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Trial for the Treatment of Extensively Drug-Resistant Gram-negative Bacilli (OVERCOME)

Sponsor
University of Michigan (Other)
Overall Status
Completed
CT.gov ID
NCT01597973
Collaborator
(none)
467
Enrollment
19
Locations
2
Arms
94.1
Actual Duration (Months)
24.6
Patients Per Site
0.3
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Approximately 444 subjects who are greater than or equal to 18 to 95 years of age, are non-pregnant, and are in the inpatient setting of one of the study sites will be evaluated to treatment efficacy. Analysis will include subjects with bloodstream infection (BSI) or pneumonia due to at least one of the following gram-negative bacilli organisms: Acinetobacter baumannii, Klebsiella spp, Escherichia coli, Enterobacter spp. and/or Pseudomonas aeruginosa that demonstrates in vitro non-susceptibility defined as extensively drug-resistant Gram-negative bacilli (XDR-GNB) which includes XDR-AB, XDR-PA and CRE. If a subject has both BSI and pneumonia at the time of study enrollment, they will be included as a subject with pneumonia.

Objectives:
Primary:

•Determine whether the treatment regimen of Colistimethate sodium (colistin) combined with a carbapenem (imipenem or meropenem) is associated with a decreased risk for mortality compared to colistin alone for subjects with bloodstream infection (BSI) and/or pneumonia due to XDR-GNB.

Secondary:

•Determine what treatment regimen (colistin monotherapy or colistin combined with a carbapenem (imipenem or meropenem) is more likely to reduce the emergence of colistin resistance among XDR-GNB isolates during therapy.

Condition or Disease Intervention/Treatment Phase
  • Drug: colistin and meropenem
  • Drug: colistin and placebo
 Phase 3

Detailed Description

The Gram-negative bacilli organisms Acinetobacter baumannii, Klebsiella spp., Escherichia coli, Enterobacter spp. and Pseudomonas aeruginosa have become a frequent cause of bloodstream infection and pneumonia in the hospital and other healthcare settings. Among these pathogens, antimicrobial resistance has emerged to many classes of antimicrobial agents. Most concerning, has been the emergence of resistance to group 2 carbapenems (such as imipenem). In several regions of the world, including Southeastern Michigan, strains of extensively-drug resistant Gram-negative bacilli (XDR-GNB) that exhibit resistance to most, and in some cases all types of available antimicrobial agents, including group 2 carbapenems, have emerged and disseminated. Treatment options for XDR-GNB typically include Colistimethate sodium (referred to as colistin in this study), used alone (monotherapy) or in combination with other agents. Unfortunately, resistance to colistin has begun to emerge in some strains of XDR-GNB, which is a truly concerning development, since colistin is one of the last remaining treatment options for XDR-GNB. No prospective, randomized controlled trials have been conducted to evaluate the clinical efficacy of colistin monotherapy versus colistin-containing combination therapy or the impact of these therapeutic modalities on the emergence of colistin resistance among XDR-GNB. We plan to conduct a double-blind randomized controlled trial including patients with pneumonia and bloodstream infection due to XDR-GNB. After enrollment, subjects will be randomized to receive 14 days of either colistin monotherapy or colistin plus meropenem.

In the Detroit metro area, infections due to XDR-GNB have developed into a regional challenge and common problem. We have assembled a multi-disciplinary team that includes Infectious Diseases researchers, clinicians, infectious diseases pharmacists, microbiologists, epidemiologists and statistical experts to address critically important questions and challenges regarding the management of bloodstream infection and pneumonia due to XDR-GNB. Specifically, we hypothesize that the combination of colistin and imipenem will provide superior efficacy in the treatment of XDR-GNB pneumonia and bloodstream infection and will prevent the emergence of decreased susceptibility to colistin among XDR-GNB strains. We also aim to analyze tools that could be used in "real time" to aid clinicians treating patients with infection due to XDR-GNB. For example, we aim to analyze the association between the presence of in vitro synergy of the colistin and carbapenem (imipenem or meropenem) combination (as determined by E-test) and clinical outcomes; and the association between colistin plasma levels and clinical outcomes and the development of nephrotoxicity.

August 5, 2021: Due to the growing threat of XDR-GNB around the world, several international sites were added including sites in Thailand, Taiwan, Israel, Greece, Italy and Bulgaria.

Study Design

Study Type:
Interventional
Actual Enrollment :
467 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
Randomized Controlled Trial for the Treatment of Extensively Drug-Resistant Gram-negative Bacilli (OVERCOME)
Actual Study Start Date :
Oct 6, 2012
Actual Primary Completion Date :
Aug 9, 2020
Actual Study Completion Date :
Aug 9, 2020

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: colistin and meropenem

Drug: colistin and meropenem
colistin standard loading dose, maintenance dose based on patients renal function meropenem- dose based on patients renal function
Other Names:
  • Colistimethate
  • Meropenem

    		•
    Active Comparator: colistin and placebo

    Drug: colistin and placebo
    colistin- loading dose standard, maintenance dosed based on patients renal function placebo- mimic meropenem (blinded)
    Other Names:
  • Colistimethate

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Mortality [participants will be followed daily for the duration of hospital stay, an expected average of 4 weeks]

      Determine whether the treatment regimen of colistin combined with a carbapenem (imipenem or meropenem) is associated with a decreased risk for all-cause mortality during the 30 day post-enrollment period compared to colistin combined with a placebo for subjects with bloodstream infection (BSI) and/or pneumonia due to extensively drug-resistant Gram-negative bacilli (XDR-GNB).

    Secondary Outcome Measures

    1. Number of Participants Who Develop Colistin Resistance [patients' resistance data will be collected up to 30 days]

      Determine what treatment regimen (colistin monotherapy (combined with placebo)) or colistin combined a carbapenem (imipenem or meropenem) is more likely to reduce the frequency of emergence of colistin resistance among XDR-GNB isolates during therapy. Measurements of Minimum Inhibitory Concentration of colistin to XDR-GNB. This is shown below as numbers of those subjects who develop colistin resistance and their percentages of the total completed population.

    2. Clinical Failure at the End of Therapy [48 hours after end of treatment, that is up to 16 days]

      Clinical failure as defined by either Blood Stream Infection (BSI) or Pneumonia; based on death between 48 hours and end of treatment, medication change from protocol, a positive blood culture after 5 days of blood stream infection treatment, or no improvements in PaO2/FiO2 at end of treatment.

    3. Microbiologic Cure at the End of Therapy [From 5 days after enrollment up to 14 days following enrollment (i.e. end of treatment)]

      Microbiologic cure at the end of therapy as defined by the number of participants who no longer have the causative XDR-GNB pathogens for their BSI or pneumonia identified based on microbiologic testing

    4. Number of Participants With Toxicities Related to Treatment Medications [Up to 16 days]

      Frequency is shown for each of the following: Nephrotoxicity, Hepatotoxicity, Seizures, Neurotoxicity, Hypersensitivity reaction

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 95 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Hospitalized Adults (> 18 years to 95 years of age), at one of the study sites.

