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

Type 2 Diabetes Clinical Trial

— INDORSE  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02406443
• Other study ID #: 14-8616
• Status: Completed
• Phase: Phase 4
• First received: March 30, 2015
• Last updated: January 9, 2018
• Start date: March 2015
• Est. completion date: January 2017

Study information

• Verified date: January 2018
• Source: University Health Network, Toronto
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: January 2017
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Type 2 Diabetes

Intervention

Drug:
• Sitaglitpin
Oral DPP-4 inhibitor, 100 mg tablet administered once daily for 28 days

Other:
• Placebo
Oral tablet (no medicinal ingredients) administered once daily for 28 days

Locations

Country	Name	City	State
Canada	University Health Network - Division of Nephrology	Toronto	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
University Health Network, Toronto	Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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	3 Hrs post-administration after 1 month and after 1 dose
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	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	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	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	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	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	3 Hrs post-administration after 1 month and after 1 dose