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Endocrine Cardiomyopathy in Cushing Syndrome: Response to Cyclic GMP PDE5 inhibitOrs (ERGO)

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ClinicalTrials.gov Identifier: NCT02611258
Recruitment Status : Recruiting
First Posted : November 20, 2015
Last Update Posted : January 30, 2018
Sponsor:
Information provided by (Responsible Party):
Andrea M. Isidori, University of Roma La Sapienza

Brief Summary:

Pathophysiology of Cushing's Syndrome (CS) cardiomyopathy is yet unclear and a specific treatment have not been indicated. It was already demonstrated the positive impact of phosphodiesterase type 5A (PDE5A) inhibition in several models of cardiomyopathy and in a model of endocrine cardiomyopathy due to type 2 diabetes mellitus. In this patients with diabetic cardiomyopathy it was demonstrated an improvement in cardiac kinetic, geometry and performance parameters and reduction of the ambulatory measurement of waist circumference.

This represents the first study that evaluate heart remodeling and performance changes and metabolic/immunological/molecular parameters after 5-months of Tadalafil 20 mg in Cushing's Syndrome cardiomyopathy. The proposed research will test whether phosphodiesterase 5A inhibition could become a new target for anti-remodeling drugs and to discover molecular pathways affected by this class of drugs and a network of circulating markers (miRNA) for the early diagnosis of Cushing's Syndrome cardiomyopathy.

The investigators hypothesize that:

  • the signal molecules cGMP and cAMP could underlie the hypertrophic/profibrotic triggers related to this model of endocrine cardiomyopathy and that chronic inhibition of PDE5, activating cGMP signaling pathways, could improve cardiac remodeling due to CS;
  • PDE5 inhibition could have a role in lipolytic regulation;
  • neuroendocrine (e.g. natriuretic peptides) and metabolic markers and chemokines (e.g. MCP-1, TGF-ß) might relate with left ventricular remodeling in CS;
  • there are neuroendocrine (e.g. natriuretic peptides), metabolic markers and chemokines (e.g. MCP-1, TGF-ß) related to cardiac disease in CS;
  • miRNA expression [miR-208a, 499, 1, 133, 126, 29, 233, 222, 4454] might relate with left ventricular remodeling in CS;

Condition or disease Intervention/treatment Phase
Cushing's Syndrome Cardiomyopathy Drug: Tadalafil Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Study on New Insights in Remodeling of Endocrine Cardiomyopathies: Intramyocardial, Molecular and Neuroendocrine Assessment in Response to Chronic Inhibition of Cyclic GMP Phosphodiesterase 5A in Cushing's Syndrome
Actual Study Start Date : July 2016
Estimated Primary Completion Date : January 2019
Estimated Study Completion Date : June 2019


Arm Intervention/treatment
Experimental: Tadalafil
Tadalafil 20 mg to be taken orally once daily, for 5 months
Drug: Tadalafil
Tadalafil 20 mg to be taken orally once daily, for 5 months




Primary Outcome Measures :
  1. Change of Left ventricular torsion (°) evaluated through Cardiac Magnetic Resonance [ Time Frame: Baseline and 5 months after treatment ]

Secondary Outcome Measures :
  1. Change of cardiac strain (σ - longitudinal shortening: strain %) evaluated through Cardiac Magnetic Resonance [ Time Frame: Baseline and 5 months after treatment ]
  2. Quantification of Myocardial fibrosis assessed with T1-mapping through Cardiac Magnetic Resonance [ Time Frame: Baseline and 5 months after treatment ]
  3. Assessment of inflammatory indices (TGF-beta, MCP1) [ Time Frame: Baseline and 5 months after treatment ]
  4. Assessment of endothelial function markers (ET-1, VEGF) [ Time Frame: Baseline and 5 months after treatment ]
  5. Assessment of cardiac remodeling indices (NT-proBNP) [ Time Frame: Baseline and 5 months after treatment ]
  6. Assessment of oxidative stress markers (iNOS, COX2, ROS, P Selectin, ICAM1) in monocytes [ Time Frame: Baseline and 5 months after treatment ]
  7. Assessment of plasmatic levels of cGMP [ Time Frame: Baseline and 5 months after treatment ]
  8. Correlation of biochemical parameters with cardiac parameters assessed through Cardiac Magnetic Resonance [ Time Frame: Baseline and 5 months after treatment ]
  9. Assessment of circulating microRNAs from plasma and white blood cells (miR208, 499, 1, 133, 29, 223, 222, 4454) and correlation of their levels to basal torsion, strain and fibrosis. [ Time Frame: Baseline ]
  10. Changes of circulating miRNAs from plasma and white blood cells (miR208, 499, 1, 133, 29, 223, 222, 4454) [ Time Frame: Baseline and 5 months after treatment ]
  11. Assessment of circulating pro-fibrotic and pro-inflammatory chemokines (MCP-1 and TGF-beta) and correlation to torsion, strain and fibrosis [ Time Frame: Baseline and 5 months after treatment ]
  12. Change of parameters of body composition evaluated by MOC with total body DEXA scan [ Time Frame: Baseline and 5 months after treatment ]


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • age>18 yrs;
  • patients (men and women) with previous diagnosis of Cushing Syndrome (CS), surgically and/or clinically treated according to current guidelines, with stable parameters of CS disease in the last 3 months, and with concomitant cardiac hypertrophy and/or diastolic dysfunction developed independently of CS care and detected by 2D echocardiography;
  • urinary free cortisol (UFC) levels in the normal range for sex and age;
  • normal blood pressure or controlled hypertension

Exclusion Criteria:

  • use of thiazolidinediones, or spironolactone; nitrates, doxazosin, terazosin e prazosin;
  • current use of PDE5 inhibitors or previous (wash out of two months at least);
  • congenital or valvular cardiomyopathy;
  • recent ischemic heart disease or revascularization after a myocardial infarction (MI);
  • contraindications to tadalafil use (hypersensitivity to tadalafil, nitrates use, severe cardiovascular disorders such as unstable angina or severe heart failure, severe hepatic impairment, blood pressure <90/50 mmHg, recent history of stroke or myocardial infarction and known hereditary degenerative retinal disorders such as retinitis pigmentosa);
  • contraindications to CMR.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02611258


Contacts
Contact: Elisa Giannetta, MD - Phd +39 3471482262 elisa.giannetta@uniroma1.it
Contact: Andrea M. Isidori, MD - Phd +39 0649970540 andrea.isidori@uniroma1.it

Locations
Italy
Elisa Giannetta Recruiting
Rome, Italy, 00161
Contact: Carla Di Dato, PhD         
Sub-Investigator: Elisa Giannetta, MD, PhD         
Principal Investigator: Andrea M Isidori, MD,PhD         
Sub-Investigator: Riccardo Pofi, MD         
Sub-Investigator: Carla Di Dato, MD, PhD         
Sub-Investigator: Tiziana Feola, MD         
Sub-Investigator: Daniele Gianfrilli, MD, PhD         
Sub-Investigator: Carlotta Pozza, MD, PhD         
Sub-Investigator: Emilia Sbardella, MD         
Elisa Giannetta Recruiting
Rome, Italy, 00161
Contact: elisa giannetta, MD,PhD         
Contact: Carla Di Dato, MD,PhD         
Sponsors and Collaborators
Andrea M. Isidori
Investigators
Principal Investigator: Elisa Giannetta, MD - Phd Sapienza University of Rome, Policlinico Umberto I, Department of Experimental Medicine

Publications:

Responsible Party: Andrea M. Isidori, MD - PhD, University of Roma La Sapienza
ClinicalTrials.gov Identifier: NCT02611258     History of Changes
Other Study ID Numbers: ERGO
2015-004497-15 ( EudraCT Number )
First Posted: November 20, 2015    Key Record Dates
Last Update Posted: January 30, 2018
Last Verified: January 2018

Keywords provided by Andrea M. Isidori, University of Roma La Sapienza:
Left Ventricular Hypertrophy
Diastolic Dysfunction
Myocardial Fibrosis
Cushing's Syndrome

Additional relevant MeSH terms:
Cushing Syndrome
Syndrome
Cardiomyopathies
Disease
Pathologic Processes
Heart Diseases
Cardiovascular Diseases
Adrenocortical Hyperfunction
Adrenal Gland Diseases
Endocrine System Diseases
Tadalafil
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents