Reducing Elevated Heart Rate in Patients With Multiple Organ Dysfunction Syndrome (MODS) by Ivabradine

Study Overview
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Brief Summary
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MODIfY is a prospective, single center, open label, randomized, controlled two arms, Phase II-trial to evaluate the ability of ivabradine to reduce an elevated heart rate in Multiple Organ Dysfunction Syndrome (MODS) patients. The primary end point is the proportion of patients with a reduction of heart rate by at least 10 beats per minute (bpm) within 4 days. This trial will randomize 70 patients (men and women, aged ≥ 18 years) with newly diagnosed MODS (Acute Physiology and Chronic Health Evaluation (APACHE) II-score ≥ 20, diagnosis within ≤ 24 hours), with an elevated heart rate (sinus rhythm with HR ≥ 90 bpm) and contraindications to beta-blockers (BBs). Treatment period will last 4 days. All patients will be followed for up to six months.

Detailed Description
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Background: Heart rate (HR) is of relevant prognostic value not only in the general population and patients with cardiovascular disease but also in critically ill patients with multiple organ dysfunction syndrome (MODS). A raised heart rate in MODS patients is associated with a worse prognosis. Beta-blocker (BB) administration showed to improve autonomic function and exhibited a significantly reduced mortality in MODS. In most cases negative inotropic effects prevent administration of BB in MODS patients which often are treated with catecholamines. In this trial we investigate, whether the funny current (If) inhibitor ivabradine is able to reduce pathologically elevated heart rate in MODS- patients. The investigators hypothesized that critically ill patients could derive particular benefit from the specific HR-lowering agent ivabradine. Methods: MODIfY is a prospective, single center, open label, randomized, controlled two arms, Phase II-trial to evaluate the ability of ivabradine to reduce an elevated heart rate in MODS patients. The primary end point is the proportion of patients with a reduction of heart rate by at least 10 beats per minute (bpm) within 4 days. This trial will randomize 70 patients (men and women, aged ≥18 years) with newly diagnosed MODS (Acute Physiology and Chronic Health Evaluation (APACHE) II-score ≥20, diagnosis within ≤24 hours), with an elevated heart rate (sinus rhythm with HR ≥90 bpm) and contraindications to BBs. Treatment period will last 4 days. All patients will be followed for up to six months.

Official Title
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Reducing Elevated Heart Rate in Patients With Multiple Organ Dysfunction Syndrome (MODS) by the Funny Channel Current (If) Inhibitor Ivabradine

Conditions
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Multiple Organ Dysfunction Syndrome

Intervention / Treatment
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* Drug: ivabradine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Multiple organ dysfunction syndrome (APACHE II score ≥ 20) due to coronary and non-coronary etiology Multiple organ dysfunction syndrome diagnosed ≤ 24 h Sinus rhythm with heart rate ≥ 90bpm Existing contraindications to beta-receptor blockade Written informed consent or identified or suspected positive will with respect to the trial treatment Exclusion Criteria: Patients who have not yet completed the 18th year of age Pregnancy, lactation Patients with a history of pre-existing chronic renal failure with a glomerular filtration rate <30ml/min Patients with malignant hyperthermia Burn patients Patients with acute rejection after organ transplantation Patients with bleedings and need for transfusion Resuscitated patients with suspected hypoxic brain injury Patients who have participated or participate in other studies within the last 3 months Other types of shock than septic or cardiogenic shock Patients with severe valvular heart disease Hypersensitivity to the active substance or any of the excipients Severe hepatic insufficiency Sick sinus syndrome Sinu-atrial block pacemaker-dependency 3rd degree AV block Use of potent cytochrome P450 3A4 inhibitors such as antifungals of the azole -type (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin per os, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone (see Summary of Product Characteristics (SPC))

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: standard treatment<br>All patients receive established medical therapy according to current guidelines and therapeutic standards. | |
| Active Comparator: ivabradine (add-on)<br>Patients in the ivabradine treatment arm receive an additional enteral preparation (orally, via nasogastric tube or percutaneous endoscopic gastrostomy-probe) of ivabradine for 4 days. | Drug: ivabradine<br>* Patients in the ivabradine treatment arm receive an additional enteral preparation (orally, via nasogastric tube or percutaneous endoscopic gastrostomy-probe) of ivabradine for 4 days. Day 1 and 2: 5,0 mg ivabradine b.i.d. if heart rate ≥60bpm (acute renal failure: ≥70bpm) Day 3 and 4: 5,0 mg ivabradine b.i.d. if 60bpm≥heart rate<90bpm (acute renal failure: 70bpm≥heart rate <90bpm 7,5 mg ivabradine b.i.d. if heart rate ≥90bpm<br>* Other names: Procoralan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| mean heart rate | percenage of patients with a reduction of the mean heart rate of at least 10 bpm 96 hours after the start of trial treatment | 4 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| morbidity | group-differences and patient-related changes of morbidity measured by serial APACHE II score monitoring and Sequential Organ Failure Assessment (SOFA) score monitoring | 4 days | 
| hemodynamic parameters | group-differences and patient-related changes of hemodynamic parameters (cardiac index and cardiac power index) as a consequence of ivabradine treatment | 4 days | 
| catecholamine dosage | required catecholamine dosage measured by a vasopressor score | 4 days | 
| microcirculation | improvement of microcirculation as measured by sublingual capillary density and flow | 4 days | 
| endothelial function | improvement of endothelial function as measured by the Reactive hyperemia peripheral arterial tonometry-index | 4 days | 
| mean heart rate | comparison of the mean heart rate between the treatment and control group after 24 and 48 hours | 48 hours | 
| mortality | 28-day and 6 months mortality | 6 months | 
| cardiac autonomic dysfunction | impact on cardiac autonomic dysfunction (heart rate variability quantified by time domain measurements (standard deviation of normal to normal interval (SDNN)) and frequency domain measurements (very low frequency (VLF)-, high frequency (HF)- and low frequency (LF)-power) as well as minimum, maximum, day and night heart rate) | 4 days | 
| number of participants with adverse events as a measure of safety and tolerability |  | 6 months | 
| plasma levels of ivabradine in patients with MODS | daily measurement of plasma levels during the treatment period (4 days) | 4 days | 
| Differences of mortality in different age groups and MODS groups | age sub-groups: patients <70 years on day of inclusion patients ≥70 years on day of inclusion MODS sub-groups: patients with cardiogenic MODS patients with septic MODS | 6 months | 
| Differences of adverse events in different age groups and MODS groups | age sub-groups: patients <70 years on day of inclusion patients ≥70 years on day of inclusion MODS sub-groups: patients with cardiogenic MODS patients with septic MODS | 6 months | 
| Differences of heart rate in different age groups and MODS groups | age sub-groups: patients <70 years on day of inclusion patients ≥70 years on day of inclusion MODS sub-groups: patients with cardiogenic MODS patients with septic MODS | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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heart rate, multiple organ dysfunction syndrome, ivabradine, sepsis, cardiogenic shock