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Randomized-controlled Trial (RCT) on Combination Antibiotic for Infections Caused by Gram-negative Bacteria (XDR-GNB)

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ClinicalTrials.gov Identifier: NCT02134106
Recruitment Status : Unknown
Verified December 2014 by David Lye, Tan Tock Seng Hospital.
Recruitment status was:  Not yet recruiting
First Posted : May 8, 2014
Last Update Posted : December 15, 2014
Sponsor:
Collaborators:
Singapore General Hospital
National University Hospital, Singapore
Changi General Hospital
Information provided by (Responsible Party):
David Lye, Tan Tock Seng Hospital

Brief Summary:

Background and rationale:

Antimicrobial resistance is a global public health threat. An increasing number of Gram-negative bacteria isolates worldwide are resistant to virtually all antibiotics including carbapenems. Although polymyxins are the current gold standard antibiotic for treatment of severe extensively drug-resistant Gram-negative bacteria (XDR-GNB - defined in Appendix I) infections, resistance development on therapy and treatment failures are common. Combination antibiotics therapy have better in vitro efficacy, but have not been formally tested in a prospective trial.

We will conduct a Phase IIB, prospective, open-label, randomized-controlled trial in 4 major Singaporean hospitals, with balanced treatment assignments achieved by permuted block randomization, stratified by hospital. There will be 75 subjects per arm, with the subjects in the comparator arm receiving standard-dose polymyxin B while the intervention arm will receive a second antibiotic, doripenem, with polymyxin B against the bacterial isolate in question. Subjects with ventilator-associated pneumonia (VAP) will additionally receive nebulized colistin. The primary outcome is 30-day mortality while secondary outcomes include microbiological clearance, time to defervescence, and toxicity of therapy, presence of secondary infections due to new multi-drug resistant bacteria and length of ICU stay. Plasma drug levels will be measured by liquid chromatography-mass spectrometry.

Hypothesis:

The underlying primary hypothesis is that combination antibiotic therapy (IV polymyxin B + IV doripenem) is superior to mono-antibiotics therapy (IV polymyxin B) in reducing 30-day mortality from XDR-GNB infections.


Condition or disease Intervention/treatment Phase
Bacteremia Healthcare-associated Pneumonia Ventilator-associated Pneumonia Drug: Polymyxin B Drug: Polymyxin B + Doripenem Phase 2 Phase 3

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Multi-center, Open-label Randomized Controlled Trial on the Efficacy of Combination Antibiotic Therapy for Serious Infections Caused by Extensively Drug-resistant Gram-negative Bacteria (XDR-GNB)
Study Start Date : January 2015
Estimated Primary Completion Date : October 2015
Estimated Study Completion Date : December 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antibiotics

Arm Intervention/treatment
Active Comparator: Polymyxin B
Intravenous polymyxin B will be started on a standard dose of 25,000 Units (U)/kg body weight, in 2 divided doses each day, infused over 2 hours. The duration of intravenous antibiotic treatment for subjects with either bacteremia or VAP or HAP will be at least 10 days. The duration of intravenous polymyxin B can be prolonged based on clinical indication, e.g., deep-seated source of infection, etc. For patients with VAP, nebulized colistin at the dose of 2 million units (MU) 8 hourly for 5 days will be prescribed.
Drug: Polymyxin B
Intravenous polymyxin B will be started on a standard dose of 25,000U/kg body weight, in 2 divided doses each day, infused over 2 hours. The duration of intravenous antibiotic treatment for subjects with either bacteremia or VAP or HAP will be at least 10 days. The duration of intravenous polymyxin B can be prolonged based on clinical indication, e.g., deep-seated source of infection, etc. For patients with VAP, nebulized colistin at the dose of 2 MU 8 hourly for 5 days will be prescribed.

Experimental: Polymyxin B + Doripenem
Standard dose of intravenous polymyxin B at 25,000U/kg body weight will be given in 2 divided doses each day with each dose infused over 2 hours and intravenous doripenem 500mg, with each dose infused over 4 hours. For patients with VAP, nebulized colistin at the dose of 2 MU 8 hourly for 5 days will be prescribed.
Drug: Polymyxin B + Doripenem
Standard dose of intravenous polymyxin B at 25,000U/kg body weight will be given in 2 divided doses each day with each dose infused over 2 hours and intravenous doripenem 500mg, with each dose infused over 4 hours. For patients with VAP, nebulized colistin at the dose of 2 MU 8 hourly for 5 days will be prescribed.




Primary Outcome Measures :
  1. The primary outcome will be all-cause mortality at 30 days post-date of randomization [ Time Frame: All-cause mortality at 30 days post-randomization ]

    Primary outcome:

    The primary outcome will be all-cause mortality at 30 days post-date of randomization. Patients that are discharged early will be called by the study team at 30 days post-date of randomization to determine survival at that point.



