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The INDORSE Study: Inhibition of Dipeptidyl Peptidase IV: Outcomes on Renal Sodium Excretion (INDORSE)

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ClinicalTrials.gov Identifier: NCT02406443
Recruitment Status : Completed
First Posted : April 2, 2015
Results First Posted : April 5, 2018
Last Update Posted : April 5, 2018
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
University Health Network, Toronto

Brief Summary:

Background: Dedicated renal hemodynamic and renal function studies are lacking for DPP-4 inhibitors in patients with Type 2 diabetes; accordingly little is known regarding the mechanisms mediating the renal effects of DPP-4 inhibitors in humans.

Objectives: To evaluate the effect of DPP-4 inhibition acutely (single dose) and following short-term therapy (28 days) on renal sodium handling and renal hemodynamics and function in patients with type 2 diabetes and systolic hypertension.

Design: double-blind, randomized, placebo-controlled trial, Phase IV.

Patient population: 32 patients with Type 2 diabetes, HbA1c (6.5%-9%), with systolic blood pressure ranging from 120-160 mmHg.

Intervention: subjects will be randomized (1:1) to either sitagliptin (100 mg daily) or to placebo (1 tablet daily) for 28 days.

Endpoints: Fractional excretion of sodium, renal function, and renal hemodynamics.


Condition or disease Intervention/treatment Phase
Type 2 Diabetes Drug: Sitaglitpin Other: Placebo Phase 4

Detailed Description:

Background: DPP-4 inhibition improves glycemic control, modestly reduces blood pressure and may also reduce albuminuria in patients with Type 2 diabetes; effects which occur without significantly modifying heart rate or body weight. While preclinical studies have demonstrated that DPP-4 inhibition acutely increases urinary sodium excretion in addition to other favorable renal effects (anti-inflammatory, anti-proteinuric), few studies have examined the renal effects of DPP-4 inhibition either acutely or following short-term therapy in humans with type 2 diabetes. Considering the world-wide prevalence of Type 2 diabetes and the increasing use of DPP-4 inhibitors amongst patients, it is important to ascertain potential non-glycemic effects of DPP-4 inhibitors including those within the kidney.

Study Objectives: To determine effect(s) of DPP-4 inhibition on tubular sodium handling, renal hemodynamics, and renal function.

Study Design: double-blind, randomized, placebo-controlled trial, Phase IV.

Study Patients: 32 patients with Type 2 Diabetes and Systolic Hypertension (SBP 120-160 mmHg).

Endpoints: Fractional excretion of sodium, renal function (measured GFR), renal hemodynamics (effective renal plasma flow, filtration fraction, renal blood flow, renal vascular resistance), systemic hemodynamics (non-invasive cardiac monitoring), plasma neurohormones, urinary vasoactive mediators, markers of free radical stress.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 36 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Other
Official Title: Effects of DPP-4 Inhibitor Therapy on Renal Sodium Handling and Renal Hemodynamics in Type 2 Diabetes Patients. The INDORSE Study: Inhibition of Dipeptidyl Peptidase IV: Outcomes on Renal Sodium Excretion
Study Start Date : March 2015
Actual Primary Completion Date : June 2016
Actual Study Completion Date : January 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Experimental arm
sitagliptin (DPP-4 inhibitor) oral tablet (100 mg); Januvia; administered once daily for 28 days
Drug: Sitaglitpin
Oral DPP-4 inhibitor, 100 mg tablet administered once daily for 28 days
Other Name: Januvia

Placebo Comparator: Placebo arm
placebo (no medicinal ingredients) oral tablet (100 mg); administered once daily for 28 days
Other: Placebo
Oral tablet (no medicinal ingredients) administered once daily for 28 days




Primary Outcome Measures :
  1. Percent Change in Fractional Excretion of Sodium (FENA) [ Time Frame: 3 Hrs post-administration after 1 month and after 1 dose ]
    FENA at 3Hrs post-study drug administration after 1 month compared to FENA at 3Hrs post-study drug administration after 1 dose expressed as percent change, sitagliptin vs. placebo


