Trial Outcomes & Findings for Renin-Angiotensin and Fibrinolysis in Humans: Effect of Long-Term PDE5 Inhibition on Glucose Homeostasis (NCT NCT01409993)

NCT ID: NCT01409993

Last Updated: 2017-04-17

Results Overview

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

• Recruitment status: TERMINATED
• Study phase: PHASE4
• Target enrollment: 78 participants
• Primary outcome timeframe: 2.5 hours after 3 months of therapy
• Results posted on: 2017-04-17

Participant Flow

Participant milestones

Measure	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.	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.	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.	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.
Overall Study STARTED	25	26	14	13
Overall Study COMPLETED	21	21	11	8
Overall Study NOT COMPLETED	4	5	3	5

Reasons for withdrawal

Measure	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.	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.	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.	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.
Overall Study Adverse Event	4	4	3	1
Overall Study Withdrawal by Subject	0	0	0	4
Overall Study Lost to Follow-up	0	1	0	0

Baseline Characteristics

Renin-Angiotensin and Fibrinolysis in Humans: Effect of Long-Term PDE5 Inhibition on Glucose Homeostasis

Baseline characteristics by cohort

Measure	Sildenafil n=39 Participants 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.	Placebo n=39 Participants matching placebo p.o. tid Administration of placebo: Subjects with prediabetes will have a baseline hyperglycemic (Aim 1) or a euglycemic (Aim 2) clamp and then receive sildenafil or placebo for 3 months. Another hyperglycemic or euglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test.	Total n=78 Participants Total of all reporting groups
Age, Continuous	48.4 years STANDARD_DEVIATION 10.6 • n=5 Participants	51.0 years STANDARD_DEVIATION 10.6 • n=7 Participants	49.58 years STANDARD_DEVIATION 10.80 • n=5 Participants
Sex: Female, Male Female	24 Participants n=5 Participants	26 Participants n=7 Participants	50 Participants n=5 Participants
Sex: Female, Male Male	15 Participants n=5 Participants	13 Participants n=7 Participants	28 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	9 Participants n=5 Participants	7 Participants n=7 Participants	16 Participants n=5 Participants
Race (NIH/OMB) White	29 Participants n=5 Participants	32 Participants n=7 Participants	61 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	39 participants n=5 Participants	39 participants n=7 Participants	78 participants n=5 Participants

PRIMARY outcome

Timeframe: 2.5 hours after 3 months of therapy

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

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

Outcome measures

Measure	Sildenafil Aim 1 n=21 Participants 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.	Placebo Aim 1 n=21 Participants 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.	Sildenafil Aim 2 sildenafil 25 mg p.o. tid Sildenafil: Subjects with prediabetes will have a baseline euglycemic clamp (Aim 2) and then receive sildenafil for 3 months. Another euglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test.	Placebo Aim 2 matching placebo p.o. tid Placebo: Subjects with prediabetes will have a baseline euglycemic clamp (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.
Insulin Secretion	109.4 microU/mL Standard Error 85	103.1 microU/mL Standard Error 67.7	—	—

PRIMARY outcome

Timeframe: 2.5 hours after 3 months of therapy

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

Outcome measures

Measure	Sildenafil Aim 1 n=21 Participants 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.	Placebo Aim 1 n=21 Participants 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.	Sildenafil Aim 2 sildenafil 25 mg p.o. tid Sildenafil: Subjects with prediabetes will have a baseline euglycemic clamp (Aim 2) and then receive sildenafil for 3 months. Another euglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test.	Placebo Aim 2 matching placebo p.o. tid Placebo: Subjects with prediabetes will have a baseline euglycemic clamp (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.
Index of Tissue Sensitivity to Insulin	6.45 (mg/kg/min per microU/mL)*100 Standard Error 0.661	4.66 (mg/kg/min per microU/mL)*100 Standard Error 0.661	—	—

PRIMARY outcome

Timeframe: 2.5 hours after 3 months of therapy

Population: one subject in the sildenafil Aim 2 arm has incomplete data from the three-month clamp due to infusion dysfunction

In the group of subjects undergoing euglycemic clamp (Aim 2)

