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Ivabradine for Heart Rate Control In Septic Shock (IRISS)

Primary Purpose

Septic Shock

Status

Unknown status

Phase

Phase 3

Locations

France

Study Type

Interventional

Intervention

Ivabradine

Placebo

About this trial

This is an interventional treatment trial for Septic Shock focused on measuring Septic shock, Ivabradine

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

18 years of age or older;
Proven or suspected site of infection;
Septic shock (defined as hypotension unresponsive to fluid resuscitation and requiring vasopressor treatment to maintain adequate blood pressure) for at least 6 hours and less than 24 hours;
In sinus rhythm with heart rate ≥ 95 bpm at time of randomization;
Informed consent obtained in accordance with local regulations;
Affiliation to a social security regime.

Exclusion Criteria:

Age < 18 years,

Cardiac arrythmia, conduction disorder, sinus syndrome ("sick sinus syndrome"), sino-atrial block; 3rd degree atrioventricular block;
Cardiogenic shock or unstable or acute heart failure, without proven or suspected infection;
Acute myocardial infarction with angiographic documentation; CCS class ≥ II angina pectoris;
Refractory shock with systolic arterial pressure <90 mm Hg despite the use of high doses of vasopressors (norepinephrine BASE or epinephrine BASE > 2.4 µg/kg/min; these doses should be multiplied by two for noradrenaline salt (tartrate or bitartrate).
Co-treatment with drugs inducing bradycardia, QT lengthening or strong inhibition of CYP4503A4, pacemaker, defibrillator, kalemia <3 mM
Known pregnancy, breast feeding, women with of childbearing potential will be tested for pregnancy and excluded if pregnant
Known allergy to ivabradine or to any of the excipients, retinitis pigmentosa, congenital galactosemia, lactase deficiency, glucose or galactose malabsorption
Severe renal failure (creatinine clearance <15 ml/min) or hepatic failure (prothrombin time <20%),
Enteral feeding impossible, vomiting, congenital galactosemia, lactase deficiency, glucose-galactose malabsorption syndrome.
Tachycardia due to hyperthyroidism, pheochromocytoma or severe anemia (<7 g/dL)
Prior enrolment in the trial, participation in another interventional study on septic shock,
Known legal incapacity (patients under guardianship or curators),
Decision to limit full care taken before obtaining informed consent.
Patient under state emergency medical help

Sites / Locations

Henri Mondor HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

Arm Label

Ivabradine (Low)

Ivabradine (High)

Control

Arm Description

Outcomes

Primary Outcome Measures

Percentage of patients with heart rate within the predefined threshold (80-94 bpm) at hour-48

for activity and treatment selection at interim analysis

Percentage of patients dead at 28 days

for efficacy and the final analysis

Secondary Outcome Measures

percentage of patients with bradycardia (heart rate <60/min), atrial fibrillation, phosphenes or blurred vision up to day-17

Tolerance of ivabradine

Percentage of patients with a heart rate within the target range (80-94 bpm) at hour-72

percentage of heart rate measurements (assessed every 3 to 4 hours) within the target range at hour-72; changes in heart rate, mean arterial pressure and cardiac output evaluated by the area under the curve (AUC) versus time at hour-72;

Organ failures free days (SOFA<3 for each organ) at day-14 and day-28,

Number of catecholamines-, vasopressor- and mechanical ventilation-free days at day-14 and day-28,

lactate clearance

Left ventricle ejection fraction

to assess left ventricle ejection fraction

cardiac troponin assessment

a blood sample will be collected for measurement of troponin T

Pharmacokinetics of ivabradine

A blood sample for measurement of plasma concentration of ivabradine will be collected at day-3 at three time points: just before study drug administration (5th dose), 60 minutes later, and during the next routine blood sampling at a random schedule (during the next blood sampling for clinical purposes).

