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Pharmacogenetics of Ace Inhibitor-Associated Angioedema

Primary Purpose

Hypertension, Diabetes Type 2

Status

Completed

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Sitagliptin (DPP4 inhibitor)

Substance P,

bradykinin

enalaprilat (ACE inhibitor)

Glucagon-like peptide 1

brain natriuretic peptide

About this trial

This is an interventional treatment trial for Hypertension focused on measuring DPPIV inhibitors, ACE inhibitors, Bradykinin, glucagon-like peptide (GLP-1), BNP, diabetes, hypertension

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Age 18 to 65 inclusive
Men and women
Black and White Americans
BMI <25

For female subjects:

Postmenopausal status for at least 1 year
Status post surgical sterilization
If childbearing potential, utilization of a barrier method of birth control and willingness to undergo blood B-hcg testing prior to drug treatment and on every study day

Exclusion Criteria:

Smoking
Diabetes type 1 or 2, as defined by a fasting glucose of 126 mg/dl or greater or the use of anti-diabetic medication
Hypertension as defined by an untreated seated SBP greater than 140 mmHg an untreated DBP greater than 90 mmHg or the use of antihypertensives
History of reported or recorded hypoglycemia (plasma glucose less than 70 mg/dl)
Pregnancy
Breast-feeding
Use of hormone replacement therapy
The use of contraceptive therapy
Use of any medication other than multivitamin
Hematocrit <35%
Cardiovascular disease such as history of myocardial infarction, presence of angina pectoris, significant arrhythmia, congestive heart failure(LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy
Asthma
History of angioedema
History of cough or other side effect during ACE inhibitor use
Impaired renal function, as defined by an eGFR<60ml/min/1.73M2
Clinically significant gastrointestinal impairment that could interfere with drug absorption
Impaired hepatic function (aspartate amino transaminase[AST] and/or alanine amino transferase [ALT]>2 x upper limit of normal range
History of alcohol or drug abuse
Treatment with any investigational drug in the 1 month preceding the study
Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study
Inability to comply with the protocol, e.g., uncooperative attitude, inability to return to follow-up visits, and the unlikelihood of completing the study

Sites / Locations

Vanderbilt University- General Clinic Research Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Placebo Comparator

Arm Label

Placebo then sitagliptin (DPP4 inhibition) group 1

Sitagliptin (DPP4 inhibition) then placebo group 1

Placebo then sitagliptin group 2

Sitagliptin (DPP4 inhibition) then comparator group 2

Arm Description

The effect of vehicle and enalaprilat on the forearm blood flow and t-PA responses to bradykinin and substance P are studied after administration of placebo or sitagliptin (DPP4 inhibition).

The effect of vehicle and enalaprilat (ACE inhibition) on the forearm blood flow and t-PA responses to substance P and bradykinin are studied after administration of sitagliptin (DPP4 inhibition) or placebo

The effect of vehicle and enalaprilat (ACE inhibition) on the forearm blood flow and t-PA responses to glucagon-like peptide-1 and brain natriuretic pepdie are studied after administration of placebo or sitagliptin (DPP4 inhibition).

The effect of vehicle and enalaprilat on the forearm blood flow and t-PA responses to glucagon-like peptide and brain natriuretic peptide are studied after administration of placebo or sitagliptin (DPP4 inhibition).

Outcomes

Primary Outcome Measures

The Effect of Enalaprilat (ACE Inhibition), Sitagliptin (DPP4 Inhibition), or the Combination on the Vasodilator Response (Forearm Blood Flow) to Substance P (SP) and Bradykinin (Group 1) or Glucagon Like Peptide-1 and Brain Naturetic Peptide (Group 2).

Forearm blood flow (FBF) was measured by strain gauge plethysmography at the completion of each dose of intra-arterial peptide. A dose response curve was therefore constructed for each vasoactive peptide substrate. The effect of sitagliptin (DPP4 inhibition) vs. placebo and enalaprilat (ACE inhibition) vs. vehicle on the forearm blood flow response to each peptide could then be determined.

