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

Primary Purpose

Multiple Organ Dysfunction Syndrome

Status
Unknown status
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
ivabradine
Sponsored by
Martin-Luther-Universität Halle-Wittenberg
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Multiple Organ Dysfunction Syndrome focused on measuring heart rate, multiple organ dysfunction syndrome, ivabradine, sepsis, cardiogenic shock

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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))

Sites / Locations

  • Department of Medicine III of the University Clinics Halle (Saale) of the Martin-Luther-University Halle-WittenbergRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

No Intervention

Active Comparator

Arm Label

standard treatment

ivabradine (add-on)

Arm Description

All patients receive established medical therapy according to current guidelines and therapeutic standards.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

morbidity
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
group-differences and patient-related changes of hemodynamic parameters (cardiac index and cardiac power index) as a consequence of ivabradine treatment
catecholamine dosage
required catecholamine dosage measured by a vasopressor score
microcirculation
improvement of microcirculation as measured by sublingual capillary density and flow
endothelial function
improvement of endothelial function as measured by the "Reactive hyperemia peripheral arterial tonometry-index"
mean heart rate
comparison of the mean heart rate between the treatment and control group after 24 and 48 hours
mortality
28-day and 6 months mortality
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)
number of participants with adverse events as a measure of safety and tolerability
plasma levels of ivabradine in patients with MODS
daily measurement of plasma levels during the treatment period (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
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
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

Full Information

First Posted
August 17, 2010
Last Updated
September 7, 2010
Sponsor
Martin-Luther-Universität Halle-Wittenberg
Collaborators
Servier, KKS Netzwerk
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1. Study Identification

Unique Protocol Identification Number
NCT01186783
Brief Title
Reducing Elevated Heart Rate in Patients With Multiple Organ Dysfunction Syndrome (MODS) by Ivabradine
Acronym
MODIfY
Official Title
Reducing Elevated Heart Rate in Patients With Multiple Organ Dysfunction Syndrome (MODS) by the "Funny Channel" Current (If) Inhibitor Ivabradine
Study Type
Interventional

2. Study Status

Record Verification Date
September 2010
Overall Recruitment Status
Unknown status
Study Start Date
May 2010 (undefined)
Primary Completion Date
November 2011 (Anticipated)
Study Completion Date
May 2012 (Anticipated)

3. Sponsor/Collaborators

Name of the Sponsor
Martin-Luther-Universität Halle-Wittenberg
Collaborators
Servier, KKS Netzwerk

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Organ Dysfunction Syndrome
Keywords
heart rate, multiple organ dysfunction syndrome, ivabradine, sepsis, cardiogenic shock

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
70 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
standard treatment
Arm Type
No Intervention
Arm Description
All patients receive established medical therapy according to current guidelines and therapeutic standards.
Arm Title
ivabradine (add-on)
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
ivabradine
Other Intervention Name(s)
Procoralan
Intervention Description
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
Primary Outcome Measure Information:
Title
mean heart rate
Description
percenage of patients with a reduction of the mean heart rate of at least 10 bpm 96 hours after the start of trial treatment
Time Frame
4 days
Secondary Outcome Measure Information:
Title
morbidity
Description
group-differences and patient-related changes of morbidity measured by serial APACHE II score monitoring and Sequential Organ Failure Assessment (SOFA) score monitoring
Time Frame
4 days
Title
hemodynamic parameters
Description
group-differences and patient-related changes of hemodynamic parameters (cardiac index and cardiac power index) as a consequence of ivabradine treatment
Time Frame
4 days
Title
catecholamine dosage
Description
required catecholamine dosage measured by a vasopressor score
Time Frame
4 days
Title
microcirculation
Description
improvement of microcirculation as measured by sublingual capillary density and flow
Time Frame
4 days
Title
endothelial function
Description
improvement of endothelial function as measured by the "Reactive hyperemia peripheral arterial tonometry-index"
Time Frame
4 days
Title
mean heart rate
Description
comparison of the mean heart rate between the treatment and control group after 24 and 48 hours
Time Frame
48 hours
Title
mortality
Description
28-day and 6 months mortality
Time Frame
6 months
Title
cardiac autonomic dysfunction
Description
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)
Time Frame
4 days
Title
number of participants with adverse events as a measure of safety and tolerability
Time Frame
6 months
Title
plasma levels of ivabradine in patients with MODS
Description
daily measurement of plasma levels during the treatment period (4 days)
Time Frame
4 days
Title
Differences of mortality in different age groups and MODS groups
Description
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
Time Frame
6 months
Title
Differences of adverse events in different age groups and MODS groups
Description
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
Time Frame
6 months
Title
Differences of heart rate in different age groups and MODS groups
Description
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
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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))
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Karl Werdan, MD, Professor
Phone
0049 345 557
Ext
2601
Email
karl.werdan@medizin.uni-halle.de
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Karl Werdan, MD, Professor
Organizational Affiliation
Medical Faculty of the Martin-Luther-University Halle-Wittenberg, Germany
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Henning Ebelt, MD
Organizational Affiliation
Medical Faculty of the Martin-Luther-University Halle-Wittenberg, Germany
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Sebastian Nuding, MD
Organizational Affiliation
Medical Faculty of the Martin-Luther-University Halle-Wittenberg, Germany
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Medicine III of the University Clinics Halle (Saale) of the Martin-Luther-University Halle-Wittenberg
City
Halle (Saale)
State/Province
Saxony-Anhalt
ZIP/Postal Code
06120
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Karl Werdan, MD, Professor
Phone
0049 345 557
Ext
2601
Email
karl.werdan@medizin.uni-halle.de

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

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