Full Information

NCT ID

NCT04031573

First Posted

July 16, 2019

Last Updated

July 12, 2021

Sponsor

Assistance Publique - Hôpitaux de Paris

1. Study Identification

Unique Protocol Identification Number

NCT04031573

Brief Title

Ivabradine for Heart Rate Control In Septic Shock

Acronym

IRISS

Official Title

A Multicenter, Prospective, Randomized, Placebo-controlled, Double-blind, Multi-arm, Multi-stage Clinical Trial of Ivabradine for Heart Rate Control In Septic Shock

Study Type

Interventional

2. Study Status

Record Verification Date

March 2021

Overall Recruitment Status

Unknown status

Study Start Date

February 24, 2021 (Actual)

Primary Completion Date

January 24, 2023 (Anticipated)

Study Completion Date

March 24, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Assistance Publique - Hôpitaux de Paris

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Septic shock is a major health problem, with several million cases annually worldwide and a mortality approaching 45%. Tachycardia is associated with excess mortality during septic shock. This pejorative effect could be related to the increase in cardiac metabolic demand, impaired cardiac diastolic function, and/or poorer tolerance of administered exogenous catecholamines. Recent studies suggest that controlling the heart rate with the use of beta blockers has beneficial effects on the morbidity and mortality of septic shock. However, the negative effects of beta-blockers on cardiac contractility and blood pressure complicate their use during septic shock, particularly because about one-half of patients exhibit a septic-associated systolic dysfunction, which often requires the use of inotropes. Ivabradine is a selective inhibitor of If channels in the sinoatrial node. It is a pure bradycardic agent with no deleterious effect on other aspects of cardiac function (contractility, conduction and repolarization) nor on blood pressure. Ivabradine can therefore alleviate sinus tachycardia without negative inotropic effects nor hypotension. Moreover, the improvement in diastolic function (ventricular filling) with ivabradine may increase stroke volume, even in case of severe impairment of systolic function. Controlling sinus tachycardia with ivabradine during septic shock would allow reducing cardiac metabolic demand (and potentially associated ischemic events) and improving the chronotropic tolerance of exogenous catecholamines. The effectiveness of ivabradine in controlling the heart rate was demonstrated in various clinical settings such as coronary artery disease, chronic heart failure and cardiogenic shock. Encouraging preliminary data are reported in critically ill patients.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Septic Shock

Keywords

Septic shock, Ivabradine

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Model Description

Multi-centre, double-blind, randomised, placebo-controlled, multi-arm multi-stage trial. The trial investigates the efficacy and safety of 2 dosing regimens of ivabradine in order to confirm the efficacy and safety of one dosing regimen for heart rate control in adult patients with septic shock.Two dosing regimens of ivabradine will be investigated in the first part and the best-performing dosing regimen will be selected for the last part of the trial. A multi-arm multi-stage (MAMS) design with 2 stages and 3 arms will be used. The trial incorporates 2 stages: 1. Activity: an interim comparison of activity using the percentage of patients with heart rate control (80-94/min) at hour-48 as primary endpoint. At the end of this stage, an interim analysis will be used in order to select the most promising ivabradine dosing protocol and compare it to placebo in the subsequent stage (pick the winner strategy). 2. Efficacy: final comparison with 28 days mortality as the primary endpoint.

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

429 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Ivabradine (Low)

Arm Type

Experimental

Arm Title

Ivabradine (High)

Arm Type

Experimental

Arm Title

Control

Arm Type

Placebo Comparator

Intervention Type

Drug

Intervention Name(s)

Ivabradine

Other Intervention Name(s)

Ivabradine Low

Intervention Description

Ivabradine will be administered via the enteral route, every 12 hours, at doses ranging from 2.5 to 5 mg to achieve a target heart rate between 80 and 94 bpm

Intervention Type

Drug

Intervention Name(s)

Ivabradine

Other Intervention Name(s)

Ivabradine High

Intervention Description

Ivabradine will be administered via the enteral route, every 12 hours, at doses ranging from 5 to 7.5 mg to achieve a target heart rate between 80 and 94

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo will be administered via the enteral route, every 12 hours.