Secondary Outcome Measures

Assess Tissue Type Plasminogen Activator (tPA) Release

Following measurement of FBF, samples will be obtained to determine the effect of ACE inhibition and/or DPP4 inhibition on tPA release in response to bradykinin and substance P (SP) (group 1)

Assess Effect of ACE and/or DPP4 Inhibition on Heart Rate Response to Substance P (SP)

Effect of Treatment (ACE or DPP4 Inhibition, or Combined) on Norepinephrine (NE) Release (Arterial Venous Gradient) in Response to Substance P (SP)

Effect of Treatment (DPP4 Inhibition vs. Placebo) on Venous GLP-1 Levels in Response to Arterial GLP-1 Infusion

Full Information

NCT ID

NCT01413542

First Posted

August 8, 2011

Last Updated

October 5, 2015

Sponsor

Vanderbilt University

1. Study Identification

Unique Protocol Identification Number

NCT01413542

Brief Title

Pharmacogenetics of Ace Inhibitor-Associated Angioedema

Official Title

Pharmacogenetics of Ace Inhibitor-Associated Angioedema:Aim 1

Study Type

Interventional

2. Study Status

Record Verification Date

October 2015

Overall Recruitment Status

Completed

Study Start Date

November 2011 (undefined)

Primary Completion Date

July 2013 (Actual)

Study Completion Date

July 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Vanderbilt University

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The investigators would like to find out if sitagliptin (dipeptidyl peptidase-4 or DPP4 inhibition), a drug to treat diabetes, affects blood vessel relaxation in healthy people receiving enalapril (angiotensin converting enzyme or ACE inhibition), a blood pressure medicine. Understanding how these drugs interact in healthy people will help us learn their potential effects in people who have diabetes.

Detailed Description

To test the hypothesis that DPPIV inhibition with sitagliptin potentiates the vasodilator response to substance P in the presence of ACE inhibition with enalaprilat and to BNP and GLP-1 even in the presence of ACE inhibition. The aim promises to provide important new data regarding the mechanism of action of DPPIV inhibitors and interactive effects of these two drug classes used in a growing population of diabetic patients.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hypertension, Diabetes Type 2

Keywords

DPPIV inhibitors, ACE inhibitors, Bradykinin, glucagon-like peptide (GLP-1), BNP, diabetes, hypertension

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Crossover Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

44 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Placebo then sitagliptin (DPP4 inhibition) group 1

Arm Type

Placebo Comparator

Arm Description

The effect of vehicle and enalaprilat on the forearm blood flow and t-PA responses to bradykinin and substance P are studied after administration of placebo or sitagliptin (DPP4 inhibition).

Arm Title

Sitagliptin (DPP4 inhibition) then placebo group 1

Arm Type

Placebo Comparator

Arm Description

Arm Title

Placebo then sitagliptin group 2

Arm Type

Placebo Comparator

Arm Description

Arm Title

Sitagliptin (DPP4 inhibition) then comparator group 2

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Sitagliptin (DPP4 inhibitor)

Other Intervention Name(s)

Januvia

Intervention Description

Sitagliptin 200 mg (DPP4 inhibitor) or matching placebo will be given one hour prior to intra-arterial infusions

Intervention Type

Drug

Intervention Name(s)

Substance P,

Intervention Description

Substance P intra-brachial artery (2,4,8 pmol/min)

Intervention Type

Drug

Intervention Name(s)

bradykinin

Intervention Description

bradykinin intra-brachial artery (23.6, 47.2, and 94.3 pmol/min)

Intervention Type

Drug

Intervention Name(s)

enalaprilat (ACE inhibitor)

Other Intervention Name(s)

vasotec

Intervention Description

intra-brachial artery(0.33 µg/min per 100 mL forearm volume)

Intervention Type

Drug

Intervention Name(s)

Glucagon-like peptide 1

Other Intervention Name(s)

GLP-1

Intervention Description

intra-brachial artery (0.45-3.60 pmol/min)

Intervention Type

Drug

Intervention Name(s)

brain natriuretic peptide

Other Intervention Name(s)

nesiritide

Intervention Description

Intra-brachial artery (0.90, 1.80 and 3.6 pmol/min)

Primary Outcome Measure Information:

