Ivabradine for Heart Rate Control In Septic Shock (IRISS)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Septic Shock
• Intervention / Treatment: Drug: Ivabradine; Drug: Ivabradine; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 429
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Armand MEKONTSO DESSAP, MD, PhD; Phone Number: +33 01 49 81 23 89; Email: armand.dessap@aphp.fr

Study Locations

• France
  • Créteil, France, 94000
    • Recruiting
    • Henri Mondor Hospital
    • Contact: Armand Mekontso-Dessap, MD,PhD; Phone Number: +33 01 49 81 23 89; Email: armand.dessap@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control	Drug: Placebo; Placebo will be administered via the enteral route, every 12 hours.
Experimental: Ivabradine (Low)	Drug: Ivabradine; 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; Other Names: Ivabradine Low; Drug: Ivabradine; 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; Other Names: Ivabradine High
Experimental: Ivabradine (High)	Drug: Ivabradine; 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; Other Names: Ivabradine Low; Drug: Ivabradine; 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; Other Names: Ivabradine High

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients with heart rate within the predefined threshold (80-94 bpm) at hour-48	for activity and treatment selection at interim analysis	hour 48 after treatment
Percentage of patients dead at 28 days	for efficacy and the final analysis	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
percentage of patients with bradycardia (heart rate <60/min), atrial fibrillation, phosphenes or blurred vision up to day-17	Tolerance of ivabradine	Day 17
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;	hour-72
Organ failures free days (SOFA<3 for each organ) at day-14 and day-28,		at day-14 and day-28
Number of catecholamines-, vasopressor- and mechanical ventilation-free days at day-14 and day-28,		at day-14 and day-28
lactate clearance		at day-2 and day-3;
Left ventricle ejection fraction	to assess left ventricle ejection fraction	at randomization (hour-0) , 12 hours, and 24 hours after the first administration of study drug
cardiac troponin assessment	a blood sample will be collected for measurement of troponin T	a blood sample will be collected at randomization, day-2 and day-3
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).	Day-3

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Study Director: Armand MEKONTSO DESSAP, MD, PhD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): February 24, 2021
• Primary Completion (Anticipated): January 24, 2023
• Study Completion (Anticipated): March 24, 2023

Study Registration Dates

• First Submitted: July 16, 2019
• First Submitted That Met QC Criteria: July 23, 2019
• First Posted (Actual): July 24, 2019

Study Record Updates

• Last Update Posted (Actual): July 13, 2021
• Last Update Submitted That Met QC Criteria: July 12, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Septic shock; Ivabradine
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock
• Other Study ID Numbers: P160925J; 2018-003801-24 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No