    • Diagnosis of BSI and/or pneumonia due to a preliminary result of gram-negative non-lactose fermenter that is oxidase negative; or a final results of XDR-A. baumannii; carbapenem-resistant Enterobacteriaceae; or XDR- P. aeruginosa and/or patients with suspected BSI and/or HAP (hospital acquired pneumonia) and who have had a prior history (within last 6 months) of XDR-GNB that was susceptible to colistin.

    o If final results do not indicate that the pathogen is an XDR-GNB, and identifies alternative treatment options, the patient would be eligible for the study if the subject is allergic to all the alternative treatment options.

    • Patients with polymicrobial respiratory or blood infections, including XDR-GNB and one or more pathogens, will be included in the study, as long as the XDR-GNB is determined to be a true pathogen (AB, CRE or PA). Other pathogens will be treated with antimicrobial agents as determined by the treating physician.

    • If more than one XDR-GNB study pathogens is identified as a study pathogen causing BSI and/or pneumonia, then the first study pathogen recovered will be considered as the primary study pathogen. If more than one study pathogen is recovered from the same culture, then the infection will be categorized as being caused by multiple study pathogens.

    • Patients with a life expectancy of > 24 hours

    • Signed written informed consent and HIPAA Authorization form (US sites)

    Exclusion Criteria:

    • Female patients who are pregnant

    • Female patients who are nursing

    • Patients who are prisoners

    • Patients who are less than 18 years of age or greater than or equal to 96 years of age

    • Patients with neutropenia (WBC < 500 cells/mm3)

    • The presence of any of the following known clinical syndromes involving XDR-GNB as a pathogen which necessitate durations of antimicrobial therapies greater than 14 days: endocarditis, osteomyelitis, prosthetic joint infections, meningitis and/or other central nervous system infections.

    • Patients receiving valproic acid (with or without a known seizure disorder).

    • Patients who received 72 hours or more of polymyxin treatment (intravenous or inhaled [pneumonia]) within 96 hours of enrollment.

    • Patients who have end-stage renal disease requiring hemodialysis, will be excluded from evaluation pertaining to nephrotoxicity in the per protocol population.

    • Patients with known Type 1 or other severe drug allergy to either of the study drugs or to β-lactams.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Jackson Memorial Hospital-Jackson Health System Miami Florida United States 33136
    2 Wayne State University Detroit Michigan United States 48201
    3 Henry Ford Health System Detroit Michigan United States 48202
    4 Beaumont Health System Royal Oak Michigan United States 48073
    5 Mount Sinai Hospital New York New York United States 10029
    6 The Ohio State University Wexner Medical Center Columbus Ohio United States 43210
    7 University Multiprofile Hospital for Active Treatment and Emergency Medicine "N.I. Pirogov" Sofia Bulgaria 1606
    8 Evangelismos General Hospital of Athens Athens Greece 10676
    9 General Hospital of Athens "Laiko" 1st Department of Medicine Athens Greece 11527
    10 Attikon University General Hospital of Athens Athens Greece 12461
    11 University Hospital of Heraklion Crete Greece 71110
    12 Hippokration General Hospital of Thessaloniki Thessaloníki Greece 54642
    13 Assaf Harofeh Medical Center Zerifin Beer Yaakov Israel 70300
    14 Rabin Medical Centre, Beilinson Campus Petach Tikva Central District Israel 49100
    15 Rambam Health Care Campus Haifa Israel 31096
    16 Tel-Aviv Sourasky Medical Center Tel Aviv Israel 64239
    17 Universita della Campania 'Luigi Vanvitelli' Naples Italy 80131
    18 Chang Gung Memorial Hospital Tao-Yuan Kwei-San Taiwan 33305
    19 Siriraj Hospital Bangkoknoi Bangkok Thailand 10700

    Sponsors and Collaborators

    • University of Michigan

    Investigators

    • Principal Investigator: Keith S Kaye, MD, MPH, University of Michigan

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Keith Kaye, Keith Kaye, M.D.,M.P.H Study PI, University of Michigan
    ClinicalTrials.gov Identifier:
    NCT01597973
    Other Study ID Numbers:
    • NIH 10-0065
    First Posted:
    May 15, 2012
    Last Update Posted:
    Nov 30, 2021
    Last Verified:
    Nov 1, 2021
    Additional relevant MeSH terms:
    Sepsis
    Meropenem
    Colistin

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail While 467 participants completed an informed consent document, 3 were deemed ineligible
    Arm/Group Title Colistin and Placebo Colistin and a Carbapenem
    Arm/Group Description colistin and placebo: colistin- loading dose standard, maintenance dosed based on patient's renal function placebo- mimic meropenem (blinded) colistin and a carbapenem: colistin standard loading dose, maintenance dose based on patient's renal function carbapenem- dose based on patient's renal function
    Period Title: Overall Study
    STARTED 234 230
    Began First Dose 230 228
    COMPLETED 214 211
    NOT COMPLETED 20 19

    Baseline Characteristics

    Arm/Group Title Colistin and Placebo Colistin and a Carbapenem Total
    Arm/Group Description colistin and placebo: colistin- loading dose standard, maintenance dosed based on patient's renal function placebo- mimic meropenem (blinded) colistin and a carbapenem: colistin standard loading dose, maintenance dose based on patient's renal function carbapenem- dose based on patient's renal function Total of all reporting groups
    Overall Participants 234 230 464
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    68.0
    (16.3)
    68.4
    (15.4)
    68.2
    (15.9)
    Sex: Female, Male (Count of Participants)
    Female
    90
    38.5%
    84
    36.5%
    174
    37.5%
    Male
    144
    61.5%
    146
    63.5%
    290
    62.5%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    2
    0.9%
    0
    0%
    2
    0.4%
    Asian
    96
    41%
    91
    39.6%
    187
    40.3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    17
    7.3%
    14
    6.1%
    31
    6.7%
    White
    116
    49.6%
    120
    52.2%
    236
    50.9%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    3
    1.3%
    5
    2.2%
    8
    1.7%
    Region of Enrollment (participants) [Number]
    Greece
    14
    6%
    15
    6.5%
    29
    6.3%
    United States
    26
    11.1%
    23
    10%
    49
    10.6%
    Taiwan
    29
    12.4%
    28
    12.2%
    57
    12.3%
    Italy
    4
    1.7%
    5
    2.2%
    9
    1.9%
    Israel
    89
    38%
    93
    40.4%
    182
    39.2%
    Thailand
    68
    29.1%
    64
    27.8%
    132
    28.4%
    Bulgaria
    4
    1.7%
    2
    0.9%
    6
    1.3%

