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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT04166331
Other study ID # 87RI18_0012 (ADAPT)
Secondary ID
Status Recruiting
Phase Phase 3
First received
Last updated
Start date September 20, 2020
Est. completion date December 20, 2024

Study information

Verified date December 2023
Source University Hospital, Limoges
Contact VIGNON Philippe, MD
Phone 555054040
Email philippe.vignon@chu-limoges.fr
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

Sepsis induces both a systolic and diastolic cardiac dysfunction. The prevalence of this septic cardiomyopathy ranges between 30 and 60% according to the timing of assessment and definition used. Although the prognostic role of septic cardiomyopathy remains debated, sepsis-induced left ventricular (LV) systolic dysfunction may be severe and associated with tissue hypoperfusion, while it appears to fully recover in survivors. Accordingly, optimization of therapeutic management of septic cardiomyopathy may contribute to improve tissue hypoperfusion in increasing oxygen delivery, and to reduce related organ dysfunctions in septic shock patients. Echocardiography is currently the recommended first-line modality to assess patients with acute circulatory failure. Current Surviving Sepsis Campaign strongly recommends Norepinephrine as the first-choice vasopressor in fluid-filled patients with septic shock. In contrast, the use of Dobutamine is only suggested (weak recommendation, low quality of evidence) in patients with persistent tissue hypoperfusion despite adequate fluid resuscitation and vasopressor support. Levosimendan, an alternative inodilator, has failed preventing acute organ dysfunction in septic patients and has induced more supraventricular tachyarrhythmias than in the control group. Data supporting Dobutamine in this setting are scarce and primarily physiologic and based on monitored effects of this drug on hemodynamics and indices of tissue perfusion. No randomized controlled trials have yet compared the effects of Dobutamine versus placebo on clinical outcomes. In open-labelled, small sample trials, the ability of septic patients to increase their oxygen delivery during Dobutamine administration appears to be associated with lower mortality. The tested hypothesis in the ADAPT trial is that Dobutamine will reduce tissue hypoperfusion and associated organ dysfunctions in patients with septic shock and associated septic cardiomyopathy. In doing so, it may participate in improving clinical outcomes.


Recruitment information / eligibility

Status Recruiting
Enrollment 270
Est. completion date December 20, 2024
Est. primary completion date December 20, 2024
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria: - Age > 18 years hospitalized in ICU - > Septic shock (Sepsis-3 definition): 1. Clinically suspected or documented acute infection 2. Responsible for organ dysfunction(s): change in SOFA = 2 points 3. With persisting hypotension (systolic and/or mean arterial pressure < 90 / < 65 mmHg) despite adequate fluid resuscitation (= 30 mL/kg, unless presence of pulmonary venous congestion) 4. Requiring vasopressor support (Norepinephrine) to maintain steady mean arterial pressure = 65 mmHg 5. And lactate > 2 mmol/L - Septic cardiomyopathy: echocardiographically measured LV ejection fraction (EF) = 40% and LV outflow tract velocity-time integral < 14 cm - Informed consent Exclusion Criteria: - Pregnancy or breast feeding - Hypersensitivity to Dobutamine, 5% Dextrose, or to the excipients - Ventricular rate > 130 bpm (sinus rhythm or not) - Severe ventricular arrhythmia - Obstructive cardiomyopathy with pressure gradient at rest = 50 mmHg unrelated to uncorrected hypovolemia - Severe aortic stenosis: mean gradient > 40 mmHg, peak aortic jet velocity > 4 m/s, aortic valve area < 1 cm² (aortic valve area index < 0.6 cm²/m²) - Acute coronary syndrome - Decision to limit care or moribund status (life expectancy < 24 h) - Absence of affiliation to Social Security - Subjects under juridical protection.

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Placebos
Placebo will initially be started at a dose of 2.5 µg/kg/min and subsequently titrated using incremental steps (predefined durations) of 2.5 µg/kg/min, up to a maximal dose of 10 µg/kg/min. Dose adaptation will be left at the discretion of attending physician.
Dobutamine
Dobutamine will initially be started at a dose of 2.5 µg/kg/min and subsequently titrated using incremental steps (predefined durations) of 2.5 µg/kg/min, up to a maximal dose of 10 µg/kg/min. Dose adaptation will be left at the discretion of attending physician.

