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Pharmacogenetics of Ace Inhibitor-Associated Angioedema

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ClinicalTrials.gov Identifier: NCT01413542
Recruitment Status : Completed
First Posted : August 10, 2011
Results First Posted : November 4, 2015
Last Update Posted : November 4, 2015
Sponsor:
Information provided by (Responsible Party):
Nancy J. Brown, Vanderbilt University

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Conditions Hypertension
Diabetes Type 2
Interventions Drug: Sitagliptin (DPP4 inhibitor)
Drug: Substance P,
Drug: bradykinin
Drug: enalaprilat (ACE inhibitor)
Drug: Glucagon-like peptide 1
Drug: brain natriuretic peptide
Enrollment 44
Recruitment Details  
Pre-assignment Details 44 participants were enrolled in this study (23 in Group 1 and 21 in Group 2) and completed screening procedures. Twelve of 23 participants met inclusion and exclusion criteria and completed all study-related procedures in Group 1. Seventeen of 21 participants met inclusion/exclusion criteria and completed all study-related procedures in Group 2.
Arm/Group Title Placebo Then Sitagliptin (DPP4 Inhibibition)=Group 1 Sitagliptin (DPP4 Inhibition) Then Placebo=Group 1 Placebo Then Sitagliptin (DPP4 Inhibition)=Group 2 Sitagliptin (DPP4 Inhibition) Then Placebo = Group 2
Hide Arm/Group Description Participants first received Placebo then Sitagliptin 200 mg by mouth one time on each of two study days. Two weeks separated each study day. Each study day examined the effect of vehicle and enalaprilat on the forearm blood flow and tPA responses to bradykinin and substance P. Participants first received Sitagliptin 200 mg then Placebo by mouth one time on each of two study days. Two weeks separated each study day. Each study day examined the effect of vehicle and enalaprilat on the forearm blood flow and tPA responses to bradykinin and substance P. Participants first received Placebo then Sitagliptin 200 mg by mouth one time on each of two study days. Two weeks separated each study day. Each study day examined the forearm blood flow and tPA responses to brain natriuretic peptide (BNP) and glucagon-like receptor 1 (GLP-1). Participants first received Sitagliptin 200 mg then Placebo by mouth one time on each of two study days. Two weeks separated each study day. Each study day examined the forearm blood flow and tPA responses to brain natriuretic peptide (BNP) and glucagon-like receptor 1 (GLP-1).
Period Title: Overall Study
Started 6 6 9 8
Completed 5 6 6 7
Not Completed 1 0 3 1
Reason Not Completed
Physician Decision             1             0             3             0
Adverse Event             0             0             0             1
Arm/Group Title Group 1 Group 2 Total
Hide Arm/Group Description 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. 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. Total of all reporting groups
Overall Number of Baseline Participants 12 17 29
Hide Baseline Analysis Population Description
This population represents the 29 participants (12 in Group 1; 17 in Group 2) who passed screening and completed at least one study arm. 1 subject did not complete the 2nd arm in Group 1. 4 subjects did not complete the second arm in Group 2. Results and baseline characteristics are presented inclusive of these patients.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 12 participants 17 participants 29 participants
38.1  (12.0) 35.4  (10.0) 36.5  (10.7)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants 17 participants 29 participants
Female
7
  58.3%
8
  47.1%
15
  51.7%
Male
5
  41.7%
9
  52.9%
14
  48.3%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants 17 participants 29 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
3
  25.0%
5
  29.4%
8
  27.6%
White
9
  75.0%
12
  70.6%
21
  72.4%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 12 participants 17 participants 29 participants
12 17 29
1.Primary Outcome
Title 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).
Hide 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.
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
Hide Outcome Measure Data
Hide Analysis Population Description
In Group 1: Peptide 1=Max dose Bradykinin; Peptide 2=Substance P (SP) In Group 2: Peptide 1=GLP-1; Peptide 2=BNP (FBF expressed as percent change for both peptides) ACE inhibition=enalaprilat DPP4 inhibition=sitagliptin
Arm/Group Title Group 1 Group 2
Hide Arm/Group Description:
Participants were randomized to sitagliptin 200 mg (DPP4 inhibitor) vs. placebo on each of two study days. On each study day, the effects of vehicle and enalaprilat (ACE inhibitor) on forearm blood flow and tPA responses to bradykinin (peptide 1) and substance P (SP) (peptide 2) were studied.
Participants were randomized to sitagliptin 200 mg (DPP4 inhibitor) vs. placebo on each of two study days. On each study day, the effect of study drug on FBF response to glucagon like peptide-1 (peptide 1) and brain natriuretic peptide (peptide 2) was studied.
Overall Number of Participants Analyzed 12 17
Mean (95% Confidence Interval)
Unit of Measure: estimate of difference(ml/min/100ml FBF)
Effect ACE inhibition on FBF response to Peptide 1
6.5
(4.0 to 9.0)
NA [1] 
(NA to NA)
Effect DPP4 inhibition on FBF Response to Peptide1
0.2
(-2.4 to 2.7)
-5.0
(-11.6 to 1.6)
Effect ACE/DPP4 inhibit on FBF response Peptide 1
5.9
(3.3 to 8.4)
NA [1] 
(NA to NA)
Effect DPP4/ACEinhib vs. ACEinhib (FBF to Pep1)
-0.6
(-3.1 to 1.9)
NA [1] 
(NA to NA)
Effect DPP4/ACEinhib vs. DPP4inhib (FBF to Pep1)
5.7
(3.2 to 8.2)
NA [1] 
(NA to NA)
Effect ACE inhibition on FBF response to Peptide 2
0.8
(-0.3 to 2.0)
NA [2] 
(NA to NA)
Effect DPP4 inhibition on FBF response to Peptide2
0.1
(-0.1 to 1.3)
-3.2
(-37.4 to 31.0)
Effect ACE/DPP4 inhibition on Peptide 2 FBF
0.6
(-0.6 to 1.7)
NA [2] 
(NA to NA)
Effect DPP4/ACEinhib vs. ACEinhib (FBF to Pep2)
-0.3
(-1.4 to 0.9)
NA [2] 
(NA to NA)
Effect DPP4/ACEinhib vs. DPP4inhib (FBF to Pep2)
0.4
(-0.8 to 1.6)
NA [2] 
(NA to NA)
[1]
effect of ace inhibition not studied in this group as peptide 1 is not a substrate of ace
[2]
effect of ace inhibition not studied in this group as peptide 2 is not a substrate of ace
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group 1, Group 2
Comments

