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Study of Cardiac MRI in the Follow up Assessment of Patients With PAH (EVITA) (EVITA)

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ClinicalTrials.gov Identifier: NCT02845518
Recruitment Status : Not yet recruiting
First Posted : July 27, 2016
Last Update Posted : July 27, 2016
Sponsor:
Information provided by (Responsible Party):
ARI CHAOUAT, Central Hospital, Nancy, France

Tracking Information
First Submitted Date  ICMJE June 21, 2016
First Posted Date  ICMJE July 27, 2016
Last Update Posted Date July 27, 2016
Study Start Date  ICMJE September 2016
Estimated Primary Completion Date September 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 26, 2016)
Unfavorable hemodynamic status (categorical variable) [ Time Frame: All visits will be pooled as one time point (unfavorable hemodynamic status from baseline to 24-month of follow up) ]
Unfavorable hemodynamic status in RHC is defined by a cardiac index (CI)< 2.5 l/min/m² or a right atrial pressure > 8 mm Hg (currently accepted criteria). Unfavorable hemodynamic status in cMRI is defined by a CI < 2.5 l/min/m² or (right ventricular ejection fraction) RVEF < 35% or an absolute decrease of RVEF of 10% or more. Sensitivity, specificity and 95 % confidence intervals of cMRI to determine an unfavorable hemodynamic status compared to the RHC criteria as the gold standard will be calculated from all couples of measures of cMRI-RHC performed during the study
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: July 26, 2016)
Morbimortality events and comparison of physical/psychological distress due to cMRI and RHC [ Time Frame: From baseline to the end of the study. The end of the study is defined by the 24-month visit of the last patient included. ]
Morbimortality events will be defined as one of the first following
  • 1 .Death from any cause
  • 2 .Lung transplantation
  • 3.Atrial septostomy
  • 4.Worsening of PAH defined by all three following criteria: a decrease in the 6-minute walk distance of at least 15 % from baseline, a worsening of PAH symptoms and an unscheduled hospitalization due to PAH
  • 5.Unsatisfactory status from non-hemodynamic parameters
Physical and psychological distress due to cMRI and RHC will be measured with questionnaires.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Cardiac MRI in the Follow up Assessment of Patients With PAH (EVITA)
Official Title  ICMJE EValuation of Cardiac Magnetic Resonance Imaging in Follow up assessmenT of Patients With Pulmonary Arterial Hypertension (EVITA)
Brief Summary

Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular (RV) failure and eventually to death. The therapeutic strategy has become complex and needs to perform recurring follow up evaluations including a right heart catheterization (RHC).

Cardiac magnetic resonance imaging (cMRI) has the advantage to accurately assess right ventricular (RV) volumes and important prognostic predictors such as cardiac index, stroke volume (SV) and right ventricular ejection fraction (RVEF).

The main objective is to assess the hemodynamic diagnosis performances (sensibility and specificity) at baseline and at follow up visits of cMRI to detect an unfavorable hemodynamic status in comparison with the results of the RHC (current guidelines).

The primary endpoint is: sensitivity and specificity of cMRI for the diagnosis of an unfavorable status defined by the current RHC criteria (with 95% confidence interval).

The secondary objectives are: to identify clinical and hemodynamic variables independently contributing to prognosis, to quantify complications due to cMRI and to RHC and to compare acceptability and tolerability of cMRI over RHC for the patient.

PAH patients will be recruited in 18 centers of the French network of severe pulmonary hypertension in a prospective cohort study.

180 subjects will be enrolled in the study: that size will give the study 90% power to find significant at the 5%-level.

If the primary endpoint were reached, since first, strategies and procedures planed in this project are consistent with those currently used in routine and second, inclusion criteria are not limited to a sub-population of PAH patients, positive results could allow to broadly extending our findings. Therefore, it will be possible to decrease the number of RHC, an invasive and cumbersome procedure without altering the prognosis. Moreover all clinical procedures would be performed in outpatient clinics and thereby would reduce the cost to assess the severity of the disease. Current recommendations for evaluation of severity and follow-up being mainly derived from consensus of opinion of the experts, positive results will also improve the level evidence of severity assessment of PAH patients.

