PDE5 Inhibition for Obesity-Related Cardiometabolic Dysfunction
3 mai 2022 mis à jour par: 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.
Aperçu de l'étude
Statut
Complété
Les conditions
Intervention / Traitement
Description détaillée
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.
Type d'étude
Interventionnel
Inscription (Réel)
141
Phase
- Phase 2
Contacts et emplacements
Cette section fournit les coordonnées de ceux qui mènent l'étude et des informations sur le lieu où cette étude est menée.
Lieux d'étude
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Tennessee
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Nashville, Tennessee, États-Unis, 37215
- Vanderbilt University Medical Center
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Critères de participation
Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.
Critère d'éligibilité
Âges éligibles pour étudier
21 ans à 50 ans (Adulte)
Accepte les volontaires sains
Oui
Sexes éligibles pour l'étude
Tout
La description
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 d'étude
Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.
Comment l'étude est-elle conçue ?
Détails de conception
- Objectif principal: Traitement
- Répartition: Randomisé
- Modèle interventionnel: Affectation parallèle
- Masquage: Tripler
Armes et Interventions
Groupe de participants / Bras |
Intervention / Traitement |
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Comparateur actif: 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).
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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.
Autres noms:
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Comparateur 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).
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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.
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Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
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Resting Energy Expenditure After 12 Weeks of Drug Therapy (kcal/Day)
Délai: 12 weeks
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Subjects will undergo a metabolic chamber protocol to measure resting exercise energy expenditure (kcal/min) at 12 weeks adjusted statistically for the baseline measurement.
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12 weeks
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Insulin Sensitivity After 12 Weeks of Drug Therapy
Délai: 12 weeks
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Subjects will undergo an insulin modified fasting intravenous glucose tolerance test (FS-IVGTT) protocol at 12 weeks adjusted statistically for the baseline measurement.
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12 weeks
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Mesures de résultats secondaires
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
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Physical Activity-induced Energy Expenditure (kcal/Day)
Délai: 12 weeks
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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.
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12 weeks
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Dual Energy X-Ray Absorptiometry (DEXA) (g)
Délai: 12 weeks
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fat mass at 12 weeks.
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12 weeks
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Quality of Life Using the Medical Outcomes Study Short-Form Health Survey (SF-36) Physical Component Score
Délai: 12 weeks
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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.
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12 weeks
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Change in cGMP/NP Ratio After 12 Weeks of Drug Therapy
Délai: 12 weeks
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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).
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12 weeks
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Maximal Oxygen Consumption
Délai: 12 weeks
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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'.
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12 weeks
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Sexual Function
Délai: 12 weeks
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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.
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12 weeks
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Maximal Exercise Energy Expenditure (kcal/Day)
Délai: 12 weeks
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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"
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12 weeks
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Collaborateurs et enquêteurs
C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.
Parrainer
Les enquêteurs
- Chercheur principal: Thomas J Wang, MD, Vanderbilt Cardiovascular Medicine
- Chercheur principal: Evan L Brittain, MD, MSCI, Vanderbilt Cardiovascular Medicine
Dates d'enregistrement des études
Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.
Dates principales de l'étude
Début de l'étude
1 juillet 2016
Achèvement primaire (Réel)
1 juin 2020
Achèvement de l'étude (Réel)
1 juin 2020
Dates d'inscription aux études
Première soumission
21 juin 2016
Première soumission répondant aux critères de contrôle qualité
27 juin 2016
Première publication (Estimation)
30 juin 2016
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Réel)
27 mai 2022
Dernière mise à jour soumise répondant aux critères de contrôle qualité
3 mai 2022
Dernière vérification
1 mai 2022
Plus d'information
Termes liés à cette étude
Termes MeSH pertinents supplémentaires
Autres numéros d'identification d'étude
- 160208
Plan pour les données individuelles des participants (IPD)
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