Title

Description

Time Frame

60 minutes post-placebo or sitagliptin (DPP4 inhibition) and over last 2 minutes of each 5 min infusion per peptide dose (30 min washout between peptides); sequence repeated with enalaprilat (ACE inhibition) or vehicle

Secondary Outcome Measure Information:

Title

Assess Tissue Type Plasminogen Activator (tPA) Release

Description

Following measurement of FBF, samples will be obtained to determine the effect of ACE inhibition and/or DPP4 inhibition on tPA release in response to bradykinin and substance P (SP) (group 1)

Time Frame

Blood for analysis of tPA release was obtained 60 minutes after sitagliptin (DPP4 inhibition) vs. placebo and after each assessment of FBF (see primary outcome measure)

Title

Assess Effect of ACE and/or DPP4 Inhibition on Heart Rate Response to Substance P (SP)

Time Frame

Heart rate was measured every 5 minutes throughout the study day (and thus during each dose of peptide infusion)

Title

Effect of Treatment (ACE or DPP4 Inhibition, or Combined) on Norepinephrine (NE) Release (Arterial Venous Gradient) in Response to Substance P (SP)

Time Frame

Blood for analysis of norepinephrine (NE) release was obtained 60 minutes after sitagliptin (DPP4 inhibition) vs. placebo and after each assessment of FBF (see primary outcome measure)

Title

Effect of Treatment (DPP4 Inhibition vs. Placebo) on Venous GLP-1 Levels in Response to Arterial GLP-1 Infusion

Time Frame

Blood for analysis of GLP-1 levels was obtained one hour after sitagliptin (DPP4 inhibition) vs. placebo administration and after each dose of GLP-1

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age 18 to 65 inclusive Men and women Black and White Americans BMI <25 For female subjects: Postmenopausal status for at least 1 year Status post surgical sterilization If childbearing potential, utilization of a barrier method of birth control and willingness to undergo blood B-hcg testing prior to drug treatment and on every study day Exclusion Criteria: Smoking Diabetes type 1 or 2, as defined by a fasting glucose of 126 mg/dl or greater or the use of anti-diabetic medication Hypertension as defined by an untreated seated SBP greater than 140 mmHg an untreated DBP greater than 90 mmHg or the use of antihypertensives History of reported or recorded hypoglycemia (plasma glucose less than 70 mg/dl) Pregnancy Breast-feeding Use of hormone replacement therapy The use of contraceptive therapy Use of any medication other than multivitamin Hematocrit <35% Cardiovascular disease such as history of myocardial infarction, presence of angina pectoris, significant arrhythmia, congestive heart failure(LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy Asthma History of angioedema History of cough or other side effect during ACE inhibitor use Impaired renal function, as defined by an eGFR<60ml/min/1.73M2 Clinically significant gastrointestinal impairment that could interfere with drug absorption Impaired hepatic function (aspartate amino transaminase[AST] and/or alanine amino transferase [ALT]>2 x upper limit of normal range History of alcohol or drug abuse Treatment with any investigational drug in the 1 month preceding the study Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study Inability to comply with the protocol, e.g., uncooperative attitude, inability to return to follow-up visits, and the unlikelihood of completing the study

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Nancy J Brown, MD

Organizational Affiliation

Vanderbilt University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Vanderbilt University- General Clinic Research Center

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37232

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

25158865

Citation

Devin JK, Pretorius M, Nian H, Yu C, Billings FT 4th, Brown NJ. Dipeptidyl-peptidase 4 inhibition and the vascular effects of glucagon-like peptide-1 and brain natriuretic peptide in the human forearm. J Am Heart Assoc. 2014 Aug 26;3(4):e001075. doi: 10.1161/JAHA.114.001075.

Results Reference

derived

PubMed Identifier

24516103

Citation

Devin JK, Pretorius M, Nian H, Yu C, Billings FT 4th, Brown NJ. Substance P increases sympathetic activity during combined angiotensin-converting enzyme and dipeptidyl peptidase-4 inhibition. Hypertension. 2014 May;63(5):951-7. doi: 10.1161/HYPERTENSIONAHA.113.02767. Epub 2014 Feb 10.

Results Reference

derived

Learn more about this trial

Pharmacogenetics of Ace Inhibitor-Associated Angioedema

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