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

The recruitment status of this study is unknown because the information has not been verified recently.

Verified September 2010 by Martin-Luther-Universität Halle-Wittenberg.
Recruitment status was Recruiting

Sponsor:

Collaborators:

Servier

Koordinierungszentrum für Klinische Studien Halle (Saale)

Information provided by:

Martin-Luther-Universität Halle-Wittenberg

ClinicalTrials.gov Identifier:

NCT01186783

First received: August 17, 2010

Last updated: September 7, 2010

Last verified: September 2010

History of Changes

Purpose

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.

Condition	Intervention	Phase
Multiple Organ Dysfunction Syndrome	Drug: ivabradine	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Reducing Elevated Heart Rate in Patients With Multiple Organ Dysfunction Syndrome (MODS) by the "Funny Channel" Current (If) Inhibitor Ivabradine

Resource links provided by NLM:

MedlinePlus related topics: Shock

U.S. FDA Resources

Further study details as provided by Martin-Luther-Universität Halle-Wittenberg:

Primary Outcome Measures:

mean heart rate [ Time Frame: 4 days ] [ Designated as safety issue: No ]
percenage of patients with a reduction of the mean heart rate of at least 10 bpm 96 hours after the start of trial treatment

Secondary Outcome Measures:

morbidity [ Time Frame: 4 days ] [ Designated as safety issue: No ]
group-differences and patient-related changes of morbidity measured by serial APACHE II score monitoring and Sequential Organ Failure Assessment (SOFA) score monitoring
hemodynamic parameters [ Time Frame: 4 days ] [ Designated as safety issue: No ]
group-differences and patient-related changes of hemodynamic parameters (cardiac index and cardiac power index) as a consequence of ivabradine treatment
catecholamine dosage [ Time Frame: 4 days ] [ Designated as safety issue: No ]
required catecholamine dosage measured by a vasopressor score
microcirculation [ Time Frame: 4 days ] [ Designated as safety issue: No ]
improvement of microcirculation as measured by sublingual capillary density and flow
endothelial function [ Time Frame: 4 days ] [ Designated as safety issue: No ]
improvement of endothelial function as measured by the "Reactive hyperemia peripheral arterial tonometry-index"
mean heart rate [ Time Frame: 48 hours ] [ Designated as safety issue: No ]
comparison of the mean heart rate between the treatment and control group after 24 and 48 hours
mortality [ Time Frame: 6 months ] [ Designated as safety issue: No ]
28-day and 6 months mortality
cardiac autonomic dysfunction [ Time Frame: 4 days ] [ Designated as safety issue: No ]
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)
number of participants with adverse events as a measure of safety and tolerability [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
plasma levels of ivabradine in patients with MODS [ Time Frame: 4 days ] [ Designated as safety issue: No ]
daily measurement of plasma levels during the treatment period (4 days)
Differences of mortality in different age groups and MODS groups [ Time Frame: 6 months ] [ Designated as safety issue: No ]
age sub-groups:
1. patients <70 years on day of inclusion
2. patients ≥70 years on day of inclusion
MODS sub-groups:
1. patients with cardiogenic MODS
2. patients with septic MODS
Differences of adverse events in different age groups and MODS groups [ Time Frame: 6 months ] [ Designated as safety issue: No ]
age sub-groups:
1. patients <70 years on day of inclusion
2. patients ≥70 years on day of inclusion
MODS sub-groups:
1. patients with cardiogenic MODS
2. patients with septic MODS
Differences of heart rate in different age groups and MODS groups [ Time Frame: 6 months ] [ Designated as safety issue: No ]
age sub-groups:
1. patients <70 years on day of inclusion
2. patients ≥70 years on day of inclusion
MODS sub-groups:
1. patients with cardiogenic MODS
2. patients with septic MODS

Estimated Enrollment:	70
Study Start Date:	May 2010
Estimated Study Completion Date:	May 2012
Estimated Primary Completion Date:	November 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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 Name: Procoralan

