Medical Center
Verification Date December 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP