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

• Sponsor: University Health Network, Toronto (Other)
• Overall Status: Completed
• CT.gov ID: NCT02406443
• Collaborator: Merck Sharp & Dohme LLC (Industry)
• Enrollment: 36
• Location: 1
• Arms: 2
• Duration (Months): 22.1
• Patients Per Site Per Month: 1.6

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• 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: Mar 1, 2015
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Jan 1, 2017

Arms and Interventions

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 Names: 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

Outcome Measures

Primary Outcome Measures

1. Percent Change in Fractional Excretion of Sodium (FENA) [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) [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) [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 [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 [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 [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) [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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Health Network - Division of Nephrology	Toronto	Ontario	Canada	M5G 2N2

Sponsors and Collaborators

• University Health Network, Toronto
• Merck Sharp & Dohme LLC

Investigators

• 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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University Health Network, Toronto
• ClinicalTrials.gov Identifier: NCT02406443
• Other Study ID Numbers: 14-8616
• First Posted: Apr 2, 2015
• Last Update Posted: Apr 5, 2018
• Last Verified: Jan 1, 2018

• Keywords provided by University Health Network, Toronto: Type 2 Diabetes, DPP-4 inhibitors, renal sodium excretion
• Additional relevant MeSH terms: Diabetes Mellitus, Type 2; Sitagliptin Phosphate

Study Results

Participant Flow

Arm/Group Title	Experimental Arm	Placebo Arm
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	18	18
COMPLETED	16	16
NOT COMPLETED	2	2

Baseline Characteristics

Arm/Group Title	Experimental Arm	Placebo Arm	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	16	16	32
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.4 (7.6)	59.3 (8.8)	59.8 (8.1)
Sex: Female, Male (Count of Participants)
Female	5 31.3%	7 43.8%	12 37.5%
Male	11 68.8%	9 56.3%	20 62.5%
Diabetes Duration (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	6.0	8.5	8.0
HbA1c (%) (Percentage) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percentage]	7.18 (0.97)	7.31 (0.84)	7.2 (0.8)

Outcome Measures

1. Primary Outcome

Title	Percent Change in Fractional Excretion of Sodium (FENA)
Description	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
Time Frame	3 Hrs post-administration after 1 month and after 1 dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental Arm	Placebo Arm
Arm/Group Description	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	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
Measure Participants	16	16
Mean (Standard Deviation) [percentage of change]	41 (43)	-5.0 (31)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Experimental Arm, Placebo Arm
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.012
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	46
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Glomerular Filtration Rate (GFR)
Description	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
Time Frame	3 Hrs post-administration after 1 month and after 1 dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental Arm	Placebo Arm
Arm/Group Description	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	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
Measure Participants	16	16
Mean (Standard Deviation) [ml per min per 1.73 m2]	3.9 (20.4)	-1.8 (17.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Experimental Arm, Placebo Arm
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.40
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	5.7
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in Fractional Excretion of Lithium (FELi)
Description	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
Time Frame	3 Hrs post-administration after 1 month and after 1 dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental Arm	Placebo Arm
Arm/Group Description	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	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
Measure Participants	16	16
Mean (Standard Deviation) [percentage of change]	29 (55)	7 (44)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Experimental Arm, Placebo Arm
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.15
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	22
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental Arm	Placebo Arm
Arm/Group Description	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	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
Measure Participants	16	16
Mean (Standard Deviation) [ng per mL]	0.5 (0.2)	0 (0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Experimental Arm, Placebo Arm
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.5
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental Arm	Placebo Arm
Arm/Group Description	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	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
Measure Participants	16	16
Mean (Standard Deviation) [ng per mL]	-2.0 (0.4)	0.4 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Experimental Arm, Placebo Arm
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.4
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change in Systolic Blood Pressure (SBP), Non-invasive Cardiac Output Monitoring
Description	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
Time Frame	3 Hrs post-administration after 1 month and after 1 dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental Arm	Placebo Arm
Arm/Group Description	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	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
Measure Participants	16	16
Mean (Standard Deviation) [mmHg]	5.7 (9.9)	0.0 (14.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Experimental Arm, Placebo Arm
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.42
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.7
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change in Effective Renal Plasma Flow (ERPF)
Description	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
Time Frame	3 Hrs post-administration after 1 month and after 1 dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Experimental Arm	Placebo Arm
Arm/Group Description	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	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
Measure Participants	16	16
Mean (Standard Deviation) [ml per min per 1.73 m2]	31.1 (152.1)	-24.7 (142.8)

Adverse Events

Adverse Event Reporting Description	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.
Arm/Group Title	Experimental Arm		Placebo Arm
Arm/Group Description	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		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
All Cause Mortality
	Experimental Arm		Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Experimental Arm		Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/17 (5.9%)		2/18 (11.1%)
Cardiac disorders
Dyspnea	0/17 (0%)	0	1/18 (5.6%)	1
Presyncope	0/17 (0%)	0	1/18 (5.6%)	1
Gastrointestinal disorders
Lower GI Bleed	1/17 (5.9%)	1	0/18 (0%)	0
Other (Not Including Serious) Adverse Events
	Experimental Arm		Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/18 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.