HypertensionNCT01413542
Pharmacogenetics of Ace Inhibitor-Associated Angioedema
A study testing Sitagliptin (DPP4 inhibitor), Substance P, and bradykinin in people with Hypertension and Diabetes Type 2, run by Vanderbilt University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Hypertension, Diabetes Type 2
- What is being tested?
- Sitagliptin (DPP4 inhibitor), Substance P, and bradykinin
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 44 participants
- Where
- 1 siteUnited States
- Study dates
- Nov 2011to Jul 2014
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 21Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Vanderbilt University- General Clinic Research Center
Nashville, Tennessee, 37232
About this study
Official title: Pharmacogenetics of Ace Inhibitor-Associated Angioedema:Aim 1
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.
Read the 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.
- Conditions
- Hypertension, Diabetes Type 2
- Being tested
- Sitagliptin (DPP4 inhibitor), Substance P,, bradykinin, enalaprilat (ACE inhibitor), Glucagon-like peptide 1
- Keywords
- DPPIV inhibitors, ACE inhibitors, Bradykinin, glucagon-like peptide (GLP-1), BNP, diabetes, hypertension
- Medical subject headings
- Hypertension, Diabetes Mellitus, Type 2, Diabetes Mellitus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Sitagliptin (DPP4 inhibitor)Drug
Also called Januvia
Sitagliptin 200 mg (DPP4 inhibitor) or matching placebo will be given one hour prior to intra-arterial infusions
Substance P,Drug
Substance P intra-brachial artery (2,4,8 pmol/min)
bradykininDrug
bradykinin intra-brachial artery (23.6, 47.2, and 94.3 pmol/min)
enalaprilat (ACE inhibitor)Drug
Also called vasotec
intra-brachial artery(0.33 µg/min per 100 mL forearm volume)
Glucagon-like peptide 1Drug
Also called GLP-1
intra-brachial artery (0.45-3.60 pmol/min)
brain natriuretic peptideDrug
Also called nesiritide
Intra-brachial artery (0.90, 1.80 and 3.6 pmol/min)
| Study group | Role | What they receive |
|---|---|---|
| Placebo then sitagliptin (DPP4 inhibition) group 1 | Placebo comparator | 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). Receives: Drug: Sitagliptin (DPP4 inhibitor); Drug: Substance P,; Drug: bradykinin; Drug: enalaprilat (ACE inhibitor) |
| Sitagliptin (DPP4 inhibition) then placebo group 1 | Placebo comparator | 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 Receives: Drug: Sitagliptin (DPP4 inhibitor); Drug: Substance P,; Drug: bradykinin; Drug: enalaprilat (ACE inhibitor) |
| Placebo then sitagliptin group 2 | Placebo comparator | 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). Receives: Drug: Sitagliptin (DPP4 inhibitor); Drug: Glucagon-like peptide 1; Drug: brain natriuretic peptide |
| Sitagliptin (DPP4 inhibition) then comparator group 2 | Placebo comparator | 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). Receives: Drug: Sitagliptin (DPP4 inhibitor); Drug: Glucagon-like peptide 1; Drug: brain natriuretic peptide |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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 outcomes (4)
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)
Measured: 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 Effect of ACE and/or DPP4 Inhibition on Heart Rate Response to Substance P (SP)
Measured: 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)
Measured: 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
Measured: 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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Aug 2011 (estimated)
- Study startNov 2011
- Primary completionJul 2013
- Study completionJul 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for HypertensionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 44 participants (actual)
Sponsor and investigators
- Lead sponsor
- Vanderbilt University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Nancy J. Brown, Vanderbilt University
- Investigators
- Nancy J Brown, MD, Principal investigator, Vanderbilt University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01413542
- Sponsor's protocol ID
- HL079184
- Status last verified
- Oct 2015
- First submitted
- 8 Aug 2011
- Last updated
- 4 Nov 2015
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 25158865Devin 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.
