Back to resultsStudy of Renin-angiotensin System in Mechanically Ventilated Subjects
Primary Purpose
Acute Lung Injury
Status
Terminated
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
Local standard of care
Mechanical ventilation
Sponsored by
About this trial
This is an interventional diagnostic trial for Acute Lung Injury focused on measuring mechanical ventilation, echocardiography, right ventricular function, Ang (1-7), Ang II, Renin-angiotensin system
Eligibility Criteria
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.
Sites / Locations
- GSK Investigational Site
- GSK Investigational Site
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Mechanically ventilated subjects
Arm Description
Subjects receiving invasive mechanical ventilation (Duration of ventilation <=48 hours) will be evaluated using standard care investigations.
Outcomes
Primary Outcome Measures
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.
Ratio of RV to Left Ventricular (LV) End-diastolic Area (RV Size Ratio)
Right ventricular size ratio was measured using TTE or TOE.
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.
Pulmonary Arterial Systolic Pressure at Indicated Time Points
Pulmonary arterial systolic pressure was measured using TTE or TOE.
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.
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.
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).
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.
Secondary Outcome Measures
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.
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.
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.
Renin-angiotensin System Cascade Biomarker: Ang(1-7) Level
Blood samples were collected for renin-angiotensin system biomarkers at indicated time points.
Renin-angiotensin System Cascade Biomarker: Ang II/ Ang(1-7) Ratio
Blood samples were collected for renin-angiotensin system biomarkers at indicated time points.
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.
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.
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03212690
Brief Title
Study of Renin-angiotensin System in Mechanically Ventilated Subjects
Official Title
Study to Elucidate the Association of the Renin-angiotensin System and Right Ventricular Function in Mechanically Ventilated Patients
Study Type
Interventional
2. Study Status
Record Verification Date
March 2020
Overall Recruitment Status
Terminated
Why Stopped
Study stopped early following termination of associated clinical development program (due to lack of efficacy)
Study Start Date
June 11, 2018 (Actual)
Primary Completion Date
July 8, 2019 (Actual)
Study Completion Date
July 8, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
GlaxoSmithKline
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Lung Injury
Keywords
mechanical ventilation, echocardiography, right ventricular function, Ang (1-7), Ang II, Renin-angiotensin system
7. Study Design
Primary Purpose
Diagnostic
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
57 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Mechanically ventilated subjects
Arm Type
Experimental
Arm Description
Subjects receiving invasive mechanical ventilation (Duration of ventilation <=48 hours) will be evaluated using standard care investigations.
Intervention Type
Drug
Intervention Name(s)
Local standard of care
Intervention Description
Local standard of care will include fluid resuscitation, use of vasopressor drugs and renal support.
Intervention Type
Procedure
Intervention Name(s)
Mechanical ventilation
Intervention Description
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).
Primary Outcome Measure Information:
Title
Renin-angiotensin System Cascade Biomarker to Include Angiotensin (Ang) II Level
Description
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.
Time Frame
Days 1, 2 and 3
Title
Ratio of RV to Left Ventricular (LV) End-diastolic Area (RV Size Ratio)
Description
Right ventricular size ratio was measured using TTE or TOE.
Time Frame
Days 1, 2 and 3
Title
Number of Participants With Paradoxical Septal Motion
Description
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.
Time Frame
Days 1, 2 and 3
Title
Pulmonary Arterial Systolic Pressure at Indicated Time Points
Description
Pulmonary arterial systolic pressure was measured using TTE or TOE.
Time Frame
Days 1, 2 and 3
Title
Right Atrial Pressure at Indicated Time Points
Description
Right atrial pressure is the blood pressure in the right atrium of the heart. Right atrial pressure was measured by TTE or TOE.
Time Frame
Days 1, 2 and 3
Title
Inferior Vena Cava Diameter at End Expiration at Indicated Time Points
Description
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.
Time Frame
Days 1, 2 and 3
Title
Pearson Correlation Coefficient Between PASP and Ang II Level
Description
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).
Time Frame
Up to Day 3
Title
Pearson Correlation Coefficient Between RV Size Ratio and Ang II Level
Description
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.
Time Frame
Up to Day 3
Secondary Outcome Measure Information:
Title
Number of Participants With Pulmonary Circulatory Dysfunction
Description
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.
Time Frame
Days 1, 2 and 3
Title
Number of Participants With Acute Cor Pulmonale
Description
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.
Time Frame
Days 1, 2 and 3
Title
Number of Participants With Severe Acute Cor Pulmonale
Description
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.
Time Frame
Days 1, 2 and 3
Title
Renin-angiotensin System Cascade Biomarker: Ang(1-7) Level
Description
Blood samples were collected for renin-angiotensin system biomarkers at indicated time points.
Time Frame
Days 1, 2 and 3
Title
Renin-angiotensin System Cascade Biomarker: Ang II/ Ang(1-7) Ratio
Description
Blood samples were collected for renin-angiotensin system biomarkers at indicated time points.
Time Frame
Days 1, 2 and 3
Title
Pearson Correlation Coefficient Between PASP and Ang(1-7)
Description
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.
Time Frame
Up to Day 3
Title
Pearson Correlation Coefficient Between PASP and Ang II/Ang(1-7)
Description
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.
Time Frame
Up to Day 3
Title
Pearson Correlation Coefficient Between RV Size Ratio and Ang(1-7)
Description
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.
Time Frame
Up to Day 3
Title
Pearson Correlation Coefficient Between RV Size Ratio and Ang II/Ang(1-7)
Description
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.
Time Frame
Up to Day 3
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
GSK Clinical Trials
Organizational Affiliation
GlaxoSmithKline
Official's Role
Study Director
Facility Information:
Facility Name
GSK Investigational Site
City
Boulogne-Billancourt
ZIP/Postal Code
92100
Country
France
Facility Name
GSK Investigational Site
City
Créteil
ZIP/Postal Code
94000
Country
France
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
IPD for this study will be made available via the Clinical Study Data Request site.
IPD Sharing Time Frame
IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
IPD Sharing Access Criteria
Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted when justified, for up to another 12 months
IPD Sharing URL
http://clinicalstudydatarequest.com
Learn more about this trial
Study of Renin-angiotensin System in Mechanically Ventilated Subjects
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