Detailed Description

EValuation of cardiac magnetic resonance Imaging (cMRI) in follow up assessmenT of patients with pulmonary Arterial hypertension (PAH).

Prospective cohort study of cMRI in PAH. Biomedical research 18 centers: CHRU de Nancy, APHP Bicetre hospital, CHRU de Bordeaux, CHRU de Brest, CHRU de Caen, CHRU de Dijon, CHRU de Grenoble, CHRU de Lille, CHRU de Lyon, CHRU de Marseille, CHRU de Montpellier, CHRU de Nice, CHRU de Poitiers, CHRU de Rennes, CHRU de Rouen, CHRU de Strasbourg, CHRU de Toulouse, CHRU de Tours.

Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular (RV) failure and eventually to death. The therapeutic strategy has become complex and needs to perform recurring follow up evaluations including a right heart catheterization (RHC). Although, RHC performed in experience centers has low mortality and low morbidity, repeated invasive pulmonary hemodynamic measurements are burdensome and still presents some risk of complications. Once the diagnosis of PAH is established, follow up evaluation devoted to modify specific therapy relies mainly on RV function parameters. Thus, echocardiography and cardiac magnetic resonance imaging (cMRI) meet many of the criteria of ideal monitoring tools.

Echocardiography is safe, inexpensive and widely available. However, this test has several limitations. Firstly, due to the complexity of the right ventricle chamber, the measurement of RV volumes is difficult. Secondly, criteria are numerous and for quantitative measurements different thresholds are applied without accepted definition. Thirdly, operator dependency could make it difficult to obtain reproducible images.

Cardiac MRI has the advantage to accurately assess RV volumes and important prognostic predictors such as cardiac index, stroke volume (SV) and right ventricular ejection fraction (RVEF).

It has been demonstrated that inter-observer and intra-observer variability for cMRI right ventricle measures in PAH patients were low. In addition, MRI-derived cardiac index, SV and RVEF significantly improved after few months of PAH specific therapy and had prognostic values regardless of changes of pulmonary vascular resistance in few trials of small size.

In a preliminary study performed in the CHRU-Nancy the investigators found a significant correlation between cardiac outputs measured with cMRI and RHC (0.85, p<0.001) in 21 PAH subjects. The agreement between the 2 methods was correct according to Bland-Altman plot.

The purpose of the present study is to investigate a strategy for assessing PAH severity. The investigators propose to replace a currently recommended method, RHC, by cMRI.

The investigators intend to use validated measurements of RV volumes and cardiac output with cMRI in order to demonstrate that cMRI can accurately evaluate the severity of the disease in a follow up strategy.

The objectives of this project are to show that a non-invasive pulmonary hemodynamic evaluation of the disease severity using the cMRI is as effective as RHC, reliable and safe. The originality of this study is to compare in a multicenter study cMRI-derived variables with the currently recommended measurements requiring a RHC.

The main objective is to assess the hemodynamic diagnosis performance (sensibility and specificity) at baseline and at follow up visits of cMRI to detect an unfavorable hemodynamic status in comparison with the results of the RHC.

Diagnostic trial: cardiac MRI compared to RHC (current guidelines).