Group 1: The effect of treatment (placebo, ACE or DPP4 inhibitor, or the combination) on vasodilator response to peptide, measured as forearm blood flow was determined.

Group 2: The effect of treatment (placebo, DPP4 inhibitor) on vasodilator response to peptide, measured as percent change in forearm blood flow was determined.

Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments Effect of ACE inhibition on FBF response to bradykinin (p<0.001). Other comparisons: Effect of DPP4 inhibition on FBF response to bradykinin (p=0.89); Effect of ACE (p=0.16), DPP4 (p=0.82), or combined inhibition (p=0.35) on FBF response to sub P.
Method Mixed Models Analysis
Comments

Effect of DPP4 inhibition on vasodilator response to GLP-1 (p=0.14) or BNP (p=0.85).

p<0.05 threshold for statistical significance.

2.Secondary Outcome
Title Assess Tissue Type Plasminogen Activator (tPA) Release
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Group 1 (Males) Group 1 (Females)
Hide Arm/Group Description:
The effect of ACE inhibition and/or DPP4 inhibition on tPA release in response to bradykinin and substance P (SP) was evaluated.
The effect of ACE inhibition and/or DPP4 inhibition on tPA release in response to bradykinin and substance P (SP) was evaluated.
Overall Number of Participants Analyzed 5 7
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: estimate of difference (ng/min/100mL)
Effect ACE inhibition on bradykinin tPA release
118.6
(78.9 to 158.4)
145.5
(107.0 to 184.1)
Effect of DPP4 inhibition on bradykinintPA release
1.6
(-38.6 to 41.8)
12.9
(-26.5 to 52.3)
Effect of ACE/DPP4 inhibitio on bradykinin tPA
90.9
(50.8 to 131.0)
132.1
(93.8 to 170.5)
effect ace/dpp4 vs. aceinhibi on bradykinin tpa
-27.8
(-68.2 to 12.6)
-13.4
(-52.1 to 25.3)
effect ace/dpp4 vs. dpp4inhib on bradykinin tpa
89.3
(48.5 to 130.1)
119.3
(80.2 to 158.3)
Effect of ACE inhibition on SP tPA release
-15.3
(-41.8 to 11.3)
43.9
(19.8 to 68.1)
Effect of DPP4 inhibition on SP tPA
-25.8
(-52.4 to 0.8)
-29.0
(-53.4 to -4.6)
Effect of ACE+DPP4 inhibition on SP tPA
0.8
(-25.8 to 27.3)
3.8
(-20.5 to 28.2)
effect ace/dpp4 vs. aceinhibi on SP tpa
16.1
(-10.5 to 42.6)
-40.1
(-64.5 to -15.7)
effect ace/dpp4 vs. dpp4inhibi on SP tpa
26.6
(0.0 to 53.1)
32.8
(8.6 to 57.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group 1 (Males), Group 1 (Females)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.02
Comments Effect of DPP4 inhibition on tPA release during sub P in women (p=0.02 vs. placebo).Effect of ACE inhibition on tPA release during sub P in women (p<0.001); effect of DPP4 inhibition on tPA release during sub P and (p=0.001 vs. ACE inhibition alone).
Method Mixed Models Analysis
Comments p<0.05 threshold for statistical significance
3.Secondary Outcome
Title Assess Effect of ACE and/or DPP4 Inhibition on Heart Rate Response to Substance P (SP)
Hide Description [Not Specified]
Time Frame Heart rate was measured every 5 minutes throughout the study day (and thus during each dose of peptide infusion)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Group 1
Hide Arm/Group Description:
The effect of ACE and/or DPP4 inhibition on change in heart rate in response to substance P (SP) was evaluated.
Overall Number of Participants Analyzed 12
Mean (Standard Error)
Unit of Measure: beats per minute
Change in Pulse after SP during Placebo -1.8  (1.76)
Change in Pulse after SP w/ACE inhibition 2.55  (1.04)
Change in Pulse after SP w/DPP4inhibition 0.45  (1.74)
Pulse change after SP w/ACE+DPP4inhibition 4.55  (1.87)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group 1
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.011
Comments Effect of combined ACE and DPP4 inhibition on change in heart rate in response to max dose substance P (p=0.011 vs placebo; ).
Method Wilcoxon signed rank
Comments p<0.05 threshold for statistical significance.
4.Secondary Outcome
Title Effect of Treatment (ACE or DPP4 Inhibition, or Combined) on Norepinephrine (NE) Release (Arterial Venous Gradient) in Response to Substance P (SP)
Hide Description [Not Specified]
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)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Group 1
Hide Arm/Group Description:
Participants were randomized to sitagliptin 200 mg (DPP4 inhibitor) vs. placebo on each of two study days. On each study day, the effects of vehicle and enalaprilat (ACE inhibitor) on forearm blood flow and tPA responses to bradykinin (peptide 1) and substance P (SP) (peptide 2) were studied.
Overall Number of Participants Analyzed 12
Mean (Standard Error)
Unit of Measure: pg/mL
Change NE AV Gradient with SP after placebo -43.18  (8.95)
Change NE AV Gradient with SP after ACEinhibition -52.18  (18.34)
Change NE AV Gradient with SP after DPP4inhibition -37.27  (12.21)
Change NE AV with SP after ACE+DPPinhibition 23.45  (31.47)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group 1
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.05
Comments Effect of combined DPP4 and ACE inhibition on the change in the norepinephrine AV gradient during substance P as compared to treatment with placebo.
Method Wilcoxon signed rank
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group 1
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.007
Comments Effect of combined DPP4 and ACE inhibition on the change in the norepinephrine AV gradient during substance P as compared to treatment with ACE inhibition alone (p=0.007).
Method Wilcoxon signed rank
Comments [Not Specified]
5.Secondary Outcome
Title Effect of Treatment (DPP4 Inhibition vs. Placebo) on Venous GLP-1 Levels in Response to Arterial GLP-1 Infusion
Hide Description [Not Specified]
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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Group 2
Hide Arm/Group Description:
The effect of treatment (placebo vs. DPP4 inhibition) on venous GLP-1 levels during intra-arterial GLP-1 infusion.
Overall Number of Participants Analyzed 14
Mean (Standard Error)
Unit of Measure: pmol/L
Venous GLP-1 levels 1 hour after placebo 5.13  (1.05)
Venous GLP-1 Levels after Max Dose GLP-1 (Placebo) 15.44  (2.94)
Venous GLP-1 levels 1 hour after DPP4 inhibition 5.39  (0.99)
Venous GLP-1 levels Max Dose GLP-1 (DPP4inhibiton) 30.63  (3.40)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group 2
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.01
Comments Effect of intra-arterial GLP-1 on venous GLP-1 concentrations during placebo (p=0.01).
Method wilxocon signed rank test
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group 2
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.01
Comments Effect of intra-arterial GLP-1 on venous GLP-1 concentrations during sitagliptin (p=0.01).
Method Wilcoxon signed rank
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Group 2
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.04
Comments Effect of DPP4 inhibition on venous GLP-1 levels at high dose of intra-arterial GLP-1 (p=0.04 vs. placebo).
Method Wilcoxon signed rank
Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description

1 Subject (Group 1) did not complete sitagliptin arm due to inability to establish arterial access.

1 Subject (Group 2) did not complete placebo arm because the Investigator withdrew them after Serious Adverse Event.

3 Subjects (Group 2) did not complete the sitagliptin arm due to inability to establish arterial access during the sitagliptin arm.

 
Arm/Group Title Group 1 (Placebo Arm) Group 1 (Sitagliptin Arm) Group 2 (Placebo Arm) Group 2 (Sitagliptin Arm)
Hide Arm/Group Description 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. 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. 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. 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.
All-Cause Mortality
Group 1 (Placebo Arm) Group 1 (Sitagliptin Arm) Group 2 (Placebo Arm) Group 2 (Sitagliptin Arm)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Group 1 (Placebo Arm) Group 1 (Sitagliptin Arm) Group 2 (Placebo Arm) Group 2 (Sitagliptin Arm)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/12 (0.00%)      0/11 (0.00%)      0/16 (0.00%)      1/14 (7.14%)    
Blood and lymphatic system disorders         
Orthostasis with Syncopal Event *  0/12 (0.00%)  0 0/11 (0.00%)  0 0/16 (0.00%)  0 1/14 (7.14%)  1
*
Indicates events were collected by non-systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Group 1 (Placebo Arm) Group 1 (Sitagliptin Arm) Group 2 (Placebo Arm) Group 2 (Sitagliptin Arm)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/12 (25.00%)      2/11 (18.18%)      3/16 (18.75%)      1/14 (7.14%)    
Blood and lymphatic system disorders         
Swelling of instrumented arm * [1]  0/12 (0.00%)  0 1/11 (9.09%)  1 0/16 (0.00%)  0 0/14 (0.00%)  0
Transient Lightheadedness *  2/12 (16.67%)  2 1/11 (9.09%)  1 2/16 (12.50%)  2 1/14 (7.14%)  1
Nervous system disorders         
Neuropraxia in the instrumented arm * [2]  0/12 (0.00%)  0 0/11 (0.00%)  0 1/16 (6.25%)  1 0/14 (0.00%)  0
Renal and urinary disorders         
Nephrolithiasis * [3]  1/12 (8.33%)  1 0/11 (0.00%)  0 0/16 (0.00%)  0 0/14 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
[1]
One woman experienced angioedema of the instrumented forearm after infusion of bradykinin and substance P on the sitagliptin treatment day.
[2]
Resolved over 2 weeks without therapy.
[3]
Within 2 weeks of completion of first study day.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Nancy J. Brown
Organization: Department of Medicine Vanderbilt University Medical Center
Phone: 615-343-8701
EMail: nancy.j.brown@vanderbilt.edu
Layout table for additonal information
Responsible Party: Nancy J. Brown, Vanderbilt University
ClinicalTrials.gov Identifier: NCT01413542     History of Changes
Obsolete Identifiers: NCT00139503
Other Study ID Numbers: HL079184
First Submitted: August 8, 2011
First Posted: August 10, 2011
Results First Submitted: November 7, 2014
Results First Posted: November 4, 2015
Last Update Posted: November 4, 2015