Efficacy of Ivabradine Hydrochloride in Heart Rate Control and 28-Day Survival in Adult Patients with Septic Shock: A Randomized, Multi-Stage Trial

Trial ID: 2024-515019-22-00
Protocol: P160925J
Sponsor: Assistance Publique Hopitaux De Paris

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Diseases & Conditions

Septic shock

Objectives

The primary objective of this clinical trial is to evaluate the **efficacy** of ivabradine in controlling heart rate and improving 28-day survival in patients with **septic shock**. This objective is clinically relevant as effective heart rate management and enhanced survival rates are critical outcomes in the treatment of septic shock, a condition associated with high mortality. The trial will be conducted in two stages: the first stage will focus on heart rate control, while the second stage will assess the impact on mortality.

Participants

The clinical trial focuses on evaluating the efficacy of ivabradine in patients diagnosed with **septic shock**. The study population includes both male and female participants, aged 18 years and older, who are in sinus rhythm with a heart rate of 95 bpm or higher at the time of randomization. Participants must have a proven or suspected site of infection and be experiencing septic shock, characterized by hypotension unresponsive to fluid resuscitation and requiring vasopressor treatment. The trial population is selected based on these criteria, and informed consent is obtained in accordance with local regulations. The sponsor has not provided information regarding the total number of participants. The study includes individuals affiliated with a social security regime and considers vulnerable populations. Lifestyle factors such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is a **Phase III**, prospective, randomized, placebo-controlled, double-blind, multi-arm, multi-stage study designed to evaluate the efficacy of **ivabradine** in patients with **septic shock**. The primary objective is to assess the control of heart rate and improvement in 28-day survival. The trial will be conducted over an estimated period from February 2021 to May 2026. Participants will be randomly assigned to one of three arms: a placebo arm or one of two ivabradine arms. The study will include a screening visit, multiple follow-up visits, and an end-of-study visit.

During the initial screening visit, eligibility criteria will be confirmed, including age (18 years or older), presence of a proven or suspected infection site, and septic shock characterized by hypotension unresponsive to fluid resuscitation. Participants must be in sinus rhythm with a heart rate of at least 95 bpm at the time of randomization. Informed consent will be obtained in accordance with local regulations. The trial will proceed with an interim analysis focusing on heart rate control at 48 hours, with the primary endpoint being the percentage of patients achieving a heart rate within the predefined threshold of 80-94 bpm. The final analysis will assess 28-day mortality.

Follow-up visits will monitor the tolerance of ivabradine, its impact on systemic hemodynamics, myocardial stress, organ dysfunction, morbidity, and intensive care mortality. Pharmacokinetics of ivabradine will also be evaluated. The expected length of participant involvement is up to 14 days, with a maximum daily dose of 7.5 mg and a total dose not exceeding 210 mg. Conditions that may lead to early termination from the study include adverse reactions, withdrawal of consent, or any situation where continued participation is deemed unsafe by the investigator.

Treatment

The clinical trial involves the administration of **Procoralan 5 mg film-coated tablets**, which contain the active substance **ivabradine hydrochloride**. This medication is formulated as film-coated tablets and is administered via an **enteral feeding tube**. The maximum daily dose is 7.5 mg, with a total maximum dose of 210 mg over a treatment period of 14 days. The primary objective of the trial is to assess the efficacy of ivabradine in controlling heart rate and improving 28-day survival in patients with septic shock. The trial is structured in two stages: the first stage focuses on heart rate control, while the second stage evaluates mortality outcomes.

In addition to the experimental treatment, a **placebo** of Procoralan 5 mg is used as a comparator in the study. The placebo is designed to match the experimental medication in appearance and administration route, ensuring blinding of participants and investigators. The placebo does not contain any active pharmaceutical ingredients and serves to evaluate the efficacy of the experimental treatment by providing a baseline for comparison.

Efficacy

The efficacy of ivabradine in controlling heart rate and improving 28-day survival in patients with septic shock will be assessed through a two-stage clinical trial. The primary endpoints for efficacy evaluation include the percentage of patients achieving a heart rate within the predefined threshold of 80-94 bpm at hour-48 for treatment selection during interim analysis. In cases where similar percentages are observed, the percentage of time elapsed within the threshold between inclusion and hour-48 will be considered. The final analysis will focus on the 28-day mortality rate.

Secondary endpoints will assess the tolerance of ivabradine, its impact on systemic hemodynamics, myocardial stress, organ dysfunction, morbidity, and intensive care mortality, as well as the pharmacokinetics of ivabradine. These parameters will be measured and collected using appropriate methods and tools, ensuring accurate and reliable data for analysis. The trial is designed as a Phase III, prospective, randomized, placebo-controlled, double-blind, multi-arm, multi-stage study, with one placebo arm and two ivabradine arms, to rigorously evaluate the efficacy of ivabradine in the specified patient population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

18 years of age or older
Proven or suspected site of infection
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

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Exclusion Criteria

Cardiac arythmia, 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;
Septic shock requiring vasopressor treatment for more than 24 hours
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