Study of Renin-angiotensin System in Mechanically Ventilated Subjects

Study Overview
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Brief Summary
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The purpose of this study is to assess whether circulating Angiotensin (Ang) II and Ang (1-7) levels are associated with right ventricular (RV) dysfunction in mechanically ventilated subjects. It is also designed to further characterize the subject population for severity of RV dysfunction. This study will investigate the association of renin-angiotensin system (RAS) peptides and markers of RV function, as measured by echocardiography, in subjects requiring acute mechanical ventilation. Maximum 150 subjects will be enrolled for the study and they will be evaluated over three days period using standard of care investigations, including trans-thoracic echocardiography (TTE) and/or trans-esophageal echocardiography (TOE) echocardiography. The maximum total duration of this study for subjects is 28 days.

Official Title
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Study to Elucidate the Association of the Renin-angiotensin System and Right Ventricular Function in Mechanically Ventilated Patients

Conditions
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Acute Lung Injury

Intervention / Treatment
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* Drug: Local standard of care
* Procedure: Mechanical ventilation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subject must be 18 to 80 years of age inclusive, at the time of enrolment. Subjects who are receiving invasive mechanical ventilation (duration of ventilation less than equal to 48 hours). Body mass index within the range 18.0 - 38.0 kilograms per meter square (kg/m^2, inclusive). Clinical estimate of height and weight is acceptable. Given subjects will be mechanically ventilated upon enrolment, obtaining informed consent directly from the subjects will not be feasible. Consent will be obtained by subject's Legally Acceptable Representative (LAR) or subject will be enrolled upon emergency consent process or subject will be enrolled by signing the informed consent. Exclusion Criteria: Subjects who are moribund or whose clinical condition is deteriorating rapidly or any subject for whom the investigator does not consider there is a reasonable expectation that they will be able to complete the 3 days of observation in the study. Subjects undergoing elective surgery. Investigator will make every effort to ensure that the following exclusion criteria are met; however, in some instances it may not be possible to assess all of these criteria within the 48-hour window. In this case, a subject can be included and investigator will obtain the information when available. Chronic obstructive pulmonary disease (COPD) requiring long term oxygen treatment or home mechanical ventilation. Documented pre-existing chronic pulmonary hypertension. Massive pulmonary embolism (defined by pulmonary embolism with systemic hypotension [defined as a systolic arterial pressure less than 90 mmHg or a drop in systolic arterial pressure of at least 40 mmHg for at least 15 minutes (mins)] which is not caused by new onset arrhythmias) or shock (manifested by evidence of tissue hypo-perfusion and hypoxia, including an altered level of consciousness, oliguria, or cool, clammy extremities). Pulmonary vasculitis or pulmonary hemorrhage including diffuse alveolar hemorrhage. Lung transplantation within last 6 months. Cardiopulmonary arrest during concurrent illness. Any use of RAS modulators including Angiotensin Converting Enzyme (ACE) type 1 inhibitors, Renin inhibitors and Angiotensin Receptor Blockers within 4 days or 5.5 half live whichever is longer. Do not resuscitate status.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mechanically ventilated subjects<br>Subjects receiving invasive mechanical ventilation (Duration of ventilation <=48 hours) will be evaluated using standard care investigations. | Drug: Local standard of care<br>* Local standard of care will include fluid resuscitation, use of vasopressor drugs and renal support.<br>Procedure: Mechanical ventilation<br>* Mechanical ventilation will be based on volume-assist control mode, with a target tidal volume of 6-8 milliliter per kg (mL/kg) and a target plateau pressure of 30 centimeter of water (cmH2O).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renin-angiotensin System Cascade Biomarker to Include Angiotensin (Ang) II Level | Blood samples were collected for renin-angiotensin system biomarkers at indicated time points. Evaluable Population consisted of all participants for whom pulmonary arterial systolic pressure (PASP), ratio of right ventricular to left ventricular end-diastolic area (RV size ratio), Ang II and Ang(1-7) data have been recorded for at least one study time point, and who did not retrospectively withdraw the consent. | Days 1, 2 and 3 | 
| Ratio of RV to Left Ventricular (LV) End-diastolic Area (RV Size Ratio) | Right ventricular size ratio was measured using TTE or TOE. | Days 1, 2 and 3 | 
| Number of Participants With Paradoxical Septal Motion | Paradoxical septal motion is the systolic movement of the interventricular septum toward the RV despite normal thickening. Paradoxical septal motion was measured by TTE or TOE. Number of participants who had paradoxical septal motion have been reported. | Days 1, 2 and 3 | 
| Pulmonary Arterial Systolic Pressure at Indicated Time Points | Pulmonary arterial systolic pressure was measured using TTE or TOE. | Days 1, 2 and 3 | 
