Trial · Interventional

CompletedNot applicableResults postedRegistry data

Pharmacogenetics of Ace Inhibitor-Associated Angioedema

NCTNCT01413542Other idHL079184

Open at ClinicalTrials.govAsk about this trial

Overview

Status: Completed
Phase: Not applicable
Enrollment: 44 participants (actual)
Sponsor: Vanderbilt University · Other
Design: Randomized · Double masking
Countries: 1 country
United States
Start: Nov 2011
Primary completion: Jul 2013
Completion: Jul 2014
First posted: 10 Aug 2011 (estimated)
Last update posted: 4 Nov 2015 (estimated)
Conditions: Hypertension · Diabetes Type 2

Timeline

1 trial · 1 completed · 1 with posted results

Completed
Ongoing
Not yet recruiting
Stopped
Estimated dates (est.)
Results posted

20112012201320142015

N/A
Pharmacogenetics of Ace Inhibitor-Associated Angioedema
NCT01413542
Nov 2011 to Jul 2014

Registry summary

Text and fields below are the sponsor's entries at ClinicalTrials.gov, shown as posted.

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.

Interventions

Sitagliptin (DPP4 inhibitor)Drug
Substance P,Drug
bradykininDrug
enalaprilat (ACE inhibitor)Drug
Glucagon-like peptide 1Drug
brain natriuretic peptideDrug

Arms4

Placebo comparator
Placebo then sitagliptin (DPP4 inhibition) group 1
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).
Placebo comparator
Sitagliptin (DPP4 inhibition) then placebo group 1
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
Placebo comparator
Placebo then sitagliptin group 2
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).
Placebo comparator
Sitagliptin (DPP4 inhibition) then comparator group 2
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).

Primary outcomes1

Outcomes the sponsor listed as primary.

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).
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
Registry description
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 outcomes(4)

Assess Tissue Type Plasminogen Activator (tPA) Release
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)
Registry 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)
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)
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)
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

Posted results

Values are shown as posted at ClinicalTrials.gov, with their units. PepBank has not converted, pooled or compared them.

Primary outcome results

Primary outcomeMean· 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

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).

Group	Value (estimate of difference(ml/min/100ml FBF))
Group 1	6.5
Group 2	NA

Secondary and other outcome results(4)

Secondary outcomeNumber· 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)

Assess Tissue Type Plasminogen Activator (tPA) Release

Group	Value (estimate of difference (ng/min/100mL))
Group 1 (Males)	118.6
Group 1 (Females)	145.5

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

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

Group	Value (beats per minute)	Spread
Group 1	-1.8	1.76

Secondary outcomeMean· 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)

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

Group	Value (pg/mL)	Spread
Group 1	-43.18	8.95

Secondary outcomeMean· 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

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

Group	Value (pmol/L)	Spread
Group 2	5.13	1.05

Adverse events, as posted

Adverse events as posted: participants affected out of participants at risk, by group
Group	Deaths	Serious events	Other events
Group 1 (Placebo Arm)Participants were randomized to sitagliptin 200 mg vs. placebo on each of two study days. On each study day, the effects of vehicle and enalaprilat on forearm blood flow and tPA responses to bradykinin and substance P were studied.	–	0 / 12	3 / 12
Group 1 (Sitagliptin Arm)Participants were randomized to sitagliptin 200 mg vs. placebo on each of two study days. On each study day, the effects of vehicle and enalaprilat on forearm blood flow and tPA responses to bradykinin and substance P were studied.	–	0 / 11	2 / 11
Group 2 (Placebo Arm)Participants were randomized to sitagliptin 200 mg vs. placebo on each of two study days. On each study day, the effect of brain natriuretic peptide and glucagon like receptor-1 (GLP-1) on forearm blood flow and tPA release was studied.	–	0 / 16	3 / 16
Group 2 (Sitagliptin Arm)Participants were randomized to sitagliptin 200 mg vs. placebo on each of two study days. On each study day, the effect of brain natriuretic peptide and glucagon like receptor-1 (GLP-1) on forearm blood flow and tPA release was studied.	–	1 / 14	1 / 14

Each cell reads participants affected / participants at risk, as the registry posted them.

Registry data comes from ClinicalTrials.gov. Study results come from studies, not from the registry. How PepBank works

Studies0

Studies that cite this trial.

No study cites this trial.

Other registry references

References listed at the registry that are not in PepBank. They link to PubMed.

DerivedDevin 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. PMID 25158865
DerivedDevin 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. PMID 24516103

Eligibility

Who could join, as posted.

Sex: All
Age: from 18 Years up to 65 Years
Healthy volunteers: Accepted

Inclusion and exclusion criteria, as posted

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

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