Secondary Outcome Measures :
  1. Change in Glomerular Filtration Rate (GFR) [ Time Frame: 3 Hrs post-administration after 1 month and after 1 dose ]
    Measured GFR (Inulin Clearance) at 3Hrs post study-drug after 1 month compared to Measured GFR at 3Hrs post-study drug after 1 dose, sitagliptin vs. placebo

  2. Change in Fractional Excretion of Lithium (FELi) [ Time Frame: 3 Hrs post-administration after 1 month and after 1 dose ]
    FELi at 3 Hr post-study drug administration after 1 month compared to FELI at 3hrs post-study drug administration after 1 dose, sitagliptin vs. placebo

  3. Change From Baseline in SDF-1alpha^1-67 (Intact) Measured by Immunoaffinity and Tandem Mass Spectrometry [ Time Frame: 3 Hr vs. baseline after 1 dose ]
    Plasma concentration of SDF-1alpha^1-67 (intact) measured by quantitative mass spectrometry methods after antibody-based affinity enrichment, sitagliptin vs. placebo

  4. Change From Baseline in SDF-1alpha^3-67 (Truncated) Measured by Tandem Mass Spectrometry With Antibody-based Affinity Enrichment [ Time Frame: 3Hrs vs baseline after 1 dose ]
    Plasma concentration of SDF-1alpha^3-67 (intact) measured by quantitative mass spectrometry methods after antibody-based affinity enrichment, sitagliptin vs. placebo

  5. Change in Systolic Blood Pressure (SBP), Non-invasive Cardiac Output Monitoring [ Time Frame: 3 Hrs post-administration after 1 month and after 1 dose ]
    SBP by Non-Invasive cardiac output monitoring at 3Hrs post- study drug administration after 1 month compared to SBP by Non-invasive cardiac output monitoring at 3Hrs after 1 dose, sitagliptin vs placebo

  6. Change in Effective Renal Plasma Flow (ERPF) [ Time Frame: 3 Hrs post-administration after 1 month and after 1 dose ]
    ERPF (para-aminohippurate clearance) 3Hrs post-study drug administration after 1 month compared to ERPF at 3Hhrs post-study drug administration after 1 dose, sitagliptin vs placebo



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Individuals of 18-70 years of age,
  • with Type 2 Diabetes,
  • with an HbA1c (6.5%-9%),
  • and with a systolic blood pressure (120-160 mmHg).

Exclusion Criteria:

  • Individuals with:

    1. Type 1 Diabetes,
    2. eGFR <50mL/min/1.73m,
    3. pregnancy or breast feeding,
    4. significant cardiac, pulmonary or liver disease,
    5. prior history of pancreatitis, medullary thyroid cancer, multiple endocrine neoplasia syndromes,
    6. SBP >161 mmHg, 7) DBP >100 mmHg,
    7. alcohol or substance abuse,
    8. states of secondary hypertension.

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): NCT02406443


Locations
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Canada, Ontario
University Health Network - Division of Nephrology
Toronto, Ontario, Canada, M5G 2N2
Sponsors and Collaborators
University Health Network, Toronto
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Julie Lovshin, MD,PhD Lunenfeld Tanenbaum Reserach Institute, Divsion of Endocrinology and Metabolism, University of Toronto
Principal Investigator: David I Cherney, MD,PhD Division of Nephrology, University Health Network, University of Toronto
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: University Health Network, Toronto
ClinicalTrials.gov Identifier: NCT02406443    
Other Study ID Numbers: 14-8616
First Posted: April 2, 2015    Key Record Dates
Results First Posted: April 5, 2018
Last Update Posted: April 5, 2018
Last Verified: January 2018
Keywords provided by University Health Network, Toronto:
Type 2 Diabetes, DPP-4 inhibitors, renal sodium excretion
Additional relevant MeSH terms:
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Diabetes Mellitus, Type 2
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Sitagliptin Phosphate
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action