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| Name | Class |
|---|---|
| Merck Sharp & Dohme LLC | INDUSTRY |
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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Experimental arm | Experimental | sitagliptin (DPP-4 inhibitor) oral tablet (100 mg); Januvia; administered once daily for 28 days |
|
| Placebo arm | Placebo Comparator | placebo (no medicinal ingredients) oral tablet (100 mg); administered once daily for 28 days |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sitaglitpin | Drug | Oral DPP-4 inhibitor, 100 mg tablet administered once daily for 28 days |
|
| Measure | Description | Time Frame |
|---|---|---|
| Percent Change in Fractional Excretion of Sodium (FENA) | 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 | 3 Hrs post-administration after 1 month and after 1 dose |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Glomerular Filtration Rate (GFR) | 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 | 3 Hrs post-administration after 1 month and after 1 dose |
| Change in Fractional Excretion of Lithium (FELi) |
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Inclusion Criteria:
Exclusion Criteria:
Individuals with:
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| Name | Affiliation | Role |
|---|---|---|
| Julie Lovshin, MD,PhD | Lunenfeld Tanenbaum Reserach Institute, Divsion of Endocrinology and Metabolism, University of Toronto | Study Director |
| David I Cherney, MD,PhD | Division of Nephrology, University Health Network, University of Toronto | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Health Network - Division of Nephrology | Toronto | Ontario | M5G 2N2 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28550195 | Derived | Lovshin JA, Rajasekeran H, Lytvyn Y, Lovblom LE, Khan S, Alemu R, Locke A, Lai V, He H, Hittle L, Wang W, Drucker DJ, Cherney DZI. Dipeptidyl Peptidase 4 Inhibition Stimulates Distal Tubular Natriuresis and Increases in Circulating SDF-1alpha1-67 in Patients With Type 2 Diabetes. Diabetes Care. 2017 Aug;40(8):1073-1081. doi: 10.2337/dc17-0061. Epub 2017 May 26. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Experimental Arm | sitagliptin (DPP-4 inhibitor) oral tablet (100 mg); Januvia; administered once daily for 28 days Sitaglitpin: Oral DPP-4 inhibitor, 100 mg tablet administered once daily for 28 days |
| FG001 | Placebo Arm | placebo (no medicinal ingredients) oral tablet (100 mg); administered once daily for 28 days Placebo: Oral tablet (no medicinal ingredients) administered once daily for 28 days |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Experimental Arm | sitagliptin (DPP-4 inhibitor) oral tablet (100 mg); Januvia; administered once daily for 28 days Sitaglitpin: Oral DPP-4 inhibitor, 100 mg tablet administered once daily for 28 days |
| BG001 | Placebo Arm |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Percent Change in Fractional Excretion of Sodium (FENA) | 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 | Posted | Mean | Standard Deviation | percentage of change | 3 Hrs post-administration after 1 month and after 1 dose |
|
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The intention to treat population at risk was 17 for the experimental arm and 18 for the placebo arm, and the final per-protocol population was 16 per arm. 1 participant in the experimental arm was withdrawn due to lower GI bleeding after randomization, and 2 participants in the placebo arm were withdrawn, 1 due to dyspnea and 1 due to presyncope after randomization.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Experimental Arm | sitagliptin (DPP-4 inhibitor) oral tablet (100 mg); Januvia; administered once daily for 28 days Sitaglitpin: Oral DPP-4 inhibitor, 100 mg tablet administered once daily for 28 days |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dyspnea | Cardiac disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| University Health Network | Renal Physiology Laboratory | 416-340-4800 | 8508 | vesta.lai@uhn.ca |
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| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D000068900 | Sitagliptin Phosphate |
| ID | Term |
|---|---|
| D014230 | Triazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| Placebo | Other | Oral tablet (no medicinal ingredients) administered once daily for 28 days |
|
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 Hrs post-administration after 1 month and after 1 dose |
| Change From Baseline in SDF-1alpha^1-67 (Intact) Measured by Immunoaffinity and Tandem Mass Spectrometry | Plasma concentration of SDF-1alpha^1-67 (intact) measured by quantitative mass spectrometry methods after antibody-based affinity enrichment, sitagliptin vs. placebo | 3 Hr vs. baseline after 1 dose |
| Change From Baseline in SDF-1alpha^3-67 (Truncated) Measured by Tandem Mass Spectrometry With Antibody-based Affinity Enrichment | Plasma concentration of SDF-1alpha^3-67 (intact) measured by quantitative mass spectrometry methods after antibody-based affinity enrichment, sitagliptin vs. placebo | 3Hrs vs baseline after 1 dose |
| Change in Systolic Blood Pressure (SBP), Non-invasive Cardiac Output Monitoring | 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 | 3 Hrs post-administration after 1 month and after 1 dose |
| Change in Effective Renal Plasma Flow (ERPF) | 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 | 3 Hrs post-administration after 1 month and after 1 dose |
placebo (no medicinal ingredients) oral tablet (100 mg); administered once daily for 28 days
Placebo: Oral tablet (no medicinal ingredients) administered once daily for 28 days
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Diabetes Duration | Median | Inter-Quartile Range | years |
|
| HbA1c (%) | Mean | Standard Deviation | Percentage |
|
|
|
|
| Secondary | Change in Glomerular Filtration Rate (GFR) | 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 | Posted | Mean | Standard Deviation | ml per min per 1.73 m2 | 3 Hrs post-administration after 1 month and after 1 dose |
|
|
|
|
| Secondary | Change in Fractional Excretion of Lithium (FELi) | 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 | Posted | Mean | Standard Deviation | percentage of change | 3 Hrs post-administration after 1 month and after 1 dose |
|
|
|
|
| Secondary | Change From Baseline in SDF-1alpha^1-67 (Intact) Measured by Immunoaffinity and Tandem Mass Spectrometry | Plasma concentration of SDF-1alpha^1-67 (intact) measured by quantitative mass spectrometry methods after antibody-based affinity enrichment, sitagliptin vs. placebo | Posted | Mean | Standard Deviation | ng per mL | 3 Hr vs. baseline after 1 dose |
|
|
|
|
| Secondary | Change From Baseline in SDF-1alpha^3-67 (Truncated) Measured by Tandem Mass Spectrometry With Antibody-based Affinity Enrichment | Plasma concentration of SDF-1alpha^3-67 (intact) measured by quantitative mass spectrometry methods after antibody-based affinity enrichment, sitagliptin vs. placebo | Posted | Mean | Standard Deviation | ng per mL | 3Hrs vs baseline after 1 dose |
|
|
|
|
| Secondary | Change in Systolic Blood Pressure (SBP), Non-invasive Cardiac Output Monitoring | 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 | Posted | Mean | Standard Deviation | mmHg | 3 Hrs post-administration after 1 month and after 1 dose |
|
|
|
|
| Secondary | Change in Effective Renal Plasma Flow (ERPF) | 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 | Posted | Mean | Standard Deviation | ml per min per 1.73 m2 | 3 Hrs post-administration after 1 month and after 1 dose |
|
|
|
| 1 |
| 17 |
| 0 |
| 17 |
| EG001 | Placebo Arm | placebo (no medicinal ingredients) oral tablet (100 mg); administered once daily for 28 days Placebo: Oral tablet (no medicinal ingredients) administered once daily for 28 days | 2 | 18 | 0 | 18 |
| Presyncope | Cardiac disorders | Systematic Assessment |
|
| Lower GI Bleed | Gastrointestinal disorders | Systematic Assessment |
|
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| D004700 | Endocrine System Diseases |
| D011719 |
| Pyrazines |