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

May 12, 2023 updated by: Andrea M. Isidori

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

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;

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Mechanisms of action and evolutionary progression of Cushing's Syndrome (CS) cardiomyopathy are not yet been well elucidated and a specific treatment has not been identified. Our study aims to characterize the CS cardiomyopathy in terms of measuring the cardiac kinetic and performance parameters (tagged Cardiac Magnetic Resonance Imaging), fibrosis (T1-mapping technique). Our study will evaluate if PDE5A inhibition could become a new target for antiremodeling drugs in CS treated patients that developed cardiac hypertrophy and/or diastolic dysfunction independently of CS care accorded by current guidelines. The investigators also will explore the potential mechanisms of action of PDE5Ai: if exerted on cardiac tissue directly and contemporary also on other secondary pathways (analyzing vascular, endothelial, or metabolic markers).

A multidisciplinary approach will allow identifying a cluster of cardiovascular (NT-ProBNP, TGFb, MCP1) and metabolic indices, oxidative stress markers (iNOS, COX2, ROS, RANTES) and miRNAs, whose variations will analyze together with the CS cardiomyopathy parameters measured at CMR and 2D-echocardiography.

The Primary Objective is to evaluate the effects of PDE5Ai on Left Ventricular (LV) remodeling (kinetic and geometry parameters) at cine cardiac magnetic resonance (CMR) with tagging technique and contrast-enhanced and/or at 2D echocardiography with Tissue Doppler Imaging and speckle tracking in patients with CS cardiomyopathy

Secondary Objectives :

  • to measure the effect of PDE5Ai on LV fibrosis at T1-mapping CMR at baseline and after PDE5Ai administration.
  • to measure the effect of PDE5Ai on cardiac performance at cine CMR and at 2D echocardiography with Tissue Doppler Imaging and speckle tracking at baseline and after PDE5Ai administration.
  • to measure the effect PDE5Ai of circulating cardiac-inflammatory-metabolic-endothelial molecular markers
  • to measure the effect on bone and body composition

Patients will be screened at time 0. Follow up visits will take place every 4 weeks during treatment for 5 months and 1 month after the end of treatment.

Diagnostic procedures will include:

  • physical examination with measurement of anthropometric parameters (weight, waist circumference, hip circumference) and vital signs (blood pressure, heart rate);
  • blood sampling for assessing glucose and lipid metabolism, liver, renal, hematopoietic and coagulative function, thyroid and androgen hormones, ACTH and UFC, inflammatory parameters (cytokines, monocyte subpopulations) and microRNA;
  • SF36, FSFI (in women), IEFF e IPSS (in men) questionnaires;
  • cardiac exam, electrocardiogram and echocardiogram;
  • MOC with DEXA;
  • magnetic resonance imaging (MRI) with contrast-enhanced cardiac: T1-mapping for assessing cardiac fibrosis; tagging for evaluating kinetic parameters (torsion);

This is a pilot study proof-of-concept, then 10 patients are sufficient to detect the effect of PDE5Ai on cardiac remodeling in CS cardiomyopathy. Estimating a 80% drop-out of the study due to the complexity of CS and the related neuro-psychiatric involvement, 18 CS patients will be enrolled.

All variables will be tested for normality. Statistical analyzes will be performed using SPSS 18.0. The comparison before and after treatment will be made by non parametric Wilcoxon test. The investigators will calculate the confidence interval for the prevalence of the effect measured by χ2 test or Fisher exact test. The correlation was perfomed by Rho di Spearman.

Study Type

Interventional

Enrollment (Actual)

18

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Rome, Italy, 00161
        • Elisa Giannetta

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Tadalafil
Tadalafil 20 mg to be taken orally once daily, for 3 months
Drug: Tadalafil
Tadalafil 20 mg to be taken orally once daily, for 3 months
Other Names:
  • Cialis

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change of Left ventricular torsion (°)
Time Frame: Baseline and 3 months after treatment
Change of Left ventricular torsion (°) evaluated through Cardiac Magnetic Resonance
Baseline and 3 months after treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change of cardiac strain (σ - longitudinal shortening: strain %)
Time Frame: Baseline and 3 months after treatment
Change of cardiac strain (σ - longitudinal shortening: strain %) evaluated through Cardiac Magnetic Resonance
Baseline and 3 months after treatment
Quantification of Myocardial fibrosis
Time Frame: Baseline and 3 months after treatment
Quantification of Myocardial fibrosis assessed with T1-mapping through Cardiac Magnetic Resonance
Baseline and 3 months after treatment
Inflammatory indices
Time Frame: Baseline and 3 months after treatment
Assessment of inflammatory indices (e.g. TGF-beta, MCP1)
Baseline and 3 months after treatment
Assessment of endothelial function markers Assessment of endothelial function markers
Time Frame: Baseline and 3 months after treatment
Assessment of endothelial function markers (e.g ET-1, VEGF)
Baseline and 3 months after treatment
NT-proBNP
Time Frame: Baseline and 3 months after treatment
Assessment of NT-proBNP
Baseline and 3 months after treatment
Assessment of oxidative stress markers
Time Frame: Baseline and 3 months after treatment
Assessment of oxidative stress markers (eg iNOS, COX2, ROS, P Selectin, ICAM1)
Baseline and 3 months after treatment
cGMP
Time Frame: Baseline and 3 months after treatment
Assessment of plasmatic levels of cGMP
Baseline and 3 months after treatment
Correlation analysis
Time Frame: Baseline and 3 months after treatment
Correlation of biochemical parameters with cardiac parameters assessed through Cardiac Magnetic Resonance
Baseline and 3 months after treatment
Assessment of circulating microRNAs
Time Frame: Baseline
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.
Baseline
Changes of circulating miRNAs
Time Frame: Baseline and 3 months after treatment
Changes of circulating miRNAs from plasma and white blood cells (miR208, 499, 1, 133, 29, 223, 222, 4454)
Baseline and 3 months after treatment
Assessment of circulating pro-fibrotic and pro-inflammatory chemokines
Time Frame: Baseline and 3 months after treatment
Assessment of circulating pro-fibrotic and pro-inflammatory chemokines (MCP-1 and TGF-beta) and correlation to torsion, strain and fibrosis
Baseline and 3 months after treatment
Body composition
Time Frame: Baseline and 3 months after treatment
Change of parameters of body composition evaluated by MOC with total body DEXA scan
Baseline and 3 months after treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Andrea M. Isidori

Investigators

  • Principal Investigator: Elisa Giannetta, MD - Phd, Sapienza University of Rome, Policlinico Umberto I, Department of Experimental Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 1, 2016

Primary Completion (Actual)

January 1, 2021

Study Completion (Actual)

June 1, 2021

Study Registration Dates

First Submitted

November 16, 2015

First Submitted That Met QC Criteria

November 19, 2015

First Posted (Estimate)

November 20, 2015

Study Record Updates

Last Update Posted (Actual)

May 16, 2023

Last Update Submitted That Met QC Criteria

May 12, 2023

Last Verified

May 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ERGO
  • 2015-004497-15 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Cushing's Syndrome Cardiomyopathy

Clinical Trials on Tadalafil

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Togo

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe