Septic ShockPhase 3IRISSNCT04031573
Ivabradine for Heart Rate Control In Septic Shock
A Phase 3 study testing Ivabradine in people with Septic Shock, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Septic Shock
- What is being tested?
- Ivabradine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 429 participants
- Where
- 1 siteFrance
- Study dates
- 26 Feb 2021to 14 Apr 2026
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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 in the context of proven or suspected site of infection) for at least 2 hours and less than 24 hours (inclusion is possible before 2 hours in case of increasing doses of norepinephrine),
- 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.
Who cannot join
- Age < 18 years,
- Cardiac arythmia, conduction disorder, sinus syndrome ("sick sinus syndrome"), sino-atrial block; 3rd degree atrioventricular block, "IRISS" protocol, version 6.0 of 30/10/2023 7/47 This document is the property of DRCD / APHP. All reproduction is strictly prohibited.
- Cardiogenic shock or unstable or acute heart failure without proven or suspected infection,
- Acute myocardial infarction with angiographic documentation; CCS class
- ≥ II angina pectoris;
- Septic shock requiring vasopressor treatment for more than 24 hours,
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- 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,
- Co-treatment with verapamil or diltiazem (which are moderate CYP4503A4 inhibitors with heart rate reducing properties)
- Known pregnancy, breast feeding, women with 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 chronic 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 curatorship),
- Decision to limit full care taken before obtaining informed consent,
- Patient under AME (state emergency medical help),
- Lack of affiliation to social security.
Trial locations and contacts
1 site in 1 country.
About this study
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
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.
- Conditions
- Septic Shock
- Being tested
- Ivabradine, Placebo
- Keywords
- Septic shock, Ivabradine
- Medical subject headings
- Shock, Septic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IvabradineDrug
Also called Ivabradine Low
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
IvabradineDrug
Also called Ivabradine High
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
PlaceboDrug
Placebo will be administered via the enteral route, every 12 hours.
| Study group | Role | What they receive |
|---|---|---|
| Ivabradine (Low) | Experimental | Not described Receives: Drug: Ivabradine |
| Ivabradine (High) | Experimental | Not described Receives: Drug: Ivabradine |
| Control | Placebo comparator | Not described Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of patients with heart rate within the predefined threshold (80-94 bpm) at hour-48
for activity and treatment selection at interim analysis
Measured: hour 48 after treatment
Percentage of patients dead at 28 days
for efficacy and the final analysis
Measured: 28 days
Secondary outcomes (8)
percentage of patients with bradycardia (heart rate <60/min), atrial fibrillation, phosphenes or blurred vision up to day-17
Tolerance of ivabradine
Measured: 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;
Measured: hour-72
Organ failures free days (SOFA<3 for each organ) at day-14 and day-28,
Measured: at day-14 and day-28
Number of catecholamines-, vasopressor- and mechanical ventilation-free days at day-14 and day-28,
Measured: at day-14 and day-28
lactate clearance
Measured: at day-2 and day-3;
Left ventricle ejection fraction
to assess left ventricle ejection fraction
Measured: 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
Measured: 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).
Measured: Day-3
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Jul 2019
- Study start26 Feb 2021
- Primary completion19 Feb 2026
- Study completion14 Apr 2026
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Septic ShockStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 429 participants (actual)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Armand MEKONTSO DESSAP, MD, PhD, Study director, Assistance Publique - Hôpitaux de Paris
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04031573
- Sponsor's protocol ID
- P160925J
- Other IDs
- 2018-003801-24, 2018
- Acronym
- IRISS
- Status last verified
- Sep 2026
- First submitted
- 16 Jul 2019
- Last updated
- 3 Sep 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Data will be made available upon reasonable request wherever legally and ethically possible
Study at a glance
From the registry record, last updated by the sponsor on 3 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04031573
- Acronym / sponsor ID
- IRISS / P160925J
- Conditions
- Septic Shock
- Keywords
- Septic shock, Ivabradine
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 429 participants (actual)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Study start
- 26 Feb 2021 (actual)
- Primary completion
- 19 Feb 2026 (actual)
- Study completion
- 14 Apr 2026 (actual)
- First posted
- 24 Jul 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 3
- 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.
| Arm | Type | Receives |
|---|---|---|
| Ivabradine (Low) | Experimental | Drug: Ivabradine |
| Ivabradine (High) | Experimental | Drug: Ivabradine |
| Control | Placebo comparator | Drug: Placebo |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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 in the context of proven or suspected site of infection) for at least 2 hours and less than 24 hours (inclusion is possible before 2 hours in case of increasing doses of norepinephrine),
- In sinus rhythm with heart rate ≥ 95 bpm at time of randomization,
- Informed consent obtained in accordance with local regulations,
Key exclusion criteria (19 listed)
- Age < 18 years,
- Cardiac arythmia, conduction disorder, sinus syndrome ("sick sinus syndrome"), sino-atrial block; 3rd degree atrioventricular block, "IRISS" protocol, version 6.0 of 30/10/2023 7/47 This document is the property of DRCD / APHP. All reproduction is strictly prohibited.
- Cardiogenic shock or unstable or acute heart failure without proven or suspected infection,
- Acute myocardial infarction with angiographic documentation; CCS class
- ≥ II angina pectoris;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| IvabradineAlso: Ivabradine LowIvabradine 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 | Drug | Ivabradine (Low) |
| IvabradineAlso: Ivabradine HighIvabradine 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 | Drug | Ivabradine (High) |
| PlaceboPlacebo will be administered via the enteral route, every 12 hours. | Drug | Control |
Primary outcome
Percentage of patients with heart rate within the predefined threshold (80-94 bpm) at hour-48
Time frame: hour 48 after treatment
for activity and treatment selection at interim analysis
Percentage of patients dead at 28 days
Time frame: 28 days
for efficacy and the final analysis
8 secondary outcomes
percentage of patients with bradycardia (heart rate <60/min), atrial fibrillation, phosphenes or blurred vision up to day-17
Time frame: Day 17
Percentage of patients with a heart rate within the target range (80-94 bpm) at hour-72
Time frame: hour-72
Organ failures free days (SOFA<3 for each organ) at day-14 and day-28,
Time frame: at day-14 and day-28
Number of catecholamines-, vasopressor- and mechanical ventilation-free days at day-14 and day-28,
Time frame: at day-14 and day-28
lactate clearance
Time frame: at day-2 and day-3;
Left ventricle ejection fraction
Time frame: at randomization (hour-0) , 12 hours, and 24 hours after the first administration of study drug
cardiac troponin assessment
Time frame: a blood sample will be collected at randomization, day-2 and day-3
Pharmacokinetics of ivabradine
Time frame: Day-3
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Sep 2026.
- Individual participant dataSharing planned: Yes. Data will be made available upon reasonable request wherever legally and ethically possible
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Sepsis
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Armand MEKONTSO DESSAP, MD, PhD study director
Assistance Publique - Hôpitaux de Paris
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Ivabradine in people with Septic Shock, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of patients with heart rate within the predefined threshold (80-94 bpm) at hour-48 (time frame: hour 48 after treatment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Sep 2026.