Adjunctive DobutAmine in sePtic cardiomyopathy with Tissue hypoperfusion: a randomized controlled multi-center trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Et Universitaire De Limoges

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

Trial duration

20 Sep 2020 → 1 Jul 2025

Decision date (initial)

2024-10-10

Transition trial

Yes

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

CHU de Limoges · DGOS

External identifiers

EU CT number

2024-517839-50-00

EudraCT number

2019-000286-21

WHO UTN

U1111-1313-1511

ClinicalTrials.gov

NCT04166331

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To assess the effects of adjunctive Dobutamine infusion versus placebo on organs failure in fluid-filled septic shock patients stabilized under vasopressor support with echocardiographically documented septic cardiomyopathy

Secondary objectives 8

1. To assess the effects of Dobutamine versus placebo on (periods of assessment between brackets). Evolution of indices of tissue hypoperfusion (Day 3 after randomization)
2. To assess the effects of Dobutamine versus placebo on (periods of assessment between brackets). Requirement of organ function supports, as a reflect of underlying organ dysfunctions (ICU stay)
3. To assess the effects of Dobutamine versus placebo on (periods of assessment between brackets). Systemic hemodynamics (Day 3 after randomization)
4. To assess the effects of Dobutamine versus placebo on (periods of assessment between brackets). Severe cardiovascular adverse events (ICU stay)
5. To assess the effects of Dobutamine versus placebo on (periods of assessment between brackets). Early (Day-7), ICU and Day-28 mortality
6. To assess the effects of Dobutamine versus placebo on (periods of assessment between brackets). Days free from organ supports (ICU stay)
7. To assess the effects of Dobutamine versus placebo on (periods of assessment between brackets). ICU and hospital lengths of stay
8. To assess the effects of Dobutamine versus placebo on (periods of assessment between brackets). LV and RV systolic and diastolic function assessed using echocardiography (Day 1).

Conditions and MedDRA coding

sepsis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Age ≥ 18 years hospitalized in ICU
2. Septic shock (Sepsis-3 definition) on ICU admission or during ICU stay: 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 within the 24h preceding randomization
3. Septic cardiomyopathy: echocardiographically measured or visually assessed LV ejection fraction (EF) ≤ 40% and LV outflow tract velocity-time integral < 14±1.5 cm (or RV outflow tract velocity-time integral according to image quality) not related to persistent hypovolemia
4. Informed consent

Exclusion criteria 11

1. Pregnancy or breast feeding
2. Hypersensitivity to Dobutamine, 5% Dextrose, or to the exipients
3. Ventricular rate >150 bpm if sinus rhythm, or > 130 bpm if non-sinus rhythm
4. Severe ventricular arrhythmia
5. Obstructive cardiomyopathy with pressure gradient at rest ≥ 50 mmHg unrelated to uncorrected hypovolemia
6. 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)
7. Ongoing acute coronary syndrome
8. Indication for or insertion of any extracorporeal life support
9. Decision to limit care or moribund status (life expectancy < 24 h) not related to the severity of septic cardiomyopathy
10. Absence of affiliation to Social Security
11. Subjects under juridical protection.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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.

Secondary endpoints 8

1. Biological indices of tissue dysoxia at baseline, 6 h after initiating Dobutamine / placebo, Day 1, Day2, Day3: * Circulating lactate level as a marker of tissue hypoperfusion * Central venous oxygen saturation (ScvO2) as a marker of tissue oxygen extraction
2. Requirement of organ function supports during ICU stay: * Maximal dose and duration of open-labelled Dobutamine used as rescue therapy * Maximal dose and duration of vasopressor support (Norepinephrine, other) * Duration of invasive mechanical ventilation * Requirement and number of sessions of renal replacement therapy (excluding hemodialysis patient for chronic renal failure at the time of randomization
3. Hemodynamic status at baseline, 6 h after initiating Dobutamine / placebo, Day 1, Day2, Day3: * Arterial pressure, heart rate *Central venous pressure * Cardiac index and stroke volume measured using echocardiography or using calibrated monitoring systems (e.g., transpulmonary thermodilution)
4. Severe cardiovascular adverse events during ICU stay: * Hypotension related to worsened vasoplegia * Excessive sinus tachycardia > 160 bpm * Supraventricular arrhythmias with ventricular rate > 140 bpm * Ventricular arrhythmias * New-onset acute coronary syndrome * Stroke (ischemic or hemorrhagic)
5. Day-7, ICU, Day-28 and Day-90 all-cause mortality
6. Number of days free from vasopressor support, invasive mechanical ventilation, renal replacement therapy during ICU stay
7. Length of ICU and hospital stay
8. Echocardiography at baseline and on Day 1: LV ejection fraction using the monoplane Simpson method, velocity-time integral of LV outflow tract Doppler (stroke volume), E and A mitral Doppler maximal velocity, systolic (S’) and early diastolic maximal tissue Doppler velocity of mitral ring (E’), S’ measured at the lateral aspect of tricuspid ring and M-mode measurement of tricuspid annular plane systolic excursion (TAPSE), systolic pulmonary artery pressure, ratio of end-diastolic RV/LV areas

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Et Universitaire De Limoges

Sponsor organisation

Centre Hospitalier Et Universitaire De Limoges

Address

2 Avenue Martin Luther King

City

Limoges

Postcode

87000

Country

France

Scientific contact point

Organisation

Centre Hospitalier Et Universitaire De Limoges

Contact name

Coordonnator Investigator

Public contact point

Organisation

Centre Hospitalier Et Universitaire De Limoges

Contact name

Renaud MARTIN

Locations

1 EU/EEA country · 18 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications