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

Study Status: Completed
Recruit Status: Unknown status
Study Type: Interventional

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

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 Summary:

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.

Sponsor: Martin-Luther-Universität Halle-Wittenberg

Current Primary Outcome: mean heart rate [ Time Frame: 4 days ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

• morbidity [ Time Frame: 4 days ]
  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 ]
  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 ]
  required catecholamine dosage measured by a vasopressor score
• microcirculation [ Time Frame: 4 days ]
  improvement of microcirculation as measured by sublingual capillary density and flow
• endothelial function [ Time Frame: 4 days ]
  improvement of endothelial function as measured by the "Reactive hyperemia peripheral arterial tonometry-index"
• mean heart rate [ Time Frame: 48 hours ]
  comparison of the mean heart rate between the treatment and control group after 24 and 48 hours
• mortality [ Time Frame: 6 months ]
  28-day and 6 months mortality
• cardiac autonomic dysfunction [ Time Frame: 4 days ]
  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 ]
• plasma levels of ivabradine in patients with MODS [ Time Frame: 4 days ]
  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 ]

  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 ]

  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 ]

  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

Original Secondary Outcome:

• morbidity [ Time Frame: 4 days ]
  group-differences and patient-related changes of morbidity measured by serial APACHE II score monitoring and SOFA score monitoring
• hemodynamic parameters [ Time Frame: 4 days ]
  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 ]
  required catecholamine dosage measured by a vasopressor score
• microcirculation [ Time Frame: 4 days ]
  improvement of microcirculation as measured by sublingual capillary density and flow with the SDF technique
• endothelial function [ Time Frame: 4 days ]
  improvement of endothelial function as measured by the "Reactive hyperemia peripheral arterial tonometry-index"
• mean heart rate [ Time Frame: 48 hours ]
  comparison of the mean heart rate between the treatment and control group after 24 and 48 hours
• mortality [ Time Frame: 6 months ]
  28-day and 6 months mortality
• Differences of heart rate, morbidity, mortality and adverse events in different age groups and MODS groups [ Time Frame: 6 months ]

  age sub-groups:

  1. patients <70 years at day of inclusion
  2. patients ≥70 years at day of inclusion

  MODS sub-groups:

  1. patients with cardiogenic MODS
  2. patients with septic MODS
• cardiac autonomic dysfunction [ Time Frame: 4 days ]
  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 ]
• plasma levels of ivabradine in patients with MODS [ Time Frame: 4 days ]
  daily measurement of plasma levels during the treatment period (4 days)

Information By: Martin-Luther-Universität Halle-Wittenberg

Dates:
Date Received: August 17, 2010
Date Started: May 2010
Date Completion: May 2012
Last Updated: September 7, 2010
Last Verified: September 2010