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Obesity and its adverse cardiometabolic consequences are major public health problems. Several features of obesity contribute to the associated cardiovascular risk and are potential targets for intervention. These include insulin resistance and beta cell dysfunction, reduced metabolic rate, and impaired aerobic capacity.The purpose of this study is to examine if the phosphodiesterase type 5A inhibitor tadalafil improves cardiometabolic health in individuals who are obese and insulin resistant.
Obesity is a risk factor for nearly all cardiovascular (CV) disease including coronary artery disease, hypertension, and heart failure. Increased CV risk in obese individuals appears to depend largely on the degree of metabolic dysregulation and metabolic risk factors (glucose intolerance, dyslipidemia, etc.). Notably, interventions that improve insulin sensitivity and cardiorespiratory fitness can reduce CV risk in obese individuals, even in the absence of weight loss.
The cyclic guanylate monophosphate pathway (cGMP) is involved in energy homeostasis and systemic metabolism. Multiple lines of evidence suggest that increasing cGMP activity is beneficial from a metabolic standpoint. Tadalafil is a clinically-available drug that inhibits the enzyme that breaks down cGMP.
The study investigators hypothesize that chronic PDE5 inhibition in obese, insulin-resistant adults will improve cardiometabolic health.
Aim 1: To examine the effect of PDE5 inhibition on energy expenditure. Aim 2: To examine the effect of PDE5 inhibition on insulin sensitivity and secretion.
Aim 3: To examine the effect of PDE5 inhibition on cGMP tone and circulating mediators of cardiometabolic risk.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Tadalafil | Active Comparator | Subjects will be randomized to one of two arms. 100 obese adult subjects will be randomized to the Tadalafil arm following the screening visit. Beginning at their baseline visit, they will receive an oral daily dose of Tadalafil (20mg) that they will take for 12 weeks (through their completion of the study). After randomization has occurred, the active comparator subjects will undergo the following visit protocol: baseline visit (two half-days), an interim visit (6 weeks post-baseline), and a 12-week visit (two half-days). |
|
| Placebo | Placebo Comparator | Subjects will be randomized to one of two arms. 100 obese adult subjects will be randomized to the placebo arm following the screening visit. Beginning at their baseline visit, they will receive an oral daily dose of a placebo pill (20mg) that they will take for 12 weeks (through their completion of the study). After randomization has occurred, the placebo comparator subjects will undergo the following visit protocol: baseline visit (two half-days), an interim visit (6 weeks post-baseline), and a 12-week visit (two half-days). |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tadalafil | Drug | Tadalafil is an FDA approved, clinically-available drug that inhibits the enzyme phosphodiesterase type 5A (PDE5). Subjects who are randomized to this arm will be provided with 20mg of Tadalafil to take every day for 12 weeks, beginning at their baseline visit. |
| Measure | Description | Time Frame |
|---|---|---|
| Resting Energy Expenditure After 12 Weeks of Drug Therapy (kcal/Day) | Subjects will undergo a metabolic chamber protocol to measure resting exercise energy expenditure (kcal/min) at 12 weeks adjusted statistically for the baseline measurement. | 12 weeks |
| Insulin Sensitivity After 12 Weeks of Drug Therapy | Subjects will undergo an insulin modified fasting intravenous glucose tolerance test (FS-IVGTT) protocol at 12 weeks adjusted statistically for the baseline measurement. | 12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Physical Activity-induced Energy Expenditure (kcal/Day) | During the metabolic chamber protocol, conducted at baseline and at 12 weeks, the cardiopulmonary exercise test protocol will be conducted. The Energy Expenditure (EE) related to physical activity will be calculated as peak EE above the resting level while performing the exercise test. | 12 weeks |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Evan L Brittain, MD, MSCI | Vanderbilt Cardiovascular Medicine | Principal Investigator |
| Thomas J Wang, MD | Vanderbilt Cardiovascular Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Vanderbilt University Medical Center | Nashville | Tennessee | 37215 | United States |
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141 participants passed our screening procedures and were enrolled however only 125 were randomized due to dropouts and scheduling conflicts. We allowed up to 30 days between the screening process and the baseline visit. Participants were assigned to a group after the baseline visit.
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| ID | Title | Description |
|---|---|---|
| FG000 | Tadalafil | Subjects will be randomized to one of two arms. 100 obese adult subjects will be randomized to the Tadalafil arm following the screening visit. Beginning at their baseline visit, they will receive an oral daily dose of Tadalafil (20mg) that they will take for 12 weeks (through their completion of the study). After randomization has occurred, the active comparator subjects will undergo the following visit protocol: baseline visit (two half-days), an interim visit (6 weeks post-baseline), and a 12-week visit (two half-days). Tadalafil: Tadalafil is an FDA approved, clinically-available drug that inhibits the enzyme phosphodiesterase type 5A (PDE5). Subjects who are randomized to this arm will be provided with 20mg of Tadalafil to take every day for 12 weeks, beginning at their baseline visit. |
| FG001 | Placebo | Subjects will be randomized to one of two arms. 100 obese adult subjects will be randomized to the placebo arm following the screening visit. Beginning at their baseline visit, they will receive an oral daily dose of a placebo pill (20mg) that they will take for 12 weeks (through their completion of the study). After randomization has occurred, the placebo comparator subjects will undergo the following visit protocol: baseline visit (two half-days), an interim visit (6 weeks post-baseline), and a 12-week visit (two half-days). Placebo: 100 patients will be randomized to receive a placebo pill. Subjects in this arm will be provided with 20mg Placebo to take every day for 12 weeks, beginning at their baseline visit. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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|
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| ID | Title | Description |
|---|---|---|
| BG000 | Tadalafil | Subjects will be randomized to one of two arms. 100 obese adult subjects will be randomized to the Tadalafil arm following the screening visit. Beginning at their baseline visit, they will receive an oral daily dose of Tadalafil (20mg) that they will take for 12 weeks (through their completion of the study). After randomization has occurred, the active comparator subjects will undergo the following visit protocol: baseline visit (two half-days), an interim visit (6 weeks post-baseline), and a 12-week visit (two half-days). Tadalafil: Tadalafil is an FDA approved, clinically-available drug that inhibits the enzyme phosphodiesterase type 5A (PDE5). Subjects who are randomized to this arm will be provided with 20mg of Tadalafil to take every day for 12 weeks, beginning at their baseline visit. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| 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 | Resting Energy Expenditure After 12 Weeks of Drug Therapy (kcal/Day) | Subjects will undergo a metabolic chamber protocol to measure resting exercise energy expenditure (kcal/min) at 12 weeks adjusted statistically for the baseline measurement. | Posted | Mean | Standard Deviation | kcal/day | 12 weeks |
|
Baseline to 12 weeks
Adverse event information was collected for any untoward or unfavorable medical occurrence in a participant, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participant's participation in the research, whether or not considered related to the participant's participation in the research.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Tadalafil | Subjects will be randomized to one of two arms. 100 obese adult subjects will be randomized to the Tadalafil arm following the screening visit. Beginning at their baseline visit, they will receive an oral daily dose of Tadalafil (20mg) that they will take for 12 weeks (through their completion of the study). After randomization has occurred, the active comparator subjects will undergo the following visit protocol: baseline visit (two half-days), an interim visit (6 weeks post-baseline), and a 12-week visit (two half-days). Tadalafil: Tadalafil is an FDA approved, clinically-available drug that inhibits the enzyme phosphodiesterase type 5A (PDE5). Subjects who are randomized to this arm will be provided with 20mg of Tadalafil to take every day for 12 weeks, beginning at their baseline visit. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Back Pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Evan Brittain | Vanderbilt University Medical Center | 6153224382 | evan.brittain@vumc.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 30, 2019 | May 3, 2022 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D009765 | Obesity |
