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

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

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.

Study Overview

• Status: Unknown
• Conditions: Multiple Organ Dysfunction Syndrome
• Intervention / Treatment: Drug: ivabradine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 70
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Saxony-Anhalt
    • Halle (Saale), Saxony-Anhalt, Germany, 06120
      • Recruiting
      • Department of Medicine III of the University Clinics Halle (Saale) of the Martin-Luther-University Halle-Wittenberg
      • Contact: Karl Werdan, MD, Professor; Phone Number: 2601 0049 345 557; Email: karl.werdan@medizin.uni-halle.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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))

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: standard treatment; All patients receive established medical therapy according to current guidelines and therapeutic standards.
Active Comparator: ivabradine (add-on); 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; 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; Other Names: Procoralan

What is the study measuring?

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
mortality	28-day and 6 months mortality	6 months
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
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

Collaborators and Investigators

• Sponsor: Martin-Luther-Universität Halle-Wittenberg
• Collaborators: Servier; KKS Netzwerk
• Investigators: Study Chair: Karl Werdan, MD, Professor, Medical Faculty of the Martin-Luther-University Halle-Wittenberg, Germany; Principal Investigator: Henning Ebelt, MD, Medical Faculty of the Martin-Luther-University Halle-Wittenberg, Germany; Principal Investigator: Sebastian Nuding, MD, Medical Faculty of the Martin-Luther-University Halle-Wittenberg, Germany

Publications and helpful links

General Publications

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Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (Anticipated): November 1, 2011
• Study Completion (Anticipated): May 1, 2012

Study Registration Dates

• First Submitted: August 17, 2010
• First Submitted That Met QC Criteria: August 20, 2010
• First Posted (Estimate): August 23, 2010

Study Record Updates

• Last Update Posted (Estimate): September 8, 2010
• Last Update Submitted That Met QC Criteria: September 7, 2010
• Last Verified: September 1, 2010

More Information

Terms related to this study

• Keywords: cardiogenic shock; sepsis; ivabradine; heart rate; multiple organ dysfunction syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Shock; Syndrome; Multiple Organ Failure
• Other Study ID Numbers: KKSH-067