A Trial of Tadalafil and Glycemic Traits

Phase 3 Randomized Trial of Tadalafil and Glycemic Traits

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01444651

Enrollment

Registered

2011-10-03

Start date

2011-08-31

Completion date

2013-03-31

Last updated

2017-01-30

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Cardiovascular Disease, Glucose Intolerance, Insulin Resistance, Obesity

Keywords

Tadalafil, Phosphodiesterase 5 Inhibitors, Cyclic Guanylyl Monophosphate Pathway, Pharmacologic Actions, Vasodilator Agents, Cardiovascular Agents, Obesity, Glycemic Traits, Insulin Resistance, Glucose Metabolism

Brief summary

The purpose of this study is to find out if tadalafil can help overweight and obese people metabolize blood sugar more efficiently. The investigators also want to find out if 20 mg/day of tadalafil for 3 months is safe to take without causing too many side effects. The investigators are plan to enroll 100 subjects at Massachusetts General Hospital (MGH).

Detailed description

This study is examining changes in insulin resistance and glucose tolerance following 3 months of treatment with oral, once daily tadalafil. The investigators primary hypotheses are that measurable decreases in insulin resistance (as measured by HOMA-IR) and increases in insulin sensitivity (as measured by the Matsuda index) will occur following 3 months of treatment with oral tadalafil 20 mg daily compared to placebo. The investigators secondary hypotheses are that improvements in average glycemia (as measured by hemoglobin A1C), pancreatic beta cell function (as measured by the oral disposition index), and body composition (including weight, waist circumference, body mass index, and waist-hip ratio) will occur as a result of tadalafil-mediated changes in the cGMP pathway.

Interventions

DRUGTadalafil

20 mg Tadalafil taken once a day for 3 months

DRUGPlacebo

Placebo tablet taken by mouth once a day for 3 months

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 50 Years

Healthy volunteers

Yes

Inclusion criteria

* Age \> 18 years and \< 50 years * BMI \> 30 kg/m2 * Fasting insulin \> 10 uU/mL

Exclusion criteria

* Systolic blood pressure (SBP) \< 100, \> 150 mmHg * Current anti-hypertensive medication use, including diuretics * Current use of organic nitrates * Current use of PDE-5 inhibitors (sildenafil, tadalafil, vardenafil) * History of reaction to PDE-5 inhibitors * Known HIV infection * Use of medications that strongly alter CYP3A4 activity * History of myocardial infarction, angina, uncontrolled cardiac arrhythmia, stroke, transient ischemic attack, or seizure * Known non-arteritic ischemic optic retinopathy (NAIOR) * History of hearing loss * Estimated glomerular filtration rate (eGFR) \< 60 ml/min/1.73 m2 by the modified diet in renal disease (MDRD) equation * Hepatic transaminase (AST and ALT) levels greater than three times the upper limit of normal * Known pregnancy or those unwilling to avoid pregnancy during the course of the study * History of priapism * Use in excess of four alcoholic drinks daily * History of diabetes mellitus or use of anti-diabetic medications * Known anemia (men, Hct \< 38% and women, Hct \< 36%)

Design outcomes

Primary

Measure	Time frame	Description
Change in Insulin Resistance From Baseline to 3 Months, as Measured by HOMA-IR	Baseline and 3 months	The primary endpoint is defined as the treatment group difference in the change in insulin resistance (baseline HOMA-IR minus 3-month HOMA-IR). HOMA-IR = \[fasting glucose \* fasting insulin\]/405

Secondary

Measure	Time frame	Description
Baseline to 3-month Change in Insulin Sensitivity, as Measured by the Matsuda Index	Baseline and 3 months	The secondary endpoint is defined as the treatment group difference in the change in Matsuda Index (baseline minus 3-month). This index is a measure of insulin resistance derived from a frequently sampled oral glucose tolerance test, obtaining glucose and insulin levels in the fasting state, as well as 30, 60, 90, and 120 min after administration of oral glucose load. Matsuda index = 10,000/SQRT \[fasting glucose\fasting insulin\ (mean glucose from time 30, 60, 90, 120 min) \* (mean insulin at time 30, 60, 90, and 120 min)\]
Baseline to 3-month Change in Endothelial Function Measured by EndoPAT	Baseline and 3 months	Endothelial function was measured using the reactive hyperemia index, acquired using EndoPAT device. Peripheral arterial tonometry probes were placed on both index fingers. After a 5 min equilibration period, a blood pressure cuff was inflated to 200 mmHg and kept inflated for 5 min. The cuff was then rapidly deflated and the reactive hyperemic response pulse volume recorded, where RHI = ratio of hyperemic finger pulse volume (post-cuff inflation / pre-cuff inflation) to control finger pulse volume (post-cuff inflation / pre-cuff inflation)
Insulinogenic Index	Baseline and 3 months	The secondary endpoint is defined as the treatment group difference in the change in insulinogenic index (baseline minus 3-month). This index is thought to reflect insulin secretion, and is derived from fasting and 30 min-post oral glucose tolerance testing glucose and insulin values. Insulinogenic index = \[fasting insulin - insulin at time 30 min\] / \[fasting glucose - glucose at time 30 min\]
Baseline to 3 Month Change in Composite of Insulin Resistance and Sensitivity, as Measured by the Oral Disposition Index	Baseline and 3 months	The secondary endpoint is defined as the treatment group difference in the change in oral disposition index (baseline minus 3-month). This is thought to reflect a composite of both insulin resistance and secretion. Oral disposition index = insulinogenic index / fasting insulin
Baseline to 3-month Change in Matsuda Disposition Index	Baseline and 3 months	Change in disposition index from baseline to 3 months. This index is a composite measure thought to reflect insulin resistance and secretion. Matsuda disposition index = \[Matsuda sensitivity index \* insulinogenic index\]

Countries

United States

Participant flow

Pre-assignment details

111 participants screened, 38 excluded (34 did not meet eligibility criteria, 2 unable to obtain intravenous access, 2 withdrew consent)

Participants by arm

Arm	Count
Tadalafil 20 mg Tadalafil tablet taken by mouth once a day for 3 months Tadalafil: 20 mg Tadalafil taken once a day for 3 months	25
Placebo Placebo tablet taken by mouth once a day for 3 months Placebo: Placebo tablet taken by mouth once a day for 3 months	28
Total	53

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	3	2
Overall Study	Lost to Follow-up	5	5
Overall Study	Missing data	1	1
Overall Study	Non-fasting	2	1

Baseline characteristics

Characteristic	Placebo	Total	Tadalafil
Age, Continuous	34 years STANDARD_DEVIATION 9	33 years STANDARD_DEVIATION 9	33 years STANDARD_DEVIATION 9
Body mass index	36.8 kg/m^2 STANDARD_DEVIATION 6.8	37.7 kg/m^2 STANDARD_DEVIATION 6.8	38.7 kg/m^2 STANDARD_DEVIATION 6.8
Fasting insulin	17 microunits/mL STANDARD_DEVIATION 16	17 microunits/mL STANDARD_DEVIATION 13	17 microunits/mL STANDARD_DEVIATION 10
Gender Female	13 Participants	20 Participants	7 Participants
Gender Male	15 Participants	33 Participants	18 Participants
Region of Enrollment United States	28 participants	53 participants	25 participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	7 / 36	2 / 37
serious Total, serious adverse events	0 / 36	0 / 37

Outcome results

Primary

Change in Insulin Resistance From Baseline to 3 Months, as Measured by HOMA-IR

The primary endpoint is defined as the treatment group difference in the change in insulin resistance (baseline HOMA-IR minus 3-month HOMA-IR). HOMA-IR = \[fasting glucose \* fasting insulin\]/405