Locations

Country Name City State
France University Hospital Amiens
France Angouleme Hospital Angoulême
France Argenteuil Hospital Argenteuil
France CH de Bethune Béthune
France University Hospital Brest
France CH de Brive Brive-la-Gaillarde
France CH de Cannes Cannes
France Aphp - Henri Mondor Créteil
France Dijon university hospital Dijon
France CH d'Haguenau Haguenau
France CH de Vendée La Roche-sur-Yon
France CHU de Grenoble-Alpes La Tronche
France CH de Versailles Le Chesnay
France Le Mans Hospital Le Mans
France Lille University Hospital Lille
France Limoges University Hospital Limoges
France HCL Lyon
France Montpellier University Hospital Montpellier
France CHU de Nancy Nancy
France Nice University Hospital Nice
France CHU Orléans - service de Réanimation Orleans
France Aphp - Ambroise Paré Paris
France Hôpital Cochin - service de Réanimation Paris
France Poitiers University Hospital Poitiers
France CHU Strasbourg - service de Réanimation Strasbourg
France CH de Toulon Toulon
France CHU Tours - Service de Réanimation Tours

Sponsors (2)

Lead Sponsor Collaborator
University Hospital, Limoges Centre d'Investigation Clinique 1415

Country where clinical trial is conducted

France, 

Outcome

Type Measure Description Time frame Safety issue
Primary Sequential Organ Failure Assessment (SOFA) score evolution Evolution of a modified Sequential (Sepsis-Related) Organ Failure Assessment (SOFA) score (no gradation of the neurologic system) between baseline (before randomization) and Day 1, Day 2 and Day 3 after randomization. Min value =0. Max value =20 . The highest score means the worst situation Day 0 to Day 3
Secondary Circulating lactate level measurement Biological indices of tissue dysoxia at baseline, hour 6, Day1, Day 2 and Day 3 after initiating Dobutamine / placebo Hour 0, Hour 6, Day 1, Day 2 and Day 3
Secondary Central venous oxygen saturation (ScvO2) measurement Biological indices of tissue dysoxia at baseline, hour 6, Day1, Day 2 and Day 3 after initiating Dobutamine / placebo Hour 0, Hour 6, Day 1, Day 2 and Day 3
Secondary Open-labelled Dobutamine dayly maximal dose used as rescue therapy Requirement of organ function supports during ICU stay. Maximal dose in mcg/kg/min of open-labelled Dobutamine used as rescue therapy through study completion, an average 90 days
Secondary Open-labelled Dobutamine duration used as rescue therapy Requirement of organ function supports during ICU stay. Duration in days of open-labelled Dobutamine used as rescue therapy through study completion, an average of 90 days
Secondary Vasopressor support duration Requirement of organ function supports during ICU stay. Duration in days of vasopressor support through study completion, an average of 90 days
Secondary Vasopressor support dayly maximal dose Requirement of organ function supports during ICU stay. Maximal dose in mg/h by day of vasopressor support through study completion, an average of 90 days
Secondary Invasive mechanical ventilation duration Requirement of organ function supports during ICU stay. Duration of invasive mechanical ventilation through study completion, an average of 90 days
Secondary Renal replacement therapy number Requirement of organ function supports during ICU stay. Number of session of renal replacement therapy (excluding hemodialysis patient for chronic renal failure at the time of randomization) through study completion, an average of 90 days
Secondary Renal replacement therapy duration Requirement of organ function supports during ICU stay. Duration of renal replacement therapy (excluding hemodialysis patient for chronic renal failure at the time of randomization) through study completion, an average of 90 days
Secondary Arterial pressure measurement Systolic, diastolic and mean arterial blood pressure (in mmHg) at Baseline, h6, Day 1, Day 2 and Day3after initiating Dobutamine / placebo Hour 0, Hour 6, Day 1, Day 2 and Day 3
Secondary heart rate measurement Heart rate measurement in bpm at Baseline, Hour 6, Day 1, Day 2 and Day3 after initiating Dobutamine / placebo Hour 0, Hour 6, Day 1, Day 2 and Day 3