    Outcome Measures

    1. Primary Outcome
    Title Mortality
    Description Determine whether the treatment regimen of colistin combined with a carbapenem (imipenem or meropenem) is associated with a decreased risk for all-cause mortality during the 30 day post-enrollment period compared to colistin combined with a placebo for subjects with bloodstream infection (BSI) and/or pneumonia due to extensively drug-resistant Gram-negative bacilli (XDR-GNB).
    Time Frame participants will be followed daily for the duration of hospital stay, an expected average of 4 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Colistin and Placebo Colistin and a Carbapenem
    Arm/Group Description colistin and placebo: colistin- loading dose standard, maintenance dose based on patient's renal function placebo- mimic meropenem (blinded) colistin and a carbapenem: colistin standard loading dose, maintenance dose based on patient's renal function carbapenem- dose based on patient's renal function
    Measure Participants 214 211
    Dead
    92
    39.3%
    78
    33.9%
    Alive
    122
    52.1%
    133
    57.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Colistin and Placebo, Colistin and a Carbapenem
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.21
    Comments
    Method Chi-squared
    Comments
    2. Secondary Outcome
    Title Number of Participants Who Develop Colistin Resistance
    Description Determine what treatment regimen (colistin monotherapy (combined with placebo)) or colistin combined a carbapenem (imipenem or meropenem) is more likely to reduce the frequency of emergence of colistin resistance among XDR-GNB isolates during therapy. Measurements of Minimum Inhibitory Concentration of colistin to XDR-GNB. This is shown below as numbers of those subjects who develop colistin resistance and their percentages of the total completed population.
    Time Frame patients' resistance data will be collected up to 30 days

    Outcome Measure Data

    Analysis Population Description
    Follow up cultures were unable to be obtained for some subjects. Therefore emergence of resistance status for those subjects could not be determined.
    Arm/Group Title Colistin and Placebo Colistin and a Carbapenem
    Arm/Group Description colistin and placebo: colistin- loading dose standard, maintenance dose based on patient's renal function placebo- mimic meropenem (blinded) colistin and a carbapenem: colistin standard loading dose, maintenance dose based on patient's renal function carbapenem- dose based on patient's renal function
    Measure Participants 173 173
    Count of Participants [Participants]
    18
    7.7%
    15
    6.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Colistin and Placebo, Colistin and a Carbapenem
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5830
    Comments
    Method Chi-squared
    Comments
    3. Secondary Outcome
    Title Clinical Failure at the End of Therapy
    Description Clinical failure as defined by either Blood Stream Infection (BSI) or Pneumonia; based on death between 48 hours and end of treatment, medication change from protocol, a positive blood culture after 5 days of blood stream infection treatment, or no improvements in PaO2/FiO2 at end of treatment.
    Time Frame 48 hours after end of treatment, that is up to 16 days

    Outcome Measure Data

    Analysis Population Description
    54 patients were omitted due to death before 48 hours (n=40) or incomplete PaO2/FiO2 data (n=14).
    Arm/Group Title Colistin and Placebo Colistin and a Carbapenem
    Arm/Group Description colistin and placebo: colistin- loading dose standard, maintenance dosed based on patient's renal function placebo-mimic meropenem (blinded) colistin and a carbapenem: colistin standard loading dose, maintenance dose based on patient's renal function carbapenem- dose based on patient's renal function
    Measure Participants 186 185
    Count of Participants [Participants]
    115
    49.1%
    97
    42.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Colistin and Placebo, Colistin and a Carbapenem
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.07
    Comments
    Method Chi-squared
    Comments
    4. Secondary Outcome
    Title Microbiologic Cure at the End of Therapy
    Description Microbiologic cure at the end of therapy as defined by the number of participants who no longer have the causative XDR-GNB pathogens for their BSI or pneumonia identified based on microbiologic testing
    Time Frame From 5 days after enrollment up to 14 days following enrollment (i.e. end of treatment)

    Outcome Measure Data

    Analysis Population Description
    Some patients did not have data in the time window of interest (from 5 days following enrollment until end of treatment, 14 days) (e.g. from some specimens not being produced or available).
    Arm/Group Title Colistin and Placebo Colistin and a Carbapenem
    Arm/Group Description colistin and placebo: colistin- loading dose standard, maintenance dosed based on patient's renal function placebo- mimic meropenem (blinded) colistin and a carbapenem: colistin standard loading dose, maintenance dose based on patient's renal function carbapenem- dose based on patient's renal function
    Measure Participants 169 174
    Cure
    112
    47.9%
    105
    45.7%
    Failure
    57
    24.4%
    69
    30%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Colistin and Placebo, Colistin and a Carbapenem
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.255
    Comments
    Method Chi-squared
    Comments
    5. Secondary Outcome
    Title Number of Participants With Toxicities Related to Treatment Medications
    Description Frequency is shown for each of the following: Nephrotoxicity, Hepatotoxicity, Seizures, Neurotoxicity, Hypersensitivity reaction
    Time Frame Up to 16 days

    Outcome Measure Data

    Analysis Population Description
    Follow up creatinine clearance data was missing from many patients resulting in a smaller analysis population for nephrotoxicity.
    Arm/Group Title Colistin and Placebo Colistin and a Carbapenem
    Arm/Group Description colistin and placebo: colistin- loading dose standard, maintenance dosed based on patient's renal function placebo- mimic meropenem (blinded) colistin and a carbapenem: colistin standard loading dose, maintenance dose based on patient's renal function carbapenem- dose based on patient's renal function
    Measure Participants 214 211
    Nephrotoxicity
    88
    37.6%
    85
    37%
    Hypersensitivity reaction
    3
    1.3%
    7
    3%
    Hepatotoxicity
    32
    13.7%
    31
    13.5%
    Seizures
    4
    1.7%
    3
    1.3%
    Neurotoxicity
    11
    4.7%
    5
    2.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Colistin and Placebo, Colistin and a Carbapenem
    Comments nephrotoxicity analysis
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.59
    Comments
    Method Chi-squared
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Colistin and Placebo, Colistin and a Carbapenem
    Comments Hypersensitivity analysis
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.22
    Comments
    Method Fisher Exact
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Colistin and Placebo, Colistin and a Carbapenem
    Comments Hepatoxicity analysis
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.94
    Comments
    Method Chi-squared
    Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Colistin and Placebo, Colistin and a Carbapenem
    Comments Seizures analysis
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 1.00
    Comments
    Method Fisher Exact
    Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Colistin and Placebo, Colistin and a Carbapenem
    Comments Neurotoxicity analysis
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.20
    Comments
    Method Fisher Exact
    Comments

