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

NCT02134106 | Withdrawn Phase 2 DMC

• 1 other identifier: 2013/00609 (XDR-GNB)
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 2

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.

Conditions

Bacteremia; Healthcare-associated Pneumonia; Ventilator-associated Pneumonia

Keywords

Multicenter; Open-label; Randomized; Controlled; RCT; antibiotic; drug-resistant; Gram-negative; bacteria

Outcome Measures

Primary Outcomes (1)

• The primary outcome will be all-cause mortality at 30 days post-date of 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.

  All-cause mortality at 30 days post-randomization

Secondary Outcomes (5)

• Microbiological clearance

  On Day 3 and 7

• Time to defervescence

  Censored at Day 30

• Duration of stay in ICU

  Censored at Day 30

• Clinical improvement

  Day 3

• Clinical progression

  Day 30

Other Outcomes (1)

• Treatment related or non-related adverse events and emergence of of secondary infections caused by new multidrug-resistant bacteria or fungi

  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)

Study Arms (2)

Polymyxin B

ACTIVE COMPARATOR

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

Polymyxin B + Doripenem

EXPERIMENTAL

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

Interventions

Polymyxin B DRUG

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.

Polymyxin B

Polymyxin B + Doripenem DRUG

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.

Also known as: Doribax,

Polymyxin B + Doripenem

Eligibility Criteria

• Age: 21 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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).

Sponsors & Collaborators

• Tan Tock Seng Hospital: lead
• Singapore General Hospital: collaborator
• National University Hospital, Singapore: collaborator
• Changi General Hospital: collaborator

Study Sites (2)

National University Hospital

Singapore, 119074, Singapore

Location

Singapore General Hospital

Singapore, 169608, Singapore

Location

Related Publications (5)

• Boucher HW. Challenges in anti-infective development in the era of bad bugs, no drugs: a regulatory perspective using the example of bloodstream infection as an indication. Clin Infect Dis. 2010 Jan 1;50 Suppl 1:S4-9. doi: 10.1086/647937.

  PMID: 20067391 BACKGROUND

• Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, Harbarth S, Hindler JF, Kahlmeter G, Olsson-Liljequist B, Paterson DL, Rice LB, Stelling J, Struelens MJ, Vatopoulos A, Weber JT, Monnet DL. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012 Mar;18(3):268-81. doi: 10.1111/j.1469-0691.2011.03570.x. Epub 2011 Jul 27.

  PMID: 21793988 BACKGROUND

• Hsu LY, Tan TY, Jureen R, Koh TH, Krishnan P, Tzer-Pin Lin R, Wen-Sin Tee N, Tambyah PA. Antimicrobial drug resistance in Singapore hospitals. Emerg Infect Dis. 2007 Dec;13(12):1944-7. doi: 10.3201/eid1312.070299.

  PMID: 18258055 BACKGROUND

• Koh TH, Khoo CT, Tan TT, Arshad MA, Ang LP, Lau LJ, Hsu LY, Ooi EE. Multilocus sequence types of carbapenem-resistant Pseudomonas aeruginosa in Singapore carrying metallo-beta-lactamase genes, including the novel bla(IMP-26) gene. J Clin Microbiol. 2010 Jul;48(7):2563-4. doi: 10.1128/JCM.01905-09. Epub 2010 May 12.

  PMID: 20463166 BACKGROUND

• Koh TH, Khoo CT, Wijaya L, Leong HN, Lo YL, Lim LC, Koh TY. Global spread of New Delhi metallo-beta-lactamase 1. Lancet Infect Dis. 2010 Dec;10(12):828. doi: 10.1016/S1473-3099(10)70274-7. No abstract available.

  PMID: 21109168 BACKGROUND

MeSH Terms

Conditions

Bacteremia; Healthcare-Associated Pneumonia; Pneumonia, Ventilator-Associated

Interventions

Polymyxin B; Doripenem

Condition Hierarchy (Ancestors)

Bacterial Infections; Bacterial