| Right Atrial Pressure at Indicated Time Points | Right atrial pressure is the blood pressure in the right atrium of the heart. Right atrial pressure was measured by TTE or TOE. | Days 1, 2 and 3 | 
| Inferior Vena Cava Diameter at End Expiration at Indicated Time Points | Inferior vena cava diameter was measured using TTE or TOE. Pulmonary arterial systolic pressure was estimated from trans-tricuspid pressure and right atrial pressure or inferior vena cava diameter. | Days 1, 2 and 3 | 
| Pearson Correlation Coefficient Between PASP and Ang II Level | Pearson correlation coefficient between PASP and Ang II level was derived using all available data from participants in the evaluable population. Pearson's correlation coefficient is a measure of the linear dependence between 2 variables. A correlation of +1 or -1 may occur if the data from the 2 variables lie exactly on a line. Pearson's correlation coefficient was calculated using Statistical Analysis Software (SAS). | Up to Day 3 | 
| Pearson Correlation Coefficient Between RV Size Ratio and Ang II Level | Pearson correlation coefficient between RV size ratio and Ang II level was derived using all available data from participants in the evaluable population. Pearson's correlation coefficient is a measure of the linear dependence between 2 variables. A correlation of +1 or -1 may occur if the data from the 2 variables lie exactly on a line. Pearson's correlation coefficient was calculated using SAS. | Up to Day 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Pulmonary Circulatory Dysfunction | Pulmonary circulatory dysfunction is defined as moderate dysfunction (pulmonary arterial systolic pressure [>40 millimeters of mercury] or a dilated RV end diastolic RV/left ventricle [LV] area ratio [>=0.6] but without septal dyskinesia). At risk Population consisted of participants who satisfied following criteria: 1. pulmonary arterial systolic pressure and ratio of RV to LV end-diastolic area recorded for all three study days [regardless of the Ang II and Ang(1-7) status] and/or; 2. databased acute cor pulmonale/pulmonary circulatory dysfunction and/or acute respiratory distress syndrome (ARDS) assessment during the study period (even if they do not have three days worth of study assessments for the echo outcomes) were evaluated for acute cor pulmonale/pulmonary circulatory dysfunction and ARDS incidence rates. Number of participants with Pulmonary Circulatory Dysfunction have been reported. | Days 1, 2 and 3 | 
| Number of Participants With Acute Cor Pulmonale | Acute cor pulmonale is defined as a dilated RV in the mid-esophagus longitudinal view or apical 4-chamber view (end-diastolic RV/LV area ratio [0.6]) associated with the presence of a septal dyskinesia in the (transgastric) short-axis view of the heart. Number of participants with acute cor pulmonale have been reported. | Days 1, 2 and 3 | 
| Number of Participants With Severe Acute Cor Pulmonale | Severe acute cor pulmonale is defined as severely dilated RV (end-diastolic RV/LV area ratio >=1) with septal dyskinesia. Number of participants with severe acute cor pulmonale have been reported. | Days 1, 2 and 3 | 
| Renin-angiotensin System Cascade Biomarker: Ang(1-7) Level | Blood samples were collected for renin-angiotensin system biomarkers at indicated time points. | Days 1, 2 and 3 | 
| Renin-angiotensin System Cascade Biomarker: Ang II/ Ang(1-7) Ratio | Blood samples were collected for renin-angiotensin system biomarkers at indicated time points. | Days 1, 2 and 3 | 
| Pearson Correlation Coefficient Between PASP and Ang(1-7) | Pearson correlation coefficient between PASP and Ang(1-7) was derived using all available data from participants in the evaluable population. Pearson's correlation coefficient is a measure of the linear dependence between 2 variables. A correlation of +1 or -1 may occur if the data from the 2 variables lie exactly on a line. Pearson's correlation coefficient was calculated using SAS. | Up to Day 3 | 
| Pearson Correlation Coefficient Between PASP and Ang II/Ang(1-7) | Pearson correlation coefficient between PASP and Ang II/Ang(1-7) was derived using all available data from participants in the evaluable population. Pearson's correlation coefficient is a measure of the linear dependence between 2 variables. A correlation of +1 or -1 may occur if the data from the 2 variables lie exactly on a line. Pearson's correlation coefficient was calculated using SAS. | Up to Day 3 | 
| Pearson Correlation Coefficient Between RV Size Ratio and Ang(1-7) | Pearson correlation coefficient between RV size ratio and Ang(1-7) was derived using all available data from participants in the evaluable population. Pearson's correlation coefficient is a measure of the linear dependence between 2 variables. A correlation of +1 or -1 may occur if the data from the 2 variables lie exactly on a line. Pearson's correlation coefficient was calculated using SAS. | Up to Day 3 | 
| Pearson Correlation Coefficient Between RV Size Ratio and Ang II/Ang(1-7) | Pearson correlation coefficient between RV size ratio and Ang II/Ang(1-7) was derived using all available data from participants in the evaluable population. Pearson's correlation coefficient is a measure of the linear dependence between 2 variables. A correlation of +1 or -1 may occur if the data from the 2 variables lie exactly on a line. Pearson's correlation coefficient was calculated using SAS. | Up to Day 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mechanical ventilation, echocardiography, right ventricular function, Ang (1-7), Ang II, Renin-angiotensin system