Outcome measures

Measure	Sildenafil Aim 1 n=11 Participants 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.	Placebo Aim 1 n=7 Participants 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.	Sildenafil Aim 2 sildenafil 25 mg p.o. tid Sildenafil: Subjects with prediabetes will have a baseline euglycemic clamp (Aim 2) and then receive sildenafil for 3 months. Another euglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test.	Placebo Aim 2 matching placebo p.o. tid Placebo: Subjects with prediabetes will have a baseline euglycemic clamp (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.
Glucose Infusion Rate	140.45 mL/hr Standard Deviation 38.38	162.61 mL/hr Standard Deviation 64.49	—	—

SECONDARY outcome

Timeframe: 3 months

Outcome measures

Measure	Sildenafil Aim 1 n=21 Participants 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.	Placebo Aim 1 n=21 Participants 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.	Sildenafil Aim 2 n=11 Participants sildenafil 25 mg p.o. tid Sildenafil: Subjects with prediabetes will have a baseline euglycemic clamp (Aim 2) and then receive sildenafil for 3 months. Another euglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test.	Placebo Aim 2 n=8 Participants matching placebo p.o. tid Placebo: Subjects with prediabetes will have a baseline euglycemic clamp (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.
Fasting Plasma Glucose	98.6 mg/dL Standard Deviation 11.7	96.9 mg/dL Standard Deviation 7.6	98.8 mg/dL Standard Deviation 6.5	97.5 mg/dL Standard Deviation 11.1

SECONDARY outcome

Timeframe: 3 months

Systolic blood pressure

Outcome measures

Measure	Sildenafil Aim 1 n=21 Participants 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.	Placebo Aim 1 n=21 Participants 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.	Sildenafil Aim 2 n=11 Participants sildenafil 25 mg p.o. tid Sildenafil: Subjects with prediabetes will have a baseline euglycemic clamp (Aim 2) and then receive sildenafil for 3 months. Another euglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test.	Placebo Aim 2 n=8 Participants matching placebo p.o. tid Placebo: Subjects with prediabetes will have a baseline euglycemic clamp (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.
Blood Pressure	122 mmHg Standard Deviation 17.2	123.1 mmHg Standard Deviation 14.6	114.3 mmHg Standard Deviation 11.6	112.5 mmHg Standard Deviation 22.6

Adverse Events

Sildenafil - Aims 1 and 2

Serious events: 1 serious events

Other events: 32 other events

Deaths: 0 deaths

Placebo - Aims 1 and 2

Serious events: 0 serious events

Other events: 25 other events

Deaths: 0 deaths

Serious adverse events

Measure	Sildenafil - Aims 1 and 2 n=39 participants at risk 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.	Placebo - Aims 1 and 2 n=39 participants at risk matching placebo p.o. tid Administration of Placebo: Subjects with prediabetes will have a baseline hyperglycemic (Aim 1) or a euglycemic (Aim 2) and then receive placebo for 3 months. Another hyperglycemic or euglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test.
Cardiac disorders hypertension and bradycardia	2.6% 1/39 • Number of events 38	0.00% 0/39

Other adverse events

Measure	Sildenafil - Aims 1 and 2 n=39 participants at risk 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.	Placebo - Aims 1 and 2 n=39 participants at risk matching placebo p.o. tid Administration of Placebo: Subjects with prediabetes will have a baseline hyperglycemic (Aim 1) or a euglycemic (Aim 2) and then receive placebo for 3 months. Another hyperglycemic or euglycemic clamp will be performed followed by another 3 months off drug and an oral glucose tolerance test.
Nervous system disorders headache	38.5% 15/39	28.2% 11/39
Musculoskeletal and connective tissue disorders Musculoskeletal pain	30.8% 12/39	25.6% 10/39
Respiratory, thoracic and mediastinal disorders Upper respiratory tract infection	28.2% 11/39	33.3% 13/39
Gastrointestinal disorders Gastrointestinal symptoms	28.2% 11/39	15.4% 6/39
Vascular disorders Flushing	12.8% 5/39	2.6% 1/39
General disorders Lightheadeness	10.3% 4/39	2.6% 1/39
General disorders Edema	5.1% 2/39	0.00% 0/39
General disorders Weight gain	5.1% 2/39	0.00% 0/39
Nervous system disorders Smell or taste abnormality	5.1% 2/39	0.00% 0/39
Reproductive system and breast disorders abnormal uterine bleeding	0.00% 0/39	5.1% 2/39
Surgical and medical procedures transient numbness	0.00% 0/39	5.1% 2/39

Additional Information

Nancy J. Brown, M.D., Principal Investigator

Vanderbilt University Medical Center

Phone: 6153438701

Email: nancy.j.brown@vanderbilt.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place