The secondary objectives are 1) to 5):

  • 1. To assess the predictive value of the first occurrence of morbi-mortality events in 2 different analyses derived, firstly from RHC criteria (cardiac index (CI)< 2.5 l/min/m² or a right atrial pressure > 8 mm Hg) and secondly from cMRI criteria (CI < 2.5 l/min/m² or RVEF < 35% or an absolute decrease of 10% of RVEF at a follow-up evaluation).
  • 2. To assess the univariable association between first morbi-mortality events occurrence and New York Heart Association (NYHA) functional class, 6-minute walk distance, plasma level of B-type natriuretic peptide (BNP)/N-terminal(NT)-proBNP, and continuous hemodynamic variables from cMRI, RHC and echocardiography data collected at baseline and after 4-6 months of follow-up.
  • 3. To assess the multivariable association between first morbi-mortality events occurrence and the above factors, identifying clinical and hemodynamic variables independently contributing to prognosis. Using the results of this analysis the investigators plan to build a multiparameter prognostic score.
  • 4. To quantify complications due to cMRI and to RHC.
  • 5. To compare acceptability and tolerability of cMRI over RHC for the patient.

Primary endpoint:

Sensitivity and specificity of cMRI for the diagnosis of an unfavorable status defined by the current RHC criteria (with 95% confidence interval).

Unfavorable hemodynamic status in RHC are a cardiac index< 2.5 l/min/m² or a right atrial pressure > 8 mm Hg (currently accepted criteria) versus MRI CI < 2.5 l/min/m² or RVEF < 35% or an absolute decrease of 10% of RVEF at a follow-up evaluation.

Secondary endpoints:

In relation to each secondary objectives 1) to 3):

Morbi-mortality events will be defined as one of the first following events, which will be adjudicated by an independent committee: a) death from any cause, b) lung transplantation, c) atrial septostomy, d) worsening of PAH defined by all three following criteria: a decrease in the 6-minute walk distance of at least 15 % from baseline, a worsening of PAH symptoms and an unscheduled hospitalization due to PAH, e) unsatisfactory status from non-hemodynamic parameters at a follow up visit: clinical evidence of right ventricular failure unresponsive to oral diuretic therapy, or NYHA functional class IV or a worsening of functional class from II to III or a 6-minute walk distance < 300 m (in the absence of other causes than PAH), or a very elevated and rising BNP/NT-proBNP.

Adjudication of this morbi-mortality endpoint will be performed blinded of pulmonary hemodynamic follow-up data.

In relation to secondary endpoints 4) and 5) of secondary objective: All adverse events will be collected, physical and psychological distress due to cMRI and RHC will be assessed by questionnaires using Likert scales. The patient will complete these questionnaires few minutes after undergoing cMRI and RHC.

Prospective cohort study PAH patients will be recruited in 18 centers of the French network of severe pulmonary hypertension.

A routine search for conditions known to cause pulmonary hypertension will be performed according to current guidelines. Therefore all patients will undergo at baseline an echocardiography, a RHC and other current routine tests. This will be the screening period. Then all patients selected will sign the written informed consent. Subsequently, in the context of the study, a cMRI will be performed.

According to the current guidelines at the end of the baseline visit PAH-specific drug therapy will be initiated or associated to the treatment already in progress in incident cases and prevalent cases, respectively.

The inclusion phase will last 24 months. A comprehensive severity evaluation will be performed at 4-6 months, after 24 months of follow-up and in case of clinical worsening. According to current guidelines, these assessments will include NYHA functional class, 6-minute walk distance, plasma level of BNP/NT-proBNP and RHC. As part of an ancillary study, 30 ml of venous blood will be collected during all RHC. An echocardiography will be performed at the discretion of the investigator. According to the purpose of the present study, at all these visits a cMRI will also be performed.

All clinical procedures except cMRI are those of standard care.

Morbi-mortality will be collected prospectively until the last patient has completed his 24-month follow up visit.

RHC will be done according as currently recommended.

MRI data interpretation:

MRI protocol and post-processing guidelines will be sent prior to site initiation in order to apply the same method of cMRI in all centers. This will avoid important measurement error.

RV contouring and indexed aortic flow measurement will be performed locally with the dedicated software used in clinical practice by the physicians of each center. Cardiac index and RVEF will be derived from these measures. All cMRI images will be sent and stored at the CHRU Nancy. MRI interpretation will be performed blindly with respect of clinical and RHC data.

All adverse events will be collected during the follow up.