    Adverse Events

    Time Frame For AEs, the assessment period begins at the time of enrollment and continues until 48 hours after end of treatment, that is up to 16 days. (as 48 hours is total removal of colistin from the patient has occurred). All-Cause Mortality, the Primary Objective is assessed up to 30 days after enrollment.
    Adverse Event Reporting Description
    Arm/Group Title Colistin and Placebo Colistin and a Carbapenem
    Arm/Group Description colistin and placebo: colistin- loading dose standard, maintenance dosed based on patient's renal function placebo- mimic meropenem (blinded) colistin and carbapenem: colistin standard loading dose, maintenance dose based on patient's renal function carbapenem- dose based on patient's renal function
    All Cause Mortality
    Colistin and Placebo Colistin and a Carbapenem
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 98/230 (42.6%) 85/228 (37.3%)
    Serious Adverse Events
    Colistin and Placebo Colistin and a Carbapenem
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 13/230 (5.7%) 10/228 (4.4%)
    Cardiac disorders
    Acute coronary syndrome 0/230 (0%) 1/228 (0.4%)
    Cardiac arrest 2/230 (0.9%) 1/228 (0.4%)
    Gastrointestinal disorders
    Gastric hemorrhage 1/230 (0.4%) 0/228 (0%)
    Intestinal ischemia 0/230 (0%) 1/228 (0.4%)
    Intra-abdominal hemorrhage 0/230 (0%) 1/228 (0.4%)
    Hepatobiliary disorders
    Hepatotoxicity 0/230 (0%) 1/228 (0.4%)
    Infections and infestations
    Abdominal infection 0/230 (0%) 1/228 (0.4%)
    Lung infection 1/230 (0.4%) 1/228 (0.4%)
    Sepsis 0/230 (0%) 1/228 (0.4%)
    Skin infection 0/230 (0%) 1/228 (0.4%)
    Splenic abscess 0/230 (0%) 1/228 (0.4%)
    Investigations
    Blood bilirubin increased 0/230 (0%) 1/228 (0.4%)
    Cardiac troponin I increased 1/230 (0.4%) 0/228 (0%)
    Metabolism and nutrition disorders
    Hyperphosphatemia 0/230 (0%) 1/228 (0.4%)
    Hypocalcemia 0/230 (0%) 1/228 (0.4%)
    Hypoglycemia 1/230 (0.4%) 0/228 (0%)
    Hypophosphatemia 1/230 (0.4%) 0/228 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Progression of pre-existing cancer 1/230 (0.4%) 0/228 (0%)
    Squamous cell carcinoma of skin 0/230 (0%) 1/228 (0.4%)
    Nervous system disorders
    Depressed level of consciousness 1/230 (0.4%) 0/228 (0%)
    Seizure 3/230 (1.3%) 1/228 (0.4%)
    Stroke 1/230 (0.4%) 0/228 (0%)
    Renal and urinary disorders
    Acute kidney injury 3/230 (1.3%) 4/228 (1.8%)
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion 0/230 (0%) 1/228 (0.4%)
    Respiratory failure 2/230 (0.9%) 1/228 (0.4%)
    Skin and subcutaneous tissue disorders
    Stevens-Johnson syndrome 0/230 (0%) 1/228 (0.4%)
    Vascular disorders
    Hypotension 1/230 (0.4%) 1/228 (0.4%)
    Other (Not Including Serious) Adverse Events
    Colistin and Placebo Colistin and a Carbapenem
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 169/230 (73.5%) 161/228 (70.6%)
    Blood and lymphatic system disorders
    Anemia 12/230 (5.2%) 6/228 (2.6%)
    Hypoglobulinemia 1/230 (0.4%) 0/228 (0%)
    Leukocytosis 3/230 (1.3%) 3/228 (1.3%)
    Leukopenia 1/230 (0.4%) 2/228 (0.9%)
    Normocytic anemia 1/230 (0.4%) 0/228 (0%)
    Thrombocytopenia 1/230 (0.4%) 2/228 (0.9%)
    Thrombocytosis 1/230 (0.4%) 0/228 (0%)
    Cardiac disorders
    AV block first degree 0/230 (0%) 1/228 (0.4%)
    Acute coronary syndrome 1/230 (0.4%) 0/228 (0%)
    Asystole 1/230 (0.4%) 3/228 (1.3%)
    Atrial fibrillation 0/230 (0%) 1/228 (0.4%)
    Atrial fibrillation with rapid ventricular response 1/230 (0.4%) 0/228 (0%)
    Bradycardia 3/230 (1.3%) 2/228 (0.9%)
    Cardiac arrest 3/230 (1.3%) 1/228 (0.4%)
    Enlargement heart 0/230 (0%) 1/228 (0.4%)
    Incomplete right bundle branch block 0/230 (0%) 1/228 (0.4%)
    Interventricular septum rupture 1/230 (0.4%) 0/228 (0%)
    Mitral regurgitation 1/230 (0.4%) 0/228 (0%)
    Myocardial infarction 1/230 (0.4%) 1/228 (0.4%)
    Sinus bradycardia 1/230 (0.4%) 0/228 (0%)
    Sinus tachycardia 0/230 (0%) 1/228 (0.4%)
    Tachycardia 2/230 (0.9%) 3/228 (1.3%)
    Tako-Tsubo cardiomyopathy 1/230 (0.4%) 0/228 (0%)
    Ventricular fibrillation 0/230 (0%) 1/228 (0.4%)
    Ventricular tachycardia 1/230 (0.4%) 0/228 (0%)
    Congenital, familial and genetic disorders
    Cerebral palsy 0/230 (0%) 1/228 (0.4%)
    Open spina bifida 0/230 (0%) 1/228 (0.4%)
    Ear and labyrinth disorders
    Vertigo 1/230 (0.4%) 0/228 (0%)
    Endocrine disorders
    Adrenal mass 0/230 (0%) 1/228 (0.4%)
    Eye disorders
    Anisocoria 1/230 (0.4%) 0/228 (0%)
    Conjunctivitis 0/230 (0%) 1/228 (0.4%)
    Icteric sclera 1/230 (0.4%) 0/228 (0%)
    Gastrointestinal disorders
