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PDE5 Inhibition for Obesity-Related Cardiometabolic Dysfunction

3 de mayo de 2022 actualizado por: Evan Brittain, Vanderbilt University Medical Center
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.

Descripción general del estudio

Estado

Terminado

Condiciones

Intervención / Tratamiento

Descripción detallada

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.

Tipo de estudio

Intervencionista

Inscripción (Actual)

141

Fase

  • Fase 2

Contactos y Ubicaciones

Esta sección proporciona los datos de contacto de quienes realizan el estudio e información sobre dónde se lleva a cabo este estudio.

Ubicaciones de estudio

  • Estados Unidos
    • Tennessee
      • Nashville, Tennessee, Estados Unidos, 37215
        • Vanderbilt University Medical Center

Criterios de participación

Los investigadores buscan personas que se ajusten a una determinada descripción, denominada criterio de elegibilidad. Algunos ejemplos de estos criterios son el estado de salud general de una persona o tratamientos previos.

Criterio de elegibilidad

Edades elegibles para estudiar

21 años a 50 años (Adulto)

Acepta Voluntarios Saludables

Sí

Géneros elegibles para el estudio

Todos

Descripción

Inclusion Criteria:

  • Adults (ages 21-50)
  • Obesity (BMI ≥ 30 kg/m2)
  • Prediabetes on oral glucose tolerance test.

Exclusion Criteria:

  • Age <21 or > 50
  • BMI < 30 kg/m2
  • 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 breastfeeding 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%)
  • Menopause
  • Inability to exercise on a bicycle
  • Weight > 300 pounds

Plan de estudios

Esta sección proporciona detalles del plan de estudio, incluido cómo está diseñado el estudio y qué mide el estudio.

¿Cómo está diseñado el estudio?

Detalles de diseño

  • Propósito principal: Tratamiento
  • Asignación: Aleatorizado
  • Modelo Intervencionista: Asignación paralela
  • Enmascaramiento: Triple

Armas e Intervenciones

Grupo de participantes/brazo
Intervención / Tratamiento
Comparador activo: 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).
Droga: 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.
Otros nombres:
  • CIALIS
Comparador de placebos: 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).
Droga: 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.

¿Qué mide el estudio?

Medidas de resultado primarias

Medida de resultado
Medida Descripción
Periodo de tiempo
Resting Energy Expenditure After 12 Weeks of Drug Therapy (kcal/Day)
Periodo de tiempo: 12 weeks
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
Periodo de tiempo: 12 weeks
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

Medidas de resultado secundarias

Medida de resultado
Medida Descripción
Periodo de tiempo
Physical Activity-induced Energy Expenditure (kcal/Day)
Periodo de tiempo: 12 weeks
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
Dual Energy X-Ray Absorptiometry (DEXA) (g)
Periodo de tiempo: 12 weeks
fat mass at 12 weeks.
12 weeks
Quality of Life Using the Medical Outcomes Study Short-Form Health Survey (SF-36) Physical Component Score
Periodo de tiempo: 12 weeks
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
Periodo de tiempo: 12 weeks
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
Periodo de tiempo: 12 weeks
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
Periodo de tiempo: 12 weeks
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)
Periodo de tiempo: 12 weeks
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

Colaboradores e Investigadores

Aquí es donde encontrará personas y organizaciones involucradas en este estudio.

Patrocinador

Vanderbilt University Medical Center

Investigadores

  • Investigador principal: Thomas J Wang, MD, Vanderbilt Cardiovascular Medicine
  • Investigador principal: Evan L Brittain, MD, MSCI, Vanderbilt Cardiovascular Medicine

Fechas de registro del estudio

Estas fechas rastrean el progreso del registro del estudio y los envíos de resultados resumidos a ClinicalTrials.gov. Los registros del estudio y los resultados informados son revisados ​​por la Biblioteca Nacional de Medicina (NLM) para asegurarse de que cumplan con los estándares de control de calidad específicos antes de publicarlos en el sitio web público.

Fechas importantes del estudio

Inicio del estudio

1 de julio de 2016

Finalización primaria (Actual)

1 de junio de 2020

Finalización del estudio (Actual)

1 de junio de 2020

Fechas de registro del estudio

Enviado por primera vez

21 de junio de 2016

Primero enviado que cumplió con los criterios de control de calidad

27 de junio de 2016

Publicado por primera vez (Estimar)

30 de junio de 2016

Actualizaciones de registros de estudio

Última actualización publicada (Actual)

27 de mayo de 2022

Última actualización enviada que cumplió con los criterios de control de calidad

3 de mayo de 2022

Última verificación

1 de mayo de 2022

Más información

Términos relacionados con este estudio

Términos MeSH relevantes adicionales

Otros números de identificación del estudio

  • 160208

Plan de datos de participantes individuales (IPD)

¿Planea compartir datos de participantes individuales (IPD)?

SÍ

Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .

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