PubMed 24516103
Study at a glance
From the registry record, last updated by the sponsor on 4 Nov 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacogenetics of Ace Inhibitor-Associated Angioedema:Aim 1
- ClinicalTrials.gov ID
- NCT01413542
- Acronym / sponsor ID
- HL079184
- Conditions
- Hypertension, Diabetes Type 2
- Keywords
- DPPIV inhibitors, ACE inhibitors, Bradykinin, glucagon-like peptide (GLP-1), BNP, diabetes, hypertension
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 44 participants (actual)
- Lead sponsor
- Vanderbilt UniversityUniversity, hospital or other
- Study start
- Nov 2011
- Primary completion
- Jul 2013 (actual)
- Study completion
- Jul 2014 (actual)
- First posted
- 10 Aug 2011 (estimated)
- Results
- Posted 4 Nov 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Placebo then sitagliptin (DPP4 inhibition) group 1 | Placebo comparator | Drug: Sitagliptin (DPP4 inhibitor), Drug: Substance P,, Drug: bradykinin, Drug: enalaprilat (ACE inhibitor)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). |
| Sitagliptin (DPP4 inhibition) then placebo group 1 | Placebo comparator | Drug: Sitagliptin (DPP4 inhibitor), Drug: Substance P,, Drug: bradykinin, Drug: enalaprilat (ACE inhibitor)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 then sitagliptin group 2 | Placebo comparator | Drug: Sitagliptin (DPP4 inhibitor), Drug: Glucagon-like peptide 1, Drug: brain natriuretic peptideThe 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). |
| Sitagliptin (DPP4 inhibition) then comparator group 2 | Placebo comparator | Drug: Sitagliptin (DPP4 inhibitor), Drug: Glucagon-like peptide 1, Drug: brain natriuretic peptideThe 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). |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Age 18 to 65 inclusive
- Men and women
- Black and White Americans
- BMI <25
- Postmenopausal status for at least 1 year
Key exclusion criteria (21 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Sitagliptin (DPP4 inhibitor)Also: JanuviaSitagliptin 200 mg (DPP4 inhibitor) or matching placebo will be given one hour prior to intra-arterial infusions | Drug | Placebo then sitagliptin (DPP4 inhibition) group 1, Placebo then sitagliptin group 2, Sitagliptin (DPP4 inhibition) then comparator group 2, Sitagliptin (DPP4 inhibition) then placebo group 1 |
| Substance P,Substance P intra-brachial artery (2,4,8 pmol/min) | Drug | Placebo then sitagliptin (DPP4 inhibition) group 1, Sitagliptin (DPP4 inhibition) then placebo group 1 |
| bradykininbradykinin intra-brachial artery (23.6, 47.2, and 94.3 pmol/min) | Drug | Placebo then sitagliptin (DPP4 inhibition) group 1, Sitagliptin (DPP4 inhibition) then placebo group 1 |
| enalaprilat (ACE inhibitor)Also: vasotecintra-brachial artery(0.33 µg/min per 100 mL forearm volume) | Drug | Placebo then sitagliptin (DPP4 inhibition) group 1, Sitagliptin (DPP4 inhibition) then placebo group 1 |
| Glucagon-like peptide 1Also: GLP-1intra-brachial artery (0.45-3.60 pmol/min) | Drug | Placebo then sitagliptin group 2, Sitagliptin (DPP4 inhibition) then comparator group 2 |
| brain natriuretic peptideAlso: nesiritideIntra-brachial artery (0.90, 1.80 and 3.6 pmol/min) | Drug | Placebo then sitagliptin group 2, Sitagliptin (DPP4 inhibition) then comparator group 2 |
Primary outcome
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
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.
4 secondary outcomes
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)
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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Nov 2015.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 25158865Devin 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.
- Derived from this study: PubMed 24516103Devin 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Nancy J Brown, MD principal investigator
Vanderbilt University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Sitagliptin (DPP4 inhibitor), Substance P, and bradykinin in people with Hypertension and Diabetes Type 2, run by Vanderbilt University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Nov 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 4 Nov 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01413542, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Nov 2015.