Arms

Assigned Interventions

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 Name: Procoralan

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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))

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01186783

Contacts

Contact: Karl Werdan, MD, Professor

0049 345 557 ext 2601

karl.werdan@medizin.uni-halle.de

Locations

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

Sponsors and Collaborators

Martin-Luther-Universität Halle-Wittenberg

Servier

Koordinierungszentrum für Klinische Studien Halle (Saale)

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

More Information

Additional Information:

official homepage of the study center This link exits the ClinicalTrials.gov site

Publications:

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Cooney MT, Vartiainen E, Laatikainen T, Juolevi A, Dudina A, Graham IM. Elevated resting heart rate is an independent risk factor for cardiovascular disease in healthy men and women. Am Heart J. 2010 Apr;159(4):612-619.e3. Erratum in: Am Heart J. 2010 Jul;160(1):208. Laakitainen, Tinna [corrected to Laatikainen, Tiina].

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Heidland UE, Strauer BE. Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption. Circulation. 2001 Sep 25;104(13):1477-82.

Hennen R, Friedrich I, Hoyer D, Nuding S, Rauchhaus M, Schulze M, Schlisske S, Schwesig R, Schlitt A, Buerke M, Müller-Werdan U, Werdan K, Schmidt H. [Autonomic dysfunction and beta-adrenergic blockers in multiple organ dysfunction syndrome] Dtsch Med Wochenschr. 2008 Nov;133(48):2500-4. Epub 2008 Nov 19. German.

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Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G; International Sepsis Definitions Conference. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med. 2003 Apr;29(4):530-8. Epub 2003 Mar 28. Review.

Manz M, Reuter M, Lauck G, Omran H, Jung W. A single intravenous dose of ivabradine, a novel I(f) inhibitor, lowers heart rate but does not depress left ventricular function in patients with left ventricular dysfunction. Cardiology. 2003;100(3):149-55.

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Muller-Werdan U, Buerke M, Ebelt H, Heinroth KM, Herklotz A, Loppnow H, Ruß M, Schlegel F, Schlitt A, Schmidt HB, Söffker G, Werdan K. Septic cardiomyopathy - A not yet discovered cardiomyopathy? Exp Clin Cardiol. 2006 Fall;11(3):226-236.

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[No authors listed] Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000 May 4;342(18):1301-8.

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Werdan K, Schmidt H, Ebelt H, Zorn-Pauly K, Koidl B, Hoke RS, Heinroth K, Müller-Werdan U. Impaired regulation of cardiac function in sepsis, SIRS, and MODS. Can J Physiol Pharmacol. 2009 Apr;87(4):266-74. Review.

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Zorn-Pauly K, Pelzmann B, Lang P, Mächler H, Schmidt H, Ebelt H, Werdan K, Koidl B, Müller-Werdan U. Endotoxin impairs the human pacemaker current If. Shock. 2007 Dec;28(6):655-661.

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Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Nuding S, Ebelt H, Hoke RS, Krummenerl A, Wienke A, Müller-Werdan U, Werdan K. Reducing elevated heart rate in patients with multiple organ dysfunction syndrome by the I (f) (funny channel current) inhibitor ivabradine : MODI (f)Y trial. Clin Res Cardiol. 2011 Oct;100(10):915-23. Epub 2011 Jun 3.

Responsible Party:	Karl Werdan, MD, Professor, Medical Faculty of the Martin-Luther-University Halle-Wittenberg, Germany
ClinicalTrials.gov Identifier:	NCT01186783 History of Changes
Other Study ID Numbers:	KKSH-067
Study First Received:	August 17, 2010
Last Updated:	September 7, 2010
Health Authority:	Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by Martin-Luther-Universität Halle-Wittenberg:

heart rate
multiple organ dysfunction syndrome
ivabradine
sepsis
cardiogenic shock

Additional relevant MeSH terms:

Multiple Organ Failure
Shock
Pathologic Processes

ClinicalTrials.gov processed this record on May 19, 2013

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