Secondary Central venous pressure measurement Central venous pressure in cm H2O at Baseline, Hour 6, Day 1, Day 2 and Day3 after initiating Dobutamine / placebo Hour 0, Hour 6, Day 1, Day 2 and Day 3
Secondary Cardiac index measurement Cardiac index measurement in L/min/m2 at Baseline, Hour 6, Day 1, Day 2 and Day3 after initiating Dobutamine / placebo Hour 0, Hour 6, Day 1, Day 2 and Day 3
Secondary Stroke volume measurement Stroke volume measurement in mL status at Baseline, Hour 6, Day 1, Day 2 and Day3 after initiating Dobutamine / placebo Hour 0, Hour 6, Day 1, Day 2 and Day 3
Secondary Hypotension measurement Severe cardiovascular adverse events from inform consent to ICU discharge : Hypotension related to worsened vasoplegia Hour 0, Hour 6, Day 1, Day 2 and Day 3
Secondary Supraventricular arrhythmias measurement Severe cardiovascular adverse events from inform consent to ICU discharge. Supraventricular arrhythmias with ventricular rate > 140 bpm through study completion, an average of 90 days
Secondary Ventricular arrhythmias measurement Severe cardiovascular adverse events from inform consent to ICU discharge. Ventricular arrhythmias through study completion, an average of 90 days
Secondary Occurence of Acute coronary syndrome Severe cardiovascular adverse events from inform consent to ICU discharge. Acute coronary syndrome through study completion, an average of 90 days
Secondary Occurence of Stroke Severe cardiovascular adverse events during ICU stay. Stroke through study completion, an average of 90 days
Secondary Mortality Number of death Day 90
Secondary Mortality causes Cause of death Day 90
Secondary Organ function free supports Number of days free from vasopressor support, invasive mechanical ventilation, renal replacement therapy from inform consent to ICU discharge Day 90
Secondary Number of days in ICU and hospital Length of ICU and hospital stay Day 90
Secondary echocardiographic assessment of left ventricular systolic function ejection fraction measurement Day 0 and Day 1
Secondary Leucocyte subsets level Leucocyte subsets level according to the severity of the sepsis-induced LV systolic dysfunction and hemodynamic effects of the study drug administration Hour 6
Secondary Cytokines level tumor necrosis factor (TNF) -a, Interferon ?, Interleukin-6, 8 and 10 cytokines concentration will be assess according to the severity of the sepsis-induced LV systolic dysfunction and hemodynamic effects of the study drug administration. Result for each cytokine concentration will be given in picograms per milliliter. Hour 6
Secondary LV global longitudinal strain measurement LV segmental deformation longitudinal analysis Hour 6, Day 1, Day 2 AND Day 3
Secondary RV free wall strain measurement deformation of right ventricular myocardial tissue / routinely using with echocardiography or post exam analysis Hour 6, Day 1, Day 2 AND Day 3
Secondary LV volume measurement Ratio between systolic and diastolic left ventricular volume / routinely using with echocardiography Hour 6, Day 1, Day 2 AND Day 3
Secondary LV ejection fraction measurement Cardiac output measurement with echocardiography Doppler (in centers routinely using transpulmonary thermodilution). Quality of left ventricular contraction Hour 6, Day 1, Day 2 AND Day 3
Secondary RV volume measurement Ratio between systolic and diastolic right ventricular volume / routinely using with echocardiography Hour 6, Day 1, Day 2 AND Day 3
Secondary RV ejection fraction measurement Cardiac output measurement with echocardiography Doppler (in centers routinely using transpulmonary thermodilution). Quality of right ventricular contraction Hour 6, Day 1, Day 2 AND Day 3
Secondary Transpulmonary thermodilution measurement In selected centers routinely using continuous monitoring of cardiac output using transpulmonary thermodilution: agreement of cardiac output measurement with echocardiography Doppler. Hour 6, Day 1, Day 2 AND Day 3
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