The questionnaire assessing physical and psychological distress will be presented a few minutes after all RHC and all cMRI.

180 subjects will be enrolled in the study: that size will give the study 90% power to find significant at the 5%-level a sensitivity or specificity of:

  • 90% with a lower 95% confidence limit of 75%,
  • 60% with a lower 95% confidence limit of 40%.

General considerations:

Analysis of primary and secondary endpoints will be performed in the intention-to-treat and confirmatory analyses in the per-protocol populations. The 2-tailed significance level will set to p<0.05.

Complications of cMRI and RHC (secondary objective 4) The frequency of adverse events reported during the follow-up will be compared between groups using the Chi-Square test (or Fisher's exact test where requested).

Relative tolerability of cMRI and RHC (secondary objective 5) The investigators will use the Kruskal-Wallis test to determine if the overall physical and psychological distress scores are different across the two groups.

If the primary endpoint were reached, positive results could allow to broadly extending our findings. Therefore, it will be possible to decrease the number of RHC, an invasive and cumbersome procedure without altering the prognosis. Positive results will also improve the level evidence of severity assessment of PAH patients.

According to the secondary objectives the investigators expect to better predict morbi-mortality events with cMRI compared to RHC. Thus a composite score will be constructed including cMRI parameter and will be internally validated. Such a score can then be easily externally validated and widely used.

A biological repository will be carried out including DNA, plasma and serum at baseline and plasma and serum at follow up evaluations. The investigators will apply to other grants for funding this biobank.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Condition  ICMJE Pulmonary Arterial Hypertension
Intervention  ICMJE Procedure: Cardiac magnetic resonance imaging

RV contouring and indexed aortic flow measurement from cMRI will be performed locally with the dedicated software used in clinical practice by the physicians of each centre. Cardiac index and RVEF will be derived from these measures. MRI interpretation will be performed blind with respect of clinical and RHC data.

Right atrial pressure, pulmonary artery pressures and cardiac index will be measured with RHC as currently recommended, therefore performing RHC will not be considered as an intervention but as a routine practice

Study Arms  ICMJE Experimental: cMRI AND RHC
Cardiac Magnetic Resonance Imaging (cMRI) and Right Heart Catheterization (RHC) (the latter being recommended in the current guidelines) in all patients at the baseline visit, at 4-6 months of follow up, at 24 months of follow up and in case of clinical worsening from the baseline visit to 24-month of follow up
Intervention: Procedure: Cardiac magnetic resonance imaging
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: July 26, 2016)
180
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2021
Estimated Primary Completion Date September 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. 18-75 years of age
  2. Incident cases of PAH,
  3. Prevalent cases of PAH diagnosed for less than 12 months when a re-evaluation is indicated including a right heart catheterization,
  4. Idiopathic, heritable PAH,
  5. PAH associated with appetite suppressant, systemic scleroderma, HIV infection or portal hypertension,
  6. PAH associated with repaired (> 1 year) congenital systemic-to-pulmonary shunt,
  7. Patients included in a biomedical trial to test a pharmaceutical treatment will be eligible provided that there is no incompatibility between the 2 studies.

Exclusion Criteria:

  1. Contraindication of cMRI and impossibility to undergo MRI,
  2. Patients not in normal sinus rhythm at baseline,
  3. Patients with pulmonary hypertension due to left heart disease,
  4. Patients with pulmonary hypertension due to lung diseases and/or hypoxemia,
  5. Chronic thromboembolic pulmonary hypertension,
  6. Patients treated with intravenous or subcutaneous prostanoids at baseline or have a formal indication of such treatment after the baseline evaluation,
  7. Comorbidities with a significant impact on the cardiovascular system,
  8. Pregnancy
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02845518
Other Study ID Numbers  ICMJE PHRC-15-0210
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party ARI CHAOUAT, Central Hospital, Nancy, France
Study Sponsor  ICMJE Central Hospital, Nancy, France
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Central Hospital, Nancy, France
Verification Date June 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP