Renin-Angiotensin and Fibrinolysis in Humans: Effect of L... | NCT01409993

NCT01409993

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

No data available

No data is available for this block.

Derived Section

Miscellaneous Info Module

Status Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
sildenafil Aim 1	Experimental	sildenafil 25 mg p.o. tid	Drug: Sildenafil Diagnostic Test: Hyperglycemic clamp
placebo Aim 1	Placebo Comparator	matching placebo p.o. tid	Drug: Placebo Diagnostic Test: Hyperglycemic clamp
sildenafil Aim 2	Experimental	sildenafil 25 mg p.o. tid	Drug: Sildenafil Diagnostic Test: Euglycemic clamp
placebo Aim 2	Placebo Comparator	matching placebo p.o. tid	Drug: Placebo Diagnostic Test: Euglycemic clamp

Name	Type	Description	Arm Group Labels	Other Names
Sildenafil	Drug	Sildenafil 25 mg by mouth three times a day for three months	sildenafil Aim 1 sildenafil Aim 2

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Insulin Secretion	in the group of subjects undergoing hyperglycemic clamp (Aim 1)	2.5 hours after 3 months of therapy
Index of Tissue Sensitivity to Insulin	in the group of subjects undergoing hyperglycemic clamp (Aim 1), calculated by dividing the average glucose infusion rate during the last hour of the clamp by the average plasma insulin concentration during the same interval	2.5 hours after 3 months of therapy
Glucose Infusion Rate	In the group of subjects undergoing euglycemic clamp (Aim 2)	2.5 hours after 3 months of therapy

Measure	Description	Time Frame
Fasting Plasma Glucose		3 months
Blood Pressure	Systolic blood pressure	3 months

Eligibility Module

Eligibility Criteria

Inclusion criteria:

Age > 18 years and BMI > 25 kg/M2 (> 23 kg/M2 among Asian Americans) Elevated fasting plasma glucose (100-125 mg/dL) IGT (2 hour plasma glucose 140-199 mg/dL) OR metabolic syndrome and/or hemoglobin A1c 5.7-6.4%

Exclusion criteria:

Diabetes type 1 or type 2, as defined by a fasting glucose of 126 mg/dL or greater, a two hour plasma glucose of 200 mg/dL or greater, or the use of anti-diabetic medication.
The use of nitrates or any disease that might require the use of nitrates.
The use of any potent CYP3A4 inhibitor.
subjects who have participated in a weight-reduction program during the last 6 month or whose weight has increased or decreased more than 2 kg over the preceding 6 months.
Pregnancy. Women of child-bearing potential will be required to have undergone tubal ligation or to be using barrier methods of birth control.
Breast-feeding.
Cardiovascular disease such as myocardial infarction within 6 months prior to enrollment, 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.
Treatment with anticoagulants.
Treatment with metformin.
History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack.
History or presence of immunological or hematological disorders.
Diagnosis of asthma.
Clinically significant gastrointestinal impairment that could interfere with drug absorption.
Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino.

transaminase [ALT] >1.5 x upper limit of normal range)

Impaired renal function (serum creatinine >1.5 mg/dl).
Hematocrit <35%.
Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult.
Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days in

1 month).
Treatment with lithium salts.
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 for follow-up visits, and unlikelihood of completing the study

Name	Affiliation	Role
Nancy J Brown, MD	Vanderbilt University	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Vanderbilt University		Nashville	Tennessee	37232	United States

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
26580240	Background	Ramirez CE, Nian H, Yu C, Gamboa JL, Luther JM, Brown NJ, Shibao CA. Treatment with Sildenafil Improves Insulin Sensitivity in Prediabetes: A Randomized, Controlled Trial. J Clin Endocrinol Metab. 2015 Dec;100(12):4533-40. doi: 10.1210/jc.2015-3415. Epub 2015 Nov 18.
25173047	Derived	Ramirez CE, Shuey MM, Milne GL, Gilbert K, Hui N, Yu C, Luther JM, Brown NJ. Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans. Prostaglandins Other Lipid Mediat. 2014 Oct;113-115:38-44. doi: 10.1016/j.prostaglandins.2014.08.001. Epub 2014 Aug 28.

Arm/Group Information

ID	Title	Description
FG000	Sildenafil Aim 1	sildenafil 25 mg p.o. tid Administration of Sildenafil: Subjects with prediabetes will have a baseline hyperglycemic (Aim 1) and then receive sildenafil for 3 months. Another hyperglycemic will be performed followed by another 3 months off drug and an oral glucose tolerance test.
FG001	Placebo Aim 1	matching placebo p.o. tid Administration of Placebo: Subjects with prediabetes will have a baseline hyperglycemic (Aim 1) and then receive placebo for 3 months. Another hyperglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test.
FG002	Sildenafil Aim 2	Administration of Sildenafil: Subjects with prediabetes will have a baseline hyperinsulinemic euglycemic (Aim 2) and then receive sildenafil for 3 months. Another euglycemic will be performed followed by another 3 months off drug and an oral glucose tolerance test.
FG003	Placebo Aim 2	Administration of Placebo: Subjects with prediabetes will have a baseline hyperinsulinemic euglycemic (Aim 2) and then receive placebo for 3 months. Another euglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Sildenafil	sildenafil 25 mg p.o. tid Administration of sildenafil: Subjects with prediabetes will have a baseline hyperglycemic (Aim 1) or a euglycemic (Aim 2) clamp and then receive sildenafil for 3 months. Another hyperglycemic or euglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Insulin Secretion

in the group of subjects undergoing hyperglycemic clamp (Aim 1)

Glucose-stimulated insulin secretion from 90 to 120 minutes of hyperglycemic clamp

Posted

Mean

Standard Error

microU/mL

2.5 hours after 3 months of therapy

ID	Title	Description
OG000	Sildenafil Aim 1	sildenafil 25 mg p.o. tid Administration of Sildenafil: Subjects with prediabetes will have a baseline hyperglycemic clamp (Aim 1) and then receive sildenafil for 3 months. Another hyperglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test.
OG001	Placebo Aim 1	matching placebo p.o. tid Administration of Placebo: Subjects with prediabetes will have a baseline hyperglycemic clamp (Aim 1) and then receive placebo for 3 months. Another hyperglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Sildenafil - Aims 1 and 2	sildenafil 25 mg p.o. tid Administration of Sildenafil: Subjects with prediabetes will have a baseline hyperglycemic (Aim 1) or a euglycemic (Aim 2) and then receive sildenafil for 3 months. Another hyperglycemic or euglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test.

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
hypertension and bradycardia	Cardiac disorders		Non-systematic Assessment	Patient hospitalized with systolic blood pressure of 190 mm Hg and bradycardia. During hospitalization tested positive for a sympathomimetic drug. Subject was withdrawn from study.

ID	Term
D006943	Hyperglycemia
D044882	Glucose Metabolism Disorders
D008659	Metabolic Diseases
D009750	Nutritional and Metabolic Diseases

ID	Term
D000068677	Sildenafil Citrate
D015309	Glucose Clamp Technique

ID	Term
D013449	Sulfonamides
D000577	Amides
D009930	Organic Chemicals
D013450	Sulfones
D013457