| ID | Term |
|---|---|
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D000068581 | Tadalafil |
| ID | Term |
|---|---|
| D002243 | Carbolines |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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|
| Placebo | Drug | 100 patients will be randomized to receive a placebo pill. Subjects in this arm will be provided with 20mg Placebo to take every day for 12 weeks, beginning at their baseline visit. |
|
| Dual Energy X-Ray Absorptiometry (DEXA) (g) | fat mass at 12 weeks. | 12 weeks |
| Quality of Life Using the Medical Outcomes Study Short-Form Health Survey (SF-36) Physical Component Score | Quality of life will be assessed using the Medical Outcomes Study Short-Form Health Survey (SF-36). The SF-36 is a 36 question survey with a total score range from 0-100; higher scores indicate better quality of life. | 12 weeks |
| Change in cGMP/NP Ratio After 12 Weeks of Drug Therapy | Subjects will undergo a fasting blood draw at baseline and 12 weeks to measure the change in ratio of plasma cyclic guanylate monophosphate pathway (cGMP) to plasma natriuretic peptides (NP) in response to the drug intervention (placebo or tadalafil). | 12 weeks |
| Maximal Oxygen Consumption | Subjects will undergo a symptom-limited cardiopulmonary exercise test to measure peak oxygen consumption (VO2 max). Maximal oxygen consumption will be measured as 'mL/min'. | 12 weeks |
| Sexual Function | The Female Sexual Function Index will be used to measure sexual function in women with a range from 2-36 with higher scores indicating better sexual function. | 12 weeks |
| Maximal Exercise Energy Expenditure (kcal/Day) | Subjects will undergo a metabolic chamber protocol to measure maximal exercise energy expenditure (kcal/min) at 12 weeks adjusted statistically for the baseline measurement. Maximal Exercise Energy Expenditure will be measured as "kcal/day" | 12 weeks |
| Withdrawal by Subject |
|
| BG001 | Placebo | Subjects will be randomized to one of two arms. 100 obese adult subjects will be randomized to the placebo arm following the screening visit. Beginning at their baseline visit, they will receive an oral daily dose of a placebo pill (20mg) that they will take for 12 weeks (through their completion of the study). After randomization has occurred, the placebo comparator subjects will undergo the following visit protocol: baseline visit (two half-days), an interim visit (6 weeks post-baseline), and a 12-week visit (two half-days). Placebo: 100 patients will be randomized to receive a placebo pill. Subjects in this arm will be provided with 20mg Placebo to take every day for 12 weeks, beginning at their baseline visit. |
| BG002 | Total | Total of all reporting groups |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Placebo | Subjects will be randomized to one of two arms. 100 obese adult subjects will be randomized to the placebo arm following the screening visit. Beginning at their baseline visit, they will receive an oral daily dose of a placebo pill (20mg) that they will take for 12 weeks (through their completion of the study). After randomization has occurred, the placebo comparator subjects will undergo the following visit protocol: baseline visit (two half-days), an interim visit (6 weeks post-baseline), and a 12-week visit (two half-days). Placebo: 100 patients will be randomized to receive a placebo pill. Subjects in this arm will be provided with 20mg Placebo to take every day for 12 weeks, beginning at their baseline visit. |
|
|
| Primary | Insulin Sensitivity After 12 Weeks of Drug Therapy | Subjects will undergo an insulin modified fasting intravenous glucose tolerance test (FS-IVGTT) protocol at 12 weeks adjusted statistically for the baseline measurement. | Missing data from 2 participants in the Tadalafil arm, 5 participants in the placebo arm caused by inability to obtain intravenous access, which is necessary to make measurements for this endpoint. | Posted | Median | Inter-Quartile Range | ml/kg/min/μIU ml | 12 weeks |
|
|
|
| Secondary | Physical Activity-induced Energy Expenditure (kcal/Day) | During the metabolic chamber protocol, conducted at baseline and at 12 weeks, the cardiopulmonary exercise test protocol will be conducted. The Energy Expenditure (EE) related to physical activity will be calculated as peak EE above the resting level while performing the exercise test. | Posted | Mean | Standard Deviation | kcal/day | 12 weeks |
|
|
|
| Secondary | Dual Energy X-Ray Absorptiometry (DEXA) (g) | fat mass at 12 weeks. | Posted | Mean | Standard Deviation | grams | 12 weeks |
|
|
|
| Secondary | Quality of Life Using the Medical Outcomes Study Short-Form Health Survey (SF-36) Physical Component Score | Quality of life will be assessed using the Medical Outcomes Study Short-Form Health Survey (SF-36). The SF-36 is a 36 question survey with a total score range from 0-100; higher scores indicate better quality of life. | Posted | Mean | Standard Deviation | score on a scale | 12 weeks |
|
|
|
| Secondary | Change in cGMP/NP Ratio After 12 Weeks of Drug Therapy | Subjects will undergo a fasting blood draw at baseline and 12 weeks to measure the change in ratio of plasma cyclic guanylate monophosphate pathway (cGMP) to plasma natriuretic peptides (NP) in response to the drug intervention (placebo or tadalafil). | Due to lack of funding, the assays required to measure the participant samples were not performed and there is no data to report. | Posted | 12 weeks |
|
|
| Secondary | Maximal Oxygen Consumption | Subjects will undergo a symptom-limited cardiopulmonary exercise test to measure peak oxygen consumption (VO2 max). Maximal oxygen consumption will be measured as 'mL/min'. | Posted | Mean | Standard Deviation | mL/min | 12 weeks |
|
|
|
| Secondary | Sexual Function | The Female Sexual Function Index will be used to measure sexual function in women with a range from 2-36 with higher scores indicating better sexual function. | Test only performed in women as designed. | Posted | Mean | Standard Deviation | score on a scale | 12 weeks |
|
|
|
| Secondary | Maximal Exercise Energy Expenditure (kcal/Day) | Subjects will undergo a metabolic chamber protocol to measure maximal exercise energy expenditure (kcal/min) at 12 weeks adjusted statistically for the baseline measurement. Maximal Exercise Energy Expenditure will be measured as "kcal/day" | Posted | Mean | Standard Deviation | kcal/day | 12 weeks |
|
|
|
| 0 |
| 61 |
| 0 |
| 61 |
| 36 |
| 61 |
| EG001 | Placebo | Subjects will be randomized to one of two arms. 100 obese adult subjects will be randomized to the placebo arm following the screening visit. Beginning at their baseline visit, they will receive an oral daily dose of a placebo pill (20mg) that they will take for 12 weeks (through their completion of the study). After randomization has occurred, the placebo comparator subjects will undergo the following visit protocol: baseline visit (two half-days), an interim visit (6 weeks post-baseline), and a 12-week visit (two half-days). Placebo: 100 patients will be randomized to receive a placebo pill. Subjects in this arm will be provided with 20mg Placebo to take every day for 12 weeks, beginning at their baseline visit. | 0 | 64 | 0 | 64 | 19 | 64 |
| Blood in stool | Gastrointestinal disorders | Systematic Assessment |
|
| Vaginal spotting/breakthrough bleeding | Reproductive system and breast disorders | Systematic Assessment |
|
| Elevated liver enzymes | Hepatobiliary disorders | Systematic Assessment |
|
| Extremity pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Facial cellulitis | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Flu | Infections and infestations | Systematic Assessment |
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| Fluid retention | Renal and urinary disorders | Systematic Assessment |
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| Hair loss | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Headache | Nervous system disorders | Systematic Assessment |
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| Heartburn | Gastrointestinal disorders | Systematic Assessment |
|
| Erections | Reproductive system and breast disorders | Systematic Assessment |
|
| Foot pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Palpitations | Cardiac disorders | Systematic Assessment |
|
| Arm tingling | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Nosebleed | Blood and lymphatic system disorders | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | Systematic Assessment |
|
| Thrush | Gastrointestinal disorders | Systematic Assessment |
|
| Tonsilitis | Gastrointestinal disorders | Systematic Assessment |
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| Urinary urgency | Renal and urinary disorders | Systematic Assessment |
|
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| D001835 |
| Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D026121 |
| Indole Alkaloids |
| D007211 | Indoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006575 | Heterocyclic Compounds, 3-Ring |