Secondary Outcome Measures :
  1. Microbiological clearance [ Time Frame: On Day 3 and 7 ]
    Microbiological clearance assessed on Day 3 and 7

  2. Time to defervescence [ Time Frame: Censored at Day 30 ]
    Time to first occurence of defervescence throughout the entire study period, censored at Day 30 or date of discharge, if fever is still present.

  3. Duration of stay in ICU [ Time Frame: Censored at Day 30 ]
    Duration of first ICU stay for subjects managed in the ICU throughout entire study period (until Day 30).

  4. Clinical improvement [ Time Frame: Day 3 ]
    Clinical improvement assessed at Day 3. Clinical improvement is defined as improvement of at least two of the HAP/VAP signs and symptoms (temperature, blood pressure and respiration conditions) present at baseline without worsening of the third.

  5. Clinical progression [ Time Frame: Day 30 ]
    Clinical progression assessed at Day 30. This is defined as a lack of resolution of HAP/VAP signs and symptoms (temperature, blood pressure and respiration conditions) present at baseline and alive at Day 30 AND/OR administration of rescue antibacterial therapy and alive at Day 30.


Other Outcome Measures:
  1. Treatment related or non-related adverse events and emergence of of secondary infections caused by new multidrug-resistant bacteria or fungi [ Time Frame: Treatment of related or non-related adverse events (AE: up to 30 days; SAE: any time during the study period), secondary infections by new multidrug-resistant bacteria or fungi (within 30 days from start of study treatment) ]

    Safety outcomes:

    1. Treatment related or non-related adverse events.

      • Adverse events: Up to 30 days post last study dose.
      • Serious adverse events: Any time of the study period.
    2. Emergence of secondary infections caused by new multidrug-resistant bacteria or fungi within 30 days from starting study treatment.



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Monomicrobial XDR-GNB bacteremia.
  • Monomicrobial XDR-GNB ventilator-associated pneumonia OR healthcare-associated pneumonia.

Exclusion Criteria (will be excluded if subjects meet one or more of the following criteria):

  • Allergy to any of the study medications.
  • For female patients, the patients is pregnant.
  • Unable to provide consent and have no legally authorized representatives.
  • Currently enrolled in another trial.
  • >48 hours after XDR-GNB confirmation by the microbiology laboratory.
  • Palliative care or with less than 24 hours of life expectancy, as discussed with their primary physicians.
  • Co-infection with other aerobic Gram-negative bacteria.
  • Severe renal impairment (creatinine clearance <30 milliliters (mL)/min).

    • Concurrent infection not involving the lungs or bloodstream is not an exclusion criterion for the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02134106


Contacts
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Contact: Ying Ding, MD, PhD 64783073 ying_ding@ttsh.com.sg
Contact: Norhudah Othman, Dip-Nursing 64783056 Norhudah_OTHMAN@ttsh.com.sg

Locations
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Singapore
National University Hospital Not yet recruiting
Singapore, Singapore, 119074
Contact: Sophia Archuleta, MD    67726188    sophia@nus.edu.sg   
Principal Investigator: Sophia Archuleta, MD         
Singapore General Hospital Not yet recruiting
Singapore, Singapore, 169608
Contact: Shirin Kalimuddin, MBBS, MRCP    63213479    shirin.kalimuddin@sgh.com.sg   
Principal Investigator: Shirin Kalimuddin, MBBS, MRCP         
Sponsors and Collaborators
Tan Tock Seng Hospital
Singapore General Hospital
National University Hospital, Singapore
Changi General Hospital
Investigators
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Principal Investigator: David Lye, MBBS, FRACP Tan Tock Seng Hospital

Publications:
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Responsible Party: David Lye, Senior Consultant, Tan Tock Seng Hospital
ClinicalTrials.gov Identifier: NCT02134106     History of Changes
Other Study ID Numbers: 2013/00609 (XDR-GNB)
First Posted: May 8, 2014    Key Record Dates
Last Update Posted: December 15, 2014
Last Verified: December 2014

Keywords provided by David Lye, Tan Tock Seng Hospital:
Multicenter
Open-label
Randomized
Controlled
RCT
antibiotic
drug-resistant
Gram-negative
bacteria

Additional relevant MeSH terms:
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Anti-Bacterial Agents
Antibiotics, Antitubercular
Anti-Infective Agents
Antitubercular Agents
Pneumonia
Bacteremia
Pneumonia, Ventilator-Associated
Healthcare-Associated Pneumonia
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Bacterial Infections
Sepsis
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Cross Infection
Iatrogenic Disease
Disease Attributes
Colistin
Doripenem
Polymyxins
Polymyxin B