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

Multiple Organ Dysfunction Syndrome Clinical Trial

— MODIfY  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01186783
• Other study ID #: KKSH-067
• Status: Recruiting
• Phase: Phase 2
• First received: August 17, 2010
• Last updated: September 7, 2010
• Start date: May 2010
• Est. completion date: May 2012

Study information

• Verified date: September 2010
• Source: Martin-Luther-Universität Halle-Wittenberg
• Contact: Karl Werdan, MD, Professor
• Phone: 0049 345 557
• Email: karl.werdan[@]medizin.uni-halle.de
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 70
• Est. completion date: May 2012
• Est. primary completion date: November 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Organ Dysfunction Syndrome
• Multiple Organ Failure
• Syndrome

Intervention

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

Locations

Country	Name	City	State
Germany	Department of Medicine III of the University Clinics Halle (Saale) of the Martin-Luther-University Halle-Wittenberg	Halle (Saale)	Saxony-Anhalt

Sponsors (3)

Lead Sponsor	Collaborator
Martin-Luther-Universität Halle-Wittenberg	KKS Netzwerk, Servier

Country where clinical trial is conducted

Germany, 

References & Publications (35)

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* Note: There are 35 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	catecholamine dosage	required catecholamine dosage measured by a vasopressor score	4 days	No
Secondary	microcirculation	improvement of microcirculation as measured by sublingual capillary density and flow	4 days	No
Secondary	endothelial function	improvement of endothelial function as measured by the "Reactive hyperemia peripheral arterial tonometry-index"	4 days	No
Secondary	mean heart rate	comparison of the mean heart rate between the treatment and control group after 24 and 48 hours	48 hours	No
Secondary	mortality	28-day and 6 months mortality	6 months	No
Secondary	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	No
Secondary	number of participants with adverse events as a measure of safety and tolerability		6 months	Yes
Secondary	plasma levels of ivabradine in patients with MODS	daily measurement of plasma levels during the treatment period (4 days)	4 days	No
Secondary	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	No
Secondary	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	No
Secondary	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	No

External Links

•   official homepage of the study center