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PDE5 Inhibition for Obesity-Related Cardiometabolic Dysfunction

3 de maio de 2022 atualizado 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.

Visão geral do estudo

Status

Concluído

Condições

Intervenção / Tratamento

Descrição detalhada

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 estudo

Intervencional

Inscrição (Real)

141

Estágio

  • Fase 2

Contactos e Locais

Esta seção fornece os detalhes de contato para aqueles que conduzem o estudo e informações sobre onde este estudo está sendo realizado.

Locais de estudo

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

Critérios de participação

Os pesquisadores procuram pessoas que se encaixem em uma determinada descrição, chamada de critérios de elegibilidade. Alguns exemplos desses critérios são a condição geral de saúde de uma pessoa ou tratamentos anteriores.

Critérios de elegibilidade

Idades elegíveis para estudo

21 anos a 50 anos (Adulto)

Aceita Voluntários Saudáveis

Sim

Gêneros Elegíveis para o Estudo

Tudo

Descrição

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

Plano de estudo

Esta seção fornece detalhes do plano de estudo, incluindo como o estudo é projetado e o que o estudo está medindo.

Como o estudo é projetado?

Detalhes do projeto

  • Finalidade Principal: Tratamento
  • Alocação: Randomizado
  • Modelo Intervencional: Atribuição Paralela
  • Mascaramento: Triplo

Armas e Intervenções

Grupo de Participantes / Braço
Intervenção / Tratamento
Comparador Ativo: 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).
Medicamento: 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.
Outros nomes:
  • CIALIS
Comparador de Placebo: 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).
Medicamento: 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.

O que o estudo está medindo?

Medidas de resultados primários

Medida de resultado
Descrição da medida
Prazo
Resting Energy Expenditure After 12 Weeks of Drug Therapy (kcal/Day)
Prazo: 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
Prazo: 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 resultados secundários

Medida de resultado
Descrição da medida
Prazo
Physical Activity-induced Energy Expenditure (kcal/Day)
Prazo: 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)
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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)
Prazo: 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

É aqui que você encontrará pessoas e organizações envolvidas com este estudo.

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

Datas de registro do estudo

Essas datas acompanham o progresso do registro do estudo e os envios de resumo dos resultados para ClinicalTrials.gov. Os registros do estudo e os resultados relatados são revisados ​​pela National Library of Medicine (NLM) para garantir que atendam aos padrões específicos de controle de qualidade antes de serem publicados no site público.

Datas Principais do Estudo

Início do estudo

1 de julho de 2016

Conclusão Primária (Real)

1 de junho de 2020

Conclusão do estudo (Real)

1 de junho de 2020

Datas de inscrição no estudo

Enviado pela primeira vez

21 de junho de 2016

Enviado pela primeira vez que atendeu aos critérios de CQ

27 de junho de 2016

Primeira postagem (Estimativa)

30 de junho de 2016

Atualizações de registro de estudo

Última Atualização Postada (Real)

27 de maio de 2022

Última atualização enviada que atendeu aos critérios de controle de qualidade

3 de maio de 2022

Última verificação

1 de maio de 2022

Mais Informações

Termos relacionados a este estudo

Termos MeSH relevantes adicionais

Outros números de identificação do estudo

  • 160208

Plano para dados de participantes individuais (IPD)

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