A Trial of Tadalafil and Glycemic Traits

• Sponsor: Thomas J. Wang, MD (Other)
• Overall Status: Completed
• CT.gov ID: NCT01444651
• Collaborator: (none)
• Enrollment: 73
• Location: 1
• Arms: 2
• Duration (Months): 19
• Patients Per Site Per Month: 3.8

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Cardiovascular Disease; Insulin Resistance; Glucose Intolerance; Obesity	Drug: Tadalafil; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 73 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Phase 3 Randomized Trial of Tadalafil and Glycemic Traits
• Study Start Date: Aug 1, 2011
• Actual Primary Completion Date: Mar 1, 2013
• Actual Study Completion Date: Mar 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Tadalafil 20 mg Tadalafil tablet taken by mouth once a day for 3 months	Drug: Tadalafil; 20 mg Tadalafil taken once a day for 3 months; Other Names: Adcirca, Cialis
Placebo Comparator: Placebo Placebo tablet taken by mouth once a day for 3 months	Drug: Placebo; Placebo tablet taken by mouth once a day for 3 months; Other Names: Sugar pill

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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)]

2. 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)

3. 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]

4. 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

5. 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]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts 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%)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States

Sponsors and Collaborators

• Thomas J. Wang, MD

Investigators

• Principal Investigator: Thomas J Wang, MD, Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Thomas J. Wang, MD, Associate Professor of Medicine, Harvard Medical School, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT01444651
• Other Study ID Numbers: 2010P-001519
• First Posted: Oct 3, 2011
• Last Update Posted: Jan 30, 2017
• Last Verified: Dec 1, 2016

• Keywords provided by Thomas J. Wang, MD, Associate Professor of Medicine, Harvard Medical School, Massachusetts General Hospital: Tadalafil; Phosphodiesterase 5 Inhibitors; Cyclic Guanylyl Monophosphate Pathway; Pharmacologic Actions; Vasodilator Agents; Cardiovascular Agents; Obesity; Glycemic Traits; Insulin Resistance; Glucose Metabolism
• Additional relevant MeSH terms: Cardiovascular Diseases; Insulin Resistance; Glucose Intolerance; Tadalafil

Study Results

Participant Flow

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

Arm/Group Title	Tadalafil	Placebo
Arm/Group Description	20 mg Tadalafil tablet taken by mouth once a day for 3 months Tadalafil: 20 mg Tadalafil taken once a day for 3 months	Placebo tablet taken by mouth once a day for 3 months Placebo: Placebo tablet taken by mouth once a day for 3 months
Period Title: Overall Study
STARTED	36	37
COMPLETED	25	28
NOT COMPLETED	11	9

Baseline Characteristics

Arm/Group Title	Tadalafil	Placebo	Total
Arm/Group Description	20 mg Tadalafil tablet taken by mouth once a day for 3 months Tadalafil: 20 mg Tadalafil taken once a day for 3 months	Placebo tablet taken by mouth once a day for 3 months Placebo: Placebo tablet taken by mouth once a day for 3 months	Total of all reporting groups
Overall Participants	25	28	53
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33 (9)	34 (9)	33 (9)
Gender (Count of Participants)
Female	7 28%	13 46.4%	20 37.7%
Male	18 72%	15 53.6%	33 62.3%
Region of Enrollment (participants) [Number]
United States	25 100%	28 100%	53 100%
Body mass index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	38.7 (6.8)	36.8 (6.8)	37.7 (6.8)
Fasting insulin (microunits/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [microunits/mL]	17 (10)	17 (16)	17 (13)

Outcome Measures

1. Primary Outcome

Title	Change in Insulin Resistance From Baseline to 3 Months, as Measured by HOMA-IR
Description	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
Time Frame	Baseline and 3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tadalafil	Placebo
Arm/Group Description	20 mg Tadalafil tablet taken by mouth once a day for 3 months Tadalafil: 20 mg Tadalafil taken once a day for 3 months	Placebo tablet taken by mouth once a day for 3 months Placebo: Placebo tablet taken by mouth once a day for 3 months
Measure Participants	25	28
Baseline	3.57 (2.86)	3.84 (3.80)
3 months	3.81 (5.14)	5.06 (3.95)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tadalafil, Placebo
	Comments	Linear regression was used to model the change in HOMA-IR (3 month minus baseline value), comparing tadalafil versus placebo groups after adjusting for baseline HOMA-IR.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.34
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	beta estimate
	Estimated Value	-1.25
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.29
	Estimation Comments

2. Secondary Outcome

Title	Baseline to 3-month Change in Insulin Sensitivity, as Measured by the Matsuda Index
Description	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)]
Time Frame	Baseline and 3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tadalafil	Placebo
Arm/Group Description	20 mg Tadalafil tablet taken by mouth once a day for 3 months Tadalafil: 20 mg Tadalafil taken once a day for 3 months	Placebo tablet taken by mouth once a day for 3 months Placebo: Placebo tablet taken by mouth once a day for 3 months
Measure Participants	25	28
Baseline	3.60 (2.54)	3.51 (2.15)
3 months	4.27 (2.83)	3.28 (2.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tadalafil, Placebo
	Comments	Linear regression was used to model the change in Matsuda Index (3-month minus baseline), comparing tadalafil versus placebo groups after adjusting for baseline value.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.18
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	beta estimate
	Estimated Value	0.96
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.68
	Estimation Comments

3. Secondary Outcome

Title	Baseline to 3-month Change in Endothelial Function Measured by EndoPAT
Description	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)
Time Frame	Baseline and 3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tadalafil	Placebo
Arm/Group Description	20 mg Tadalafil tablet taken by mouth once a day for 3 months Tadalafil: 20 mg Tadalafil taken once a day for 3 months	Placebo tablet taken by mouth once a day for 3 months Placebo: Placebo tablet taken by mouth once a day for 3 months
Measure Participants	25	28
Baseline	2.1 (0.5)	2.3 (0.6)
3-month	2.1 (2.7)	2.2 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tadalafil, Placebo
	Comments	Linear regression was used to model the difference in EndoPAT (3-month minus baseline), comparing tadalafil to placebo groups after adjusting for baseline values.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.76
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	beta estimate
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.58
	Estimation Comments

4. Secondary Outcome

Title	Insulinogenic Index
Description	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]
Time Frame	Baseline and 3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tadalafil	Placebo
Arm/Group Description	20 mg Tadalafil tablet taken by mouth once a day for 3 months Tadalafil: 20 mg Tadalafil taken once a day for 3 months	Placebo tablet taken by mouth once a day for 3 months Placebo: Placebo tablet taken by mouth once a day for 3 months
Measure Participants	25	28
Baseline	0.39 (8.04)	2.17 (2.06)
3-month	2.62 (3.03)	1.04 (2.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tadalafil, Placebo
	Comments	Linear regression was used to model the change in insulinogenic index (3-month minus baseline), comparing tadalafil to placebo groups after adjusting for baseline value.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	beta estimate
	Estimated Value	1.48
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.77
	Estimation Comments

5. Secondary Outcome

Title	Baseline to 3 Month Change in Composite of Insulin Resistance and Sensitivity, as Measured by the Oral Disposition Index
Description	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
Time Frame	Baseline and 3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tadalafil	Placebo
Arm/Group Description	20 mg Tadalafil tablet taken by mouth once a day for 3 months Tadalafil: 20 mg Tadalafil taken once a day for 3 months	Placebo tablet taken by mouth once a day for 3 months Placebo: Placebo tablet taken by mouth once a day for 3 months
Measure Participants	25	28
Baseline	1.74 (11.56)	2.87 (3.67)
3-month	4.48 (4.62)	0.58 (5.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tadalafil, Placebo
	Comments	Linear regression was used to model the change in oral disposition index (3-month minus baseline), comparing tadalafil versus placebo groups after adjusting for baseline value.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	beta estimate
	Estimated Value	3.76
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.38
	Estimation Comments

6. Secondary Outcome

Title	Baseline to 3-month Change in Matsuda Disposition Index
Description	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]
Time Frame	Baseline and 3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tadalafil	Placebo
Arm/Group Description	20 mg Tadalafil tablet taken by mouth once a day for 3 months Tadalafil: 20 mg Tadalafil taken once a day for 3 months	Placebo tablet taken by mouth once a day for 3 months Placebo: Placebo tablet taken by mouth once a day for 3 months
Measure Participants	25	28
Baseline	2.23 (24.19)	6.67 (9.45)
3-month	9.22 (8.51)	0.19 (18.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tadalafil, Placebo
	Comments	Linear regression was used to model the change in Matsuda disposition index (3-month minus baseline), comparing tadalafil to placebo groups after adjusting for baseline value.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	beta estimate
	Estimated Value	8.09
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.05
	Estimation Comments

Adverse Events

Time Frame	Adverse events recorded during study duration (3 months)
Adverse Event Reporting Description	Adverse events ascertained at each follow-up visit
Arm/Group Title	Tadalafil		Placebo
Arm/Group Description	20 mg Tadalafil tablet taken by mouth once a day for 3 months Tadalafil: 20 mg Tadalafil taken once a day for 3 months		Placebo tablet taken by mouth once a day for 3 months Placebo: Placebo tablet taken by mouth once a day for 3 months
All Cause Mortality
	Tadalafil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Tadalafil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/36 (0%)		0/37 (0%)
Other (Not Including Serious) Adverse Events
	Tadalafil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/36 (19.4%)		2/37 (5.4%)
Musculoskeletal and connective tissue disorders
Back or leg pain	2/36 (5.6%)		0/37 (0%)
Headache and back ache	1/36 (2.8%)		0/37 (0%)
arm pain	0/36 (0%)		1/37 (2.7%)
Vascular disorders
Headache	4/36 (11.1%)		0/37 (0%)
Blurry vision and headache	0/36 (0%)		1/37 (2.7%)

Limitations/Caveats

[Not Specified]

More Information

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.