Primary Outcome Measure Information:

Title

Percentage of patients with heart rate within the predefined threshold (80-94 bpm) at hour-48

Description

for activity and treatment selection at interim analysis

Time Frame

hour 48 after treatment

Title

Percentage of patients dead at 28 days

Description

for efficacy and the final analysis

Time Frame

28 days

Secondary Outcome Measure Information:

Title

percentage of patients with bradycardia (heart rate <60/min), atrial fibrillation, phosphenes or blurred vision up to day-17

Description

Tolerance of ivabradine

Time Frame

Day 17

Title

Percentage of patients with a heart rate within the target range (80-94 bpm) at hour-72

Description

Time Frame

hour-72

Title

Organ failures free days (SOFA<3 for each organ) at day-14 and day-28,

Time Frame

at day-14 and day-28

Title

Number of catecholamines-, vasopressor- and mechanical ventilation-free days at day-14 and day-28,

Time Frame

at day-14 and day-28

Title

lactate clearance

Time Frame

at day-2 and day-3;

Title

Left ventricle ejection fraction

Description

to assess left ventricle ejection fraction

Time Frame

at randomization (hour-0) , 12 hours, and 24 hours after the first administration of study drug

Title

cardiac troponin assessment

Description

a blood sample will be collected for measurement of troponin T

Time Frame

a blood sample will be collected at randomization, day-2 and day-3

Title

Pharmacokinetics of ivabradine

Description

Time Frame

Day-3

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 18 years of age or older; Proven or suspected site of infection; Septic shock (defined as hypotension unresponsive to fluid resuscitation and requiring vasopressor treatment to maintain adequate blood pressure) for at least 6 hours and less than 24 hours; In sinus rhythm with heart rate ≥ 95 bpm at time of randomization; Informed consent obtained in accordance with local regulations; Affiliation to a social security regime. Exclusion Criteria: Age < 18 years, Cardiac arrythmia, conduction disorder, sinus syndrome ("sick sinus syndrome"), sino-atrial block; 3rd degree atrioventricular block; Cardiogenic shock or unstable or acute heart failure, without proven or suspected infection; Acute myocardial infarction with angiographic documentation; CCS class ≥ II angina pectoris; Refractory shock with systolic arterial pressure <90 mm Hg despite the use of high doses of vasopressors (norepinephrine BASE or epinephrine BASE > 2.4 µg/kg/min; these doses should be multiplied by two for noradrenaline salt (tartrate or bitartrate). Co-treatment with drugs inducing bradycardia, QT lengthening or strong inhibition of CYP4503A4, pacemaker, defibrillator, kalemia <3 mM Known pregnancy, breast feeding, women with of childbearing potential will be tested for pregnancy and excluded if pregnant Known allergy to ivabradine or to any of the excipients, retinitis pigmentosa, congenital galactosemia, lactase deficiency, glucose or galactose malabsorption Severe renal failure (creatinine clearance <15 ml/min) or hepatic failure (prothrombin time <20%), Enteral feeding impossible, vomiting, congenital galactosemia, lactase deficiency, glucose-galactose malabsorption syndrome. Tachycardia due to hyperthyroidism, pheochromocytoma or severe anemia (<7 g/dL) Prior enrolment in the trial, participation in another interventional study on septic shock, Known legal incapacity (patients under guardianship or curators), Decision to limit full care taken before obtaining informed consent. Patient under state emergency medical help

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Armand MEKONTSO DESSAP, MD, PhD

Phone

01 49 81 23 89

Ext

+33

armand.dessap@aphp.fr

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Armand MEKONTSO DESSAP, MD, PhD

Organizational Affiliation

Assistance Publique - Hôpitaux de Paris

Official's Role

Study Director

Facility Information:

Facility Name

Henri Mondor Hospital

City

Créteil

ZIP/Postal Code

94000

Country

France

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Armand Mekontso-Dessap, MD,PhD

Phone

01 49 81 23 89

Ext

+33

armand.dessap@aphp.fr

12. IPD Sharing Statement

Learn more about this trial

Ivabradine for Heart Rate Control In Septic Shock

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