    Abdominal distension 1/230 (0.4%) 2/228 (0.9%)
    Abdominal pain generalised 0/230 (0%) 1/228 (0.4%)
    Abdominal tenderness 0/230 (0%) 1/228 (0.4%)
    Colonic obstruction 0/230 (0%) 1/228 (0.4%)
    Constipation 1/230 (0.4%) 1/228 (0.4%)
    Diarrhea 5/230 (2.2%) 2/228 (0.9%)
    Enterocutaneous fistula 1/230 (0.4%) 0/228 (0%)
    Esophageal perforation 0/230 (0%) 1/228 (0.4%)
    Gastroesophageal reflux disease 0/230 (0%) 1/228 (0.4%)
    Gastrointestinal ischemia 0/230 (0%) 1/228 (0.4%)
    Nausea 1/230 (0.4%) 0/228 (0%)
    Numbness oral 1/230 (0.4%) 0/228 (0%)
    Oedema of mouth 1/230 (0.4%) 0/228 (0%)
    Pain oral 1/230 (0.4%) 0/228 (0%)
    Pancreatitis 0/230 (0%) 1/228 (0.4%)
    Perioral paraesthesia 1/230 (0.4%) 0/228 (0%)
    Vomiting 3/230 (1.3%) 1/228 (0.4%)
    General disorders
    Acute pain 0/230 (0%) 1/228 (0.4%)
    Anasarca 2/230 (0.9%) 0/228 (0%)
    Drug fever 1/230 (0.4%) 0/228 (0%)
    Edema limbs 0/230 (0%) 1/228 (0.4%)
    Febrile reaction 1/230 (0.4%) 0/228 (0%)
    Fever 4/230 (1.7%) 4/228 (1.8%)
    General body pain 2/230 (0.9%) 1/228 (0.4%)
    General physical health deterioration 0/230 (0%) 1/228 (0.4%)
    Hypothermia 2/230 (0.9%) 1/228 (0.4%)
    Localized edema 1/230 (0.4%) 0/228 (0%)
    Sudden death 0/230 (0%) 1/228 (0.4%)
    Hepatobiliary disorders
    Cholangitis acute 1/230 (0.4%) 1/228 (0.4%)
    Impaired liver function 0/230 (0%) 1/228 (0.4%)
    Infections and infestations
    Acinetobacter infection 0/230 (0%) 1/228 (0.4%)
    Acute bronchitis 1/230 (0.4%) 0/228 (0%)
    Biliary tract infection 0/230 (0%) 1/228 (0.4%)
    C.difficile diarrhea 1/230 (0.4%) 0/228 (0%)
    Cellulitis of arm 1/230 (0.4%) 0/228 (0%)
    Empyema 1/230 (0.4%) 0/228 (0%)
    Influenza A virus infection 1/230 (0.4%) 0/228 (0%)
    Intra-abdominal infection 1/230 (0.4%) 0/228 (0%)
    Klebsiella bacteraemia 1/230 (0.4%) 0/228 (0%)
    Liver abscess 1/230 (0.4%) 0/228 (0%)
    Lobar pneumonia 0/230 (0%) 1/228 (0.4%)
    Lung infection 0/230 (0%) 1/228 (0.4%)
    Lung infection NOS 1/230 (0.4%) 0/228 (0%)
    Nosocomial infection 1/230 (0.4%) 0/228 (0%)
    Pneumonia 3/230 (1.3%) 4/228 (1.8%)
    Pulmonary tuberculosis 1/230 (0.4%) 0/228 (0%)
    Respiratory infection 1/230 (0.4%) 0/228 (0%)
    Sepsis 24/230 (10.4%) 22/228 (9.6%)
    Septic shock 8/230 (3.5%) 2/228 (0.9%)
    Septicemia due to Escherichia coli (E. coli) 1/230 (0.4%) 0/228 (0%)
    Thrush oral 1/230 (0.4%) 0/228 (0%)
    Unspecified osteomyelitis involving lower leg 0/230 (0%) 1/228 (0.4%)
    Urinary tract infection 0/230 (0%) 1/228 (0.4%)
    Ventilator associated pneumonia 1/230 (0.4%) 0/228 (0%)
    Injury, poisoning and procedural complications
    Multiple fractures 0/230 (0%) 1/228 (0.4%)
    Pulmonary contusion 1/230 (0.4%) 0/228 (0%)
    Investigations
    ALT increased 3/230 (1.3%) 7/228 (3.1%)
    APTT increased 0/230 (0%) 1/228 (0.4%)
    AST increased 2/230 (0.9%) 2/228 (0.9%)
    Abnormal ECG 2/230 (0.9%) 0/228 (0%)
    Abnormal EEG 1/230 (0.4%) 0/228 (0%)
    Abnormal arterial blood gases 6/230 (2.6%) 2/228 (0.9%)
    Absolute lymphocyte count decreased 1/230 (0.4%) 1/228 (0.4%)
    Absolute lymphocyte count increased 1/230 (0.4%) 2/228 (0.9%)
    Absolute monocyte count increased 2/230 (0.9%) 1/228 (0.4%)
    Absolute neutrophil count increased 2/230 (0.9%) 1/228 (0.4%)
    Acinetobacter baumannii test positive 0/230 (0%) 1/228 (0.4%)
    Activated partial thromboplastin time increased 3/230 (1.3%) 1/228 (0.4%)
    Activated partial thromboplastin time prolonged 0/230 (0%) 1/228 (0.4%)
    Alanine aminotransferase 0/230 (0%) 1/228 (0.4%)
    Alanine aminotransferase decreased 1/230 (0.4%) 1/228 (0.4%)
    Alanine aminotransferase increased 6/230 (2.6%) 2/228 (0.9%)
    Albumin globulin ratio decreased 1/230 (0.4%) 0/228 (0%)
    Alkaline phosphatase increased 8/230 (3.5%) 3/228 (1.3%)
    Amylase increased 0/230 (0%) 1/228 (0.4%)
    Anion gap decreased 1/230 (0.4%) 0/228 (0%)
    Arterial blood pH increased 1/230 (0.4%) 0/228 (0%)
    Aspartate aminotransferase increase 13/230 (5.7%) 10/228 (4.4%)
    Aspartate aminotransferase increased 8/230 (3.5%) 9/228 (3.9%)
    BUN decreased 2/230 (0.9%) 1/228 (0.4%)
    Bacteria urine identified 2/230 (0.9%) 2/228 (0.9%)
    Band neutrophil count increased 3/230 (1.3%) 3/228 (1.3%)
    Bilirubin increased 0/230 (0%) 1/228 (0.4%)
    Bilirubin total decreased 0/230 (0%) 1/228 (0.4%)
    Bilirubin total increased 1/230 (0.4%) 3/228 (1.3%)
    Blood alkaline phosphatase decreased 1/230 (0.4%) 0/228 (0%)
    Blood alkaline phosphatase increased 3/230 (1.3%) 2/228 (0.9%)
    Blood amylase decreased 1/230 (0.4%) 0/228 (0%)
    Blood bicarbonate increased 2/230 (0.9%) 1/228 (0.4%)
    Blood bilirubin increased 13/230 (5.7%) 9/228 (3.9%)
    Blood carbon dioxide decreased 2/230 (0.9%) 0/228 (0%)
    Blood carbon dioxide increased 0/230 (0%) 3/228 (1.3%)
    Blood chloride decreased 1/230 (0.4%) 2/228 (0.9%)
    Blood chloride increased 2/230 (0.9%) 3/228 (1.3%)
    Blood eosinophils 1/230 (0.4%) 0/228 (0%)
    Blood eosinophils increased 2/230 (0.9%) 2/228 (0.9%)
    Blood gases abnormal 1/230 (0.4%) 1/228 (0.4%)
    Blood in urine 0/230 (0%) 1/228 (0.4%)
    Blood lactate dehydrogenase increased 8/230 (3.5%) 3/228 (1.3%)
    Blood lactic acid increased 1/230 (0.4%) 0/228 (0%)
    Blood myoglobin increased 1/230 (0.4%) 0/228 (0%)
    Blood pH decreased 3/230 (1.3%) 1/228 (0.4%)
    Blood pH increased 2/230 (0.9%) 0/228 (0%)
    Blood phosphorus increased 2/230 (0.9%) 1/228 (0.4%)
    Blood pressure diastolic decreased 8/230 (3.5%) 2/228 (0.9%)
    Blood pressure diastolic increased 1/230 (0.4%) 0/228 (0%)
    Blood pressure systolic decreased 1/230 (0.4%) 0/228 (0%)
    Blood prolactin abnormal 1/230 (0.4%) 0/228 (0%)
    Blood urea nitrogen increased 4/230 (1.7%) 3/228 (1.3%)
    Blood urea nitrogen/creatinine ratio increased 1/230 (0.4%) 0/228 (0%)
    Body temperature decrease 2/230 (0.9%) 2/228 (0.9%)
    Body temperature decreased 1/230 (0.4%) 0/228 (0%)
    Body temperature increased 1/230 (0.4%) 0/228 (0%)
    C-reactive protein increased 1/230 (0.4%) 0/228 (0%)
    Calcium ionized decreased 1/230 (0.4%) 1/228 (0.4%)
    Carbon dioxide decreased 2/230 (0.9%) 1/228 (0.4%)
    Cardiac troponin I increased 1/230 (0.4%) 0/228 (0%)
    Cardiac troponin T increased 0/230 (0%) 1/228 (0.4%)
    Chloride serum increased 1/230 (0.4%) 0/228 (0%)
    Cholesterol blood decreased 2/230 (0.9%) 0/228 (0%)
    Clostridium difficile test positive 0/230 (0%) 1/228 (0.4%)
    Copper decreased 0/230 (0%) 1/228 (0.4%)
    Creatine increased 0/230 (0%) 1/228 (0.4%)
    Creatinine decreased 1/230 (0.4%) 1/228 (0.4%)
    Creatinine increased 54/230 (23.5%) 46/228 (20.2%)
    Creatinine urine decreased 1/230 (0.4%) 0/228 (0%)
    Crystal urine present 1/230 (0.4%) 0/228 (0%)
    Digoxin level increased 1/230 (0.4%) 0/228 (0%)
    Direct bilirubin increased 3/230 (1.3%) 2/228 (0.9%)
    Ejection fraction decreased 1/230 (0.4%) 0/228 (0%)
    Electrocardiogram T wave abnormal 0/230 (0%) 1/228 (0.4%)
    Elevated liver enzyme levels 1/230 (0.4%) 1/228 (0.4%)
    Enterococcus test positive 1/230 (0.4%) 0/228 (0%)
    Eosinophil count increased 0/230 (0%) 1/228 (0.4%)
    Eosinophil percentage increased 0/230 (0%) 1/228 (0.4%)
    Fecal occult blood 0/230 (0%) 1/228 (0.4%)
    Ferritin increased 2/230 (0.9%) 0/228 (0%)
    GFR decreased 0/230 (0%) 1/228 (0.4%)
    Glucose urine abnormal 1/230 (0.4%) 0/228 (0%)
    Glucose urine present 0/230 (0%) 1/228 (0.4%)
    HDL cholesterol decreased 1/230 (0.4%) 0/228 (0%)
    HDL cholesterol increased 1/230 (0.4%) 0/228 (0%)
    HDL decreased 1/230 (0.4%) 0/228 (0%)
    Haptoglobin high 1/230 (0.4%) 1/228 (0.4%)
    HbA1C increased 1/230 (0.4%) 0/228 (0%)
    Hematocrit decreased 0/230 (0%) 1/228 (0.4%)
    Hemoglobin decreased 0/230 (0%) 2/228 (0.9%)
    Hepatitis A antibody positive 0/230 (0%) 1/228 (0.4%)
    INR increased 4/230 (1.7%) 3/228 (1.3%)
    Increased platelets 1/230 (0.4%) 0/228 (0%)
    Increased serum creatinine 0/230 (0%) 1/228 (0.4%)
    Influenza A virus test positive 1/230 (0.4%) 0/228 (0%)
    Ionized calcium decreased 2/230 (0.9%) 1/228 (0.4%)
    Ionized calcium increased 1/230 (0.4%) 0/228 (0%)
    Iron binding capacity decreased 1/230 (0.4%) 1/228 (0.4%)
    Iron binding capacity unsaturated decreased 1/230 (0.4%) 0/228 (0%)
    Iron decreased 2/230 (0.9%) 1/228 (0.4%)
    Ketone bodies urine positive 0/230 (0%) 1/228 (0.4%)
    Lipase increased 0/230 (0%) 1/228 (0.4%)
    Lymphocyte count decreased 1/230 (0.4%) 2/228 (0.9%)
    Lymphocyte percentage decreased 3/230 (1.3%) 2/228 (0.9%)
    Lymphocytes atypical 1/230 (0.4%) 1/228 (0.4%)
    MAP increased 1/230 (0.4%) 0/228 (0%)
    Mean cell volume increased 0/230 (0%) 1/228 (0.4%)
    Mean platelet volume increased 3/230 (1.3%) 0/228 (0%)
    Metamyelocyte count increased 0/230 (0%) 1/228 (0.4%)
    Monocyte percentage decreased 1/230 (0.4%) 0/228 (0%)
    Monocytes increased 2/230 (0.9%) 1/228 (0.4%)
    Myelocyte count increased 0/230 (0%) 1/228 (0.4%)
    NT-proBNP increased 1/230 (0.4%) 0/228 (0%)
    Neutrophil count increased 0/230 (0%) 1/228 (0.4%)
    Neutrophil percentage increased 1/230 (0.4%) 0/228 (0%)
    Neutrophils increased 1/230 (0.4%) 1/228 (0.4%)
    Nitrite urine present 2/230 (0.9%) 0/228 (0%)
    Opiates positive 1/230 (0.4%) 0/228 (0%)
    Oxygen saturation decreased 0/230 (0%) 1/228 (0.4%)
    Oxygen saturation low 1/230 (0.4%) 0/228 (0%)
    PCO2 increased 1/230 (0.4%) 0/228 (0%)
    PO2 increased 1/230 (0.4%) 0/228 (0%)
    PTH increased 1/230 (0.4%) 0/228 (0%)
    Platelet count decreased 2/230 (0.9%) 3/228 (1.3%)
    Platelet count increased 0/230 (0%) 2/228 (0.9%)
    Platelets decreased 1/230 (0.4%) 0/228 (0%)
    Prealbumin decreased 3/230 (1.3%) 0/228 (0%)
    Protein total decreased 1/230 (0.4%) 0/228 (0%)
    Protein total increased 1/230 (0.4%) 0/228 (0%)
    Prothrombin time increased 3/230 (1.3%) 4/228 (1.8%)
    Prothrombin time prolonged 0/230 (0%) 1/228 (0.4%)
    Pulse decreased 1/230 (0.4%) 0/228 (0%)
    Red blood cell distribution width increased 1/230 (0.4%) 1/228 (0.4%)
    Red blood cell morphology abnormal 0/230 (0%) 2/228 (0.9%)
    Respiratory rate decreased 1/230 (0.4%) 0/228 (0%)
    Respiratory rate increased 1/230 (0.4%) 1/228 (0.4%)
    Reticulocyte count increased 1/230 (0.4%) 0/228 (0%)
    Serum calcium decreased 0/230 (0%) 1/228 (0.4%)
    Serum chloride increased 2/230 (0.9%) 0/228 (0%)
    Serum creatinine decreased 0/230 (0%) 1/228 (0.4%)
    Serum creatinine increased 0/230 (0%) 1/228 (0.4%)
    Serum osmolality increased 0/230 (0%) 1/228 (0.4%)
    Serum total protein decreased 3/230 (1.3%) 3/228 (1.3%)
    Sinus rhythm 0/230 (0%) 1/228 (0.4%)
    Specific gravity urine decreased 0/230 (0%) 1/228 (0.4%)
    Specific gravity urine increased 1/230 (0.4%) 0/228 (0%)
    Staphylococcus aureus test positive 0/230 (0%) 1/228 (0.4%)
    TSH increased 1/230 (0.4%) 0/228 (0%)
    Thoracentesis 0/230 (0%) 1/228 (0.4%)
    Transferrin decreased 3/230 (1.3%) 0/228 (0%)
    Triglyceride increased 1/230 (0.4%) 0/228 (0%)
    Troponin I increased 1/230 (0.4%) 2/228 (0.9%)
    Troponin NOS 0/230 (0%) 1/228 (0.4%)
    Urinary casts present 1/230 (0.4%) 1/228 (0.4%)
    Urine RBC increased 1/230 (0.4%) 0/228 (0%)
    Urine analysis abnormal 1/230 (0.4%) 0/228 (0%)
    Urine bilirubin increased 1/230 (0.4%) 1/228 (0.4%)
    Urine calcium oxalate crystal present 1/230 (0.4%) 0/228 (0%)
    Urine epithelial cells increased 3/230 (1.3%) 0/228 (0%)
    Urine ketone body present 1/230 (0.4%) 0/228 (0%)
    Urine leukocyte esterase positive 2/230 (0.9%) 4/228 (1.8%)
    Urine red blood cells increased 1/230 (0.4%) 2/228 (0.9%)
    Urine white blood cell increased 1/230 (0.4%) 0/228 (0%)
    Urobilinogen urine increased 0/230 (0%) 2/228 (0.9%)
    Vitamin B12 increased 1/230 (0.4%) 0/228 (0%)
    Vitamin D decreased 1/230 (0.4%) 0/228 (0%)
    WBC increased 1/230 (0.4%) 2/228 (0.9%)
    Weight increased 2/230 (0.9%) 0/228 (0%)
    White blood cell count decreased 1/230 (0.4%) 1/228 (0.4%)
    White blood cell count increased 1/230 (0.4%) 0/228 (0%)
    White blood cells urine increased 2/230 (0.9%) 1/228 (0.4%)
    White blood cells urine positive 1/230 (0.4%) 0/228 (0%)
    Zinc decreased 0/230 (0%) 1/228 (0.4%)
    Metabolism and nutrition disorders
    Acidosis 0/230 (0%) 2/228 (0.9%)
    Alkalosis 0/230 (0%) 1/228 (0.4%)
    Dehydration 0/230 (0%) 2/228 (0.9%)
    Diabetes mellitus 1/230 (0.4%) 1/228 (0.4%)
    Glucose intolerance 0/230 (0%) 1/228 (0.4%)
    Hypercalcemia 1/230 (0.4%) 1/228 (0.4%)
    Hyperchloremia 0/230 (0%) 1/228 (0.4%)
    Hyperglycemia 6/230 (2.6%) 4/228 (1.8%)
    Hyperkalemia 5/230 (2.2%) 2/228 (0.9%)
    Hypermagnesemia 0/230 (0%) 1/228 (0.4%)
    Hypernatremia 4/230 (1.7%) 4/228 (1.8%)
    Hyperphosphatemia 3/230 (1.3%) 2/228 (0.9%)
    Hypertriglyceridemia 3/230 (1.3%) 0/228 (0%)
    Hyperuricemia 1/230 (0.4%) 0/228 (0%)
    Hypoalbuminaemia 0/230 (0%) 1/228 (0.4%)
    Hypoalbuminemia 9/230 (3.9%) 5/228 (2.2%)
    Hypocalcemia 6/230 (2.6%) 3/228 (1.3%)
    Hypochloraemia 1/230 (0.4%) 0/228 (0%)
    Hypoglycemia 4/230 (1.7%) 2/228 (0.9%)
    Hypokalemia 11/230 (4.8%) 10/228 (4.4%)
    Hypomagnesemia 7/230 (3%) 5/228 (2.2%)
    Hyponatremia 7/230 (3%) 2/228 (0.9%)
    Hypophosphatemia 3/230 (1.3%) 0/228 (0%)
    Hypoproteinemia 1/230 (0.4%) 0/228 (0%)
    Malnutrition 1/230 (0.4%) 1/228 (0.4%)
    Obesity 1/230 (0.4%) 2/228 (0.9%)
    Musculoskeletal and connective tissue disorders
    Generalized muscle weakness 0/230 (0%) 1/228 (0.4%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colorectal cancer metastatic 1/230 (0.4%) 0/228 (0%)
    Pancreas cancer 1/230 (0.4%) 1/228 (0.4%)
    Tumor pain 0/230 (0%) 1/228 (0.4%)
    Nervous system disorders
    Dementia 1/230 (0.4%) 0/228 (0%)
    Depressed level of consciousness 1/230 (0.4%) 0/228 (0%)
    Dizziness 1/230 (0.4%) 0/228 (0%)
    Headache 2/230 (0.9%) 0/228 (0%)
    Hemiplegia 0/230 (0%) 1/228 (0.4%)
    Intracranial hemorrhage 0/230 (0%) 1/228 (0.4%)
    Migraine headache 0/230 (0%) 1/228 (0.4%)
    Myoclonus 1/230 (0.4%) 0/228 (0%)
    Neurotoxicity 1/230 (0.4%) 0/228 (0%)
    Peripheral neuropathy NOS 1/230 (0.4%) 1/228 (0.4%)
    Seizure 2/230 (0.9%) 2/228 (0.9%)
    Somnolence 1/230 (0.4%) 0/228 (0%)
    Psychiatric disorders
    Agitation 2/230 (0.9%) 0/228 (0%)
    Anxiety 1/230 (0.4%) 1/228 (0.4%)
    Confusion 1/230 (0.4%) 1/228 (0.4%)
    Delirium tremens 1/230 (0.4%) 0/228 (0%)
    Depression 0/230 (0%) 1/228 (0.4%)
    Mental status changes 1/230 (0.4%) 0/228 (0%)
    Restlessness aggravated 1/230 (0.4%) 0/228 (0%)
    Renal and urinary disorders
    Acute kidney injury 78/230 (33.9%) 69/228 (30.3%)
    Chronic kidney disease 0/230 (0%) 1/228 (0.4%)
    End stage renal disease (ESRD) 2/230 (0.9%) 1/228 (0.4%)
    Hematuria 3/230 (1.3%) 4/228 (1.8%)
    Nephrotoxicity 0/230 (0%) 1/228 (0.4%)
    Polyuria 0/230 (0%) 1/228 (0.4%)
    Progressive renal failure 1/230 (0.4%) 3/228 (1.3%)
    Proteinuria 5/230 (2.2%) 5/228 (2.2%)
    Renal injury 1/230 (0.4%) 2/228 (0.9%)
    Urinary incontinence 1/230 (0.4%) 0/228 (0%)
    Reproductive system and breast disorders
    Benign prostatic hypertrophy 0/230 (0%) 1/228 (0.4%)
    Enlarged prostate 0/230 (0%) 1/228 (0.4%)
    Genital rash 1/230 (0.4%) 0/228 (0%)
    Scrotal ulcer 0/230 (0%) 1/228 (0.4%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 1/230 (0.4%) 0/228 (0%)
    Adult respiratory distress syndrome 1/230 (0.4%) 0/228 (0%)
    Aspiration 0/230 (0%) 1/228 (0.4%)
    Atelectasis 1/230 (0.4%) 2/228 (0.9%)
    Bradypnea 0/230 (0%) 1/228 (0.4%)
    Bronchial mucus plug 0/230 (0%) 1/228 (0.4%)
    Bronchospasm 1/230 (0.4%) 1/228 (0.4%)
    COPD 1/230 (0.4%) 0/228 (0%)
    Cough nonproductive 0/230 (0%) 1/228 (0.4%)
    Dyspnea 2/230 (0.9%) 1/228 (0.4%)
    Hypoxia 3/230 (1.3%) 1/228 (0.4%)
    Increased bronchial secretion 1/230 (0.4%) 0/228 (0%)
    Pleural effusion 0/230 (0%) 1/228 (0.4%)
    Pleural effusion recurrent 0/230 (0%) 1/228 (0.4%)
    Pneumonia aspiration 0/230 (0%) 1/228 (0.4%)
    Pulmonary alveolar hemorrhage 1/230 (0.4%) 0/228 (0%)
    Pulmonary congestion 0/230 (0%) 1/228 (0.4%)
    Pulmonary edema 1/230 (0.4%) 0/228 (0%)
    Respiratory distress 3/230 (1.3%) 1/228 (0.4%)
    Respiratory failure 5/230 (2.2%) 2/228 (0.9%)
    Tachypnea 5/230 (2.2%) 4/228 (1.8%)
    Tracheo-bronchial secretion excess 0/230 (0%) 1/228 (0.4%)
    Skin and subcutaneous tissue disorders
    Bed sore 1/230 (0.4%) 0/228 (0%)
    Blistering 1/230 (0.4%) 0/228 (0%)
    Decubitus ulcer 1/230 (0.4%) 1/228 (0.4%)
    Erythroderma 0/230 (0%) 1/228 (0.4%)
    Generalized itching 0/230 (0%) 1/228 (0.4%)
    Itching 1/230 (0.4%) 0/228 (0%)
    Maculo-papular rash 1/230 (0.4%) 2/228 (0.9%)
    Maculopapular rash 0/230 (0%) 3/228 (1.3%)
    Pressure sore 1/230 (0.4%) 0/228 (0%)
    Pruritus 2/230 (0.9%) 1/228 (0.4%)
    Scar 1/230 (0.4%) 0/228 (0%)
    Skin ulcer 0/230 (0%) 1/228 (0.4%)
    Skin ulceration 0/230 (0%) 1/228 (0.4%)
    Subcutaneous emphysema 0/230 (0%) 2/228 (0.9%)
    Social circumstances
    Bedridden 0/230 (0%) 1/228 (0.4%)
    Surgical and medical procedures
    Above knee amputation 0/230 (0%) 1/228 (0.4%)
    Blood transfusion 0/230 (0%) 1/228 (0.4%)
    Central line placement 1/230 (0.4%) 0/228 (0%)
    Chemotherapy 0/230 (0%) 1/228 (0.4%)
    Chest tube insertion 0/230 (0%) 1/228 (0.4%)
    Dialysis device insertion 0/230 (0%) 1/228 (0.4%)
    Endotracheal intubation 0/230 (0%) 1/228 (0.4%)
    Foley catheter 0/230 (0%) 1/228 (0.4%)
    Hemodialysis 0/230 (0%) 1/228 (0.4%)
    Jugular catheterisation 0/230 (0%) 1/228 (0.4%)
    Nasogastric tube insertion 0/230 (0%) 1/228 (0.4%)
    Nephrostomy tube placement 0/230 (0%) 1/228 (0.4%)
    TPN 1/230 (0.4%) 0/228 (0%)
    Vena cava filter insertion 0/230 (0%) 1/228 (0.4%)
    Vascular disorders
    Hemodynamic instability 0/230 (0%) 1/228 (0.4%)
    Hypertension 4/230 (1.7%) 2/228 (0.9%)
    Hypotension 3/230 (1.3%) 3/228 (1.3%)
    Thromboembolic event 1/230 (0.4%) 0/228 (0%)
    Thrombophlebitis 0/230 (0%) 1/228 (0.4%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Jolene Daniel
    Organization University of Michigan
    Phone 732 235-7713
    Email jd1557@rwjms.rutgers.edu
    Responsible Party:
    Keith Kaye, Keith Kaye, M.D.,M.P.H Study PI, University of Michigan
    ClinicalTrials.gov Identifier:
    NCT01597973
    Other Study ID Numbers:
    • NIH 10-0065
    First Posted:
    May 15, 2012
    Last Update Posted:
    Nov 30, 2021
    Last Verified:
    Nov 1, 2021