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The Impact of IVIG Treatment on Critical Illness Polyneuropathy and/or Myopathy in Patients With MOF and SIRS/Sepsis (CIPNM)

Primary Purpose

Polyneuropathies

Status
Terminated
Phase
Phase 1
Locations
Austria
Study Type
Interventional
Intervention
IgM-enriched Intravenous Immunoglobulins
Human Albumin
Sponsored by
Medical University of Vienna
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Polyneuropathies focused on measuring Critical illness, Critical illness polyneuropathy and/or myopathy, Intravenous immunoglobulins, Multiple organ failure, SIRS, Sepsis

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Critically ill patients with failure of at least 2 organ systems diagnosed with SIRS or sepsis fulfilling the following inclusion criteria will be included in this study.

  1. Age Range: 18 - 80 years
  2. written information and consent as early as possible
  3. Male and female patients
  4. Clinical signs of incipient CIPNM:

    • decreased tendon reflexes as compared to the admission examination at the ICU
    • or weakness in responsive and co-operative patients as compared to the ad-mission examination at the ICU
    • or signs of incipient muscular atrophy as compared to the admission examination at the ICU

Organ failure:

Patients have to meet at least two of the following 5 criteria:

  • cardiovascular system dysfunction: arterial systolic blood pressure<90mm Hg, or mean arterial pressure < 70mm Hg for at least one hour despite adequate fluid resuscitation, adequate intravascular volume status or the use of vasopressors in an attempt to maintain a systolic blood pressure >90mm Hg or a mean arterial pressure >70mm Hg.
  • kidney dysfunction: Urine output < 0,5ml/kg body weight/ hour for 1 hour, despite adequate fluid resuscitation
  • respiratory system dysfunction: Ratio of PaO2 to FiO2 < 250 in the presence of other dysfunctional organs or systems
  • hematologic dysfunction: Platelet count <80.000/mm3 or decreased by 50% in the 3 days preceding enrollment (in the absence of liver cirrhosis or previously known hematological disease)
  • metabolic dysfunction: In case of unexplained metabolic acidosis - pH<7,30 or base deficit >5.0mmol/ litre in association with a plasma lactate level >1,5 times of the upper normal limit

SIRS:

Patients have to meet at least three of the following four criteria:

  • core temperature >38 or <36°C
  • heart rate >90 beats /min, except medical conditions known to increase heart rate
  • respiratory rate >20 breaths/min or a PaCO2 of <32mm Hg or the use of mechanical ventilation for an acute respiratory process
  • a white- cell count of>12.000 cells/mm3 or <4.000 cells/mm3 or a differential count showing >10% immature neutrophils

Sepsis:

Known or suspected infection evidenced by one or more of the following:

  • white cells or bacteria in a normally sterile body fluid
  • perforated viscus
  • radiographic evidence of pneumonia in the association with the production of purulent sputum
  • a syndrome associated with a high risk of infection

Exclusion Criteria:

The inclusion criteria have to be met at the time of enrolment into the study, i.e. at the start of the baseline period. Patients with any of the following conditions will be excluded from the study:

  1. Age < 18 years or > 80 years
  2. Weight >135 kg
  3. Pregnancy or breast-feeding
  4. Patients with known absolute IgA-deficiency with proven antibody formation against IgA
  5. Patients with known IVIG-intolerability
  6. Patients with known pre-existing neuromuscular disorders will not be included. Patients with documented pre-existing severe polyneuropathy will be excluded.
  7. Patients with known diseases of the peripheral nerval system and patients with pre-existing disease of the central nerval system with relevant impairment of the motor function.
  8. Patients with relevant pulmonary edema secondary to severe heart failure will be excluded because of the relatively high infusion volume (5ml /kg body weight per day over 3 days) determined by the study medication
  9. Patients not expected to survive 28 days because of uncorrectable medical condition, such as poorly controlled neoplasma or other end-stage disease
  10. Moribund state in which death is perceived to be imminent
  11. HIV infection in association with a last known CD4 count of<50/mm3
  12. Prediction, based on clinical judgement, that the patient will require chronic ventilatory support for non-respiratory reasons (e.g. neuromuscular disease, paraplegia

Sites / Locations

  • Medical University of Vienna

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

IgM-enriched Intravenous Immunoglobulins

Human Albumin

Arm Description

IgM-enriched IVIG (Pentaglobin, Biotest Pharma GmbH, Dreieich, Germany) at a dose of 0.25g/kg body weight/day as a continuous intravenous infusion at a rate of 2g/h over a period of 3 days

Human albumin 1% (Biotest Pharma GmbH, Dreieich, Germany) as placebo at a dose of 0.25g/kg body weight/day as a continuous intravenous infusion at a rate of 2g/h over a period of 3 days

Outcomes

Primary Outcome Measures

Effect of early IVIG versus placebo on CIPNM on day 14
The primary outcome was to assess the effect of early IVIG (IgM-enriched Intravenous immunoglobulins) versus placebo to mitigate CIPNM in critically ill patients as assessed by the CIPNM severity sum score on day 14. The CIPNM severity sum score is based on electrophysiological stimulation of the median, ulnar, and tibial nerves on days 0, 4, 7, 14 and on the histological evaluation of muscle biopsies on days 0 and 14 and ranged from 0 (no CIPNM) to 8 (very severe CIPNM).

Secondary Outcome Measures

Effect of early IVIG versus placebo on mortality from any cause within a 28-day period
This secondary outcome aimed to assess the effect of early IVIG versus placebo on mortality from any cause within a 28-day period.
Effect of early IVIG versus placebo on length of the ICU stay.
This secondary outcome aimed to assess the effect of early IVIG versus placebo on the length of the ICU stay. Length of ICU stay is defined as the time difference difference between admission of the patient to the ICU and discharge to a (non-ICU) ward or death. This outcome will be assessed an the day of ICU discharge.

Full Information

First Posted
May 23, 2013
Last Updated
May 29, 2013
Sponsor
Medical University of Vienna
Collaborators
Biotest Pharma GmbH, National Bank of Austria
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1. Study Identification

Unique Protocol Identification Number
NCT01867645
Brief Title
The Impact of IVIG Treatment on Critical Illness Polyneuropathy and/or Myopathy in Patients With MOF and SIRS/Sepsis
Acronym
CIPNM
Official Title
The Impact of Early Treatment With IgM-enriched IVIG on Critical Illness Polyneuropathy and/or Myopathy in Patients With Multiple Organ Failure and SIRS/Sepsis: A Prospective, Randomized, Placebo-controlled, Double-blinded Trial
Study Type
Interventional

2. Study Status

Record Verification Date
May 2013
Overall Recruitment Status
Terminated
Why Stopped
The trial was terminated early due to futility in reaching the primary endpoint.
Study Start Date
December 2004 (undefined)
Primary Completion Date
April 2009 (Actual)
Study Completion Date
April 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Medical University of Vienna
Collaborators
Biotest Pharma GmbH, National Bank of Austria

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
Critical illness polyneuropathy and/or myopathy (CIPNM) is a severe complication of critical illness. Retrospective data suggest that early application of IgM-enriched intravenous immunoglobulin (IVIG) may prevent or mitigate CIPNM. Therefore, the primary objective was to assess the effect of early IgM-enriched IVIG versus placebo to mitigate CIPNM in a prospective setting.
Detailed Description
Background: Critical illness polyneuropathy and/or myopathy (CIPNM) is a severe complication of critical illness. Retrospective data suggest that early application of IgM-enriched intravenous immunoglobulin (IVIG) may prevent or mitigate CIPNM. Therefore, the primary objective will be to assess the effect of early IgM-enriched IVIG versus placebo to mitigate CIPNM in a prospective setting. Design: Prospective, randomized, double-blinded and placebo-controlled trial Setting: Eight-bed medical ICU of a university hospital. Participants: Critically ill patients will be screened for eligibility defined as multiple organ failure (MOF) and SIRS/sepsis. Patients fulfilling these criteria will be further assessed by a neurologist for clinical signs of CIPNM. Critically ill patients with multiple organ failure (MOF), SIRS/sepsis, and early clinical signs of CIPNM will be randomized.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Polyneuropathies
Keywords
Critical illness, Critical illness polyneuropathy and/or myopathy, Intravenous immunoglobulins, Multiple organ failure, SIRS, Sepsis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
38 (Actual)

8. Arms, Groups, and Interventions

Arm Title
IgM-enriched Intravenous Immunoglobulins
Arm Type
Active Comparator
Arm Description
IgM-enriched IVIG (Pentaglobin, Biotest Pharma GmbH, Dreieich, Germany) at a dose of 0.25g/kg body weight/day as a continuous intravenous infusion at a rate of 2g/h over a period of 3 days
Arm Title
Human Albumin
Arm Type
Placebo Comparator
Arm Description
Human albumin 1% (Biotest Pharma GmbH, Dreieich, Germany) as placebo at a dose of 0.25g/kg body weight/day as a continuous intravenous infusion at a rate of 2g/h over a period of 3 days
Intervention Type
Drug
Intervention Name(s)
IgM-enriched Intravenous Immunoglobulins
Other Intervention Name(s)
IVIG, IgM-enriched IVIG
Intervention Description
IgM-enriched IVIG (Pentaglobin, Biotest Pharma GmbH, Dreieich, Germany) at a dose of 0.25g/kg body weight/day as a continuous intravenous infusion at a rate of 2g/h over a period of 3 days.
Intervention Type
Drug
Intervention Name(s)
Human Albumin
Other Intervention Name(s)
Placebo
Intervention Description
Human albumin 1% (Biotest Pharma GmbH, Dreieich, Germany) as placebo at a dose of 0.25g/kg body weight/day as a continuous intravenous infusion at a rate of 2g/h over a period of 3 days
Primary Outcome Measure Information:
Title
Effect of early IVIG versus placebo on CIPNM on day 14
Description
The primary outcome was to assess the effect of early IVIG (IgM-enriched Intravenous immunoglobulins) versus placebo to mitigate CIPNM in critically ill patients as assessed by the CIPNM severity sum score on day 14. The CIPNM severity sum score is based on electrophysiological stimulation of the median, ulnar, and tibial nerves on days 0, 4, 7, 14 and on the histological evaluation of muscle biopsies on days 0 and 14 and ranged from 0 (no CIPNM) to 8 (very severe CIPNM).
Time Frame
day 14
Secondary Outcome Measure Information:
Title
Effect of early IVIG versus placebo on mortality from any cause within a 28-day period
Description
This secondary outcome aimed to assess the effect of early IVIG versus placebo on mortality from any cause within a 28-day period.
Time Frame
28 days
Title
Effect of early IVIG versus placebo on length of the ICU stay.
Description
This secondary outcome aimed to assess the effect of early IVIG versus placebo on the length of the ICU stay. Length of ICU stay is defined as the time difference difference between admission of the patient to the ICU and discharge to a (non-ICU) ward or death. This outcome will be assessed an the day of ICU discharge.
Time Frame
ICU stay, an expected average of 30 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Critically ill patients with failure of at least 2 organ systems diagnosed with SIRS or sepsis fulfilling the following inclusion criteria will be included in this study. Age Range: 18 - 80 years written information and consent as early as possible Male and female patients Clinical signs of incipient CIPNM: decreased tendon reflexes as compared to the admission examination at the ICU or weakness in responsive and co-operative patients as compared to the ad-mission examination at the ICU or signs of incipient muscular atrophy as compared to the admission examination at the ICU Organ failure: Patients have to meet at least two of the following 5 criteria: cardiovascular system dysfunction: arterial systolic blood pressure<90mm Hg, or mean arterial pressure < 70mm Hg for at least one hour despite adequate fluid resuscitation, adequate intravascular volume status or the use of vasopressors in an attempt to maintain a systolic blood pressure >90mm Hg or a mean arterial pressure >70mm Hg. kidney dysfunction: Urine output < 0,5ml/kg body weight/ hour for 1 hour, despite adequate fluid resuscitation respiratory system dysfunction: Ratio of PaO2 to FiO2 < 250 in the presence of other dysfunctional organs or systems hematologic dysfunction: Platelet count <80.000/mm3 or decreased by 50% in the 3 days preceding enrollment (in the absence of liver cirrhosis or previously known hematological disease) metabolic dysfunction: In case of unexplained metabolic acidosis - pH<7,30 or base deficit >5.0mmol/ litre in association with a plasma lactate level >1,5 times of the upper normal limit SIRS: Patients have to meet at least three of the following four criteria: core temperature >38 or <36°C heart rate >90 beats /min, except medical conditions known to increase heart rate respiratory rate >20 breaths/min or a PaCO2 of <32mm Hg or the use of mechanical ventilation for an acute respiratory process a white- cell count of>12.000 cells/mm3 or <4.000 cells/mm3 or a differential count showing >10% immature neutrophils Sepsis: Known or suspected infection evidenced by one or more of the following: white cells or bacteria in a normally sterile body fluid perforated viscus radiographic evidence of pneumonia in the association with the production of purulent sputum a syndrome associated with a high risk of infection Exclusion Criteria: The inclusion criteria have to be met at the time of enrolment into the study, i.e. at the start of the baseline period. Patients with any of the following conditions will be excluded from the study: Age < 18 years or > 80 years Weight >135 kg Pregnancy or breast-feeding Patients with known absolute IgA-deficiency with proven antibody formation against IgA Patients with known IVIG-intolerability Patients with known pre-existing neuromuscular disorders will not be included. Patients with documented pre-existing severe polyneuropathy will be excluded. Patients with known diseases of the peripheral nerval system and patients with pre-existing disease of the central nerval system with relevant impairment of the motor function. Patients with relevant pulmonary edema secondary to severe heart failure will be excluded because of the relatively high infusion volume (5ml /kg body weight per day over 3 days) determined by the study medication Patients not expected to survive 28 days because of uncorrectable medical condition, such as poorly controlled neoplasma or other end-stage disease Moribund state in which death is perceived to be imminent HIV infection in association with a last known CD4 count of<50/mm3 Prediction, based on clinical judgement, that the patient will require chronic ventilatory support for non-respiratory reasons (e.g. neuromuscular disease, paraplegia
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christian Madl, MD
Organizational Affiliation
Medical University of Vienna
Official's Role
Principal Investigator
Facility Information:
Facility Name
Medical University of Vienna
City
Vienna
ZIP/Postal Code
1090
Country
Austria

12. IPD Sharing Statement

Citations:
PubMed Identifier
24088271
Citation
Brunner R, Rinner W, Haberler C, Kitzberger R, Sycha T, Herkner H, Warszawska J, Madl C, Holzinger U. Early treatment with IgM-enriched intravenous immunoglobulin does not mitigate critical illness polyneuropathy and/or myopathy in patients with multiple organ failure and SIRS/sepsis: a prospective, randomized, placebo-controlled, double-blinded trial. Crit Care. 2013 Oct 2;17(5):R213. doi: 10.1186/cc13028.
Results Reference
derived

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The Impact of IVIG Treatment on Critical Illness Polyneuropathy and/or Myopathy in Patients With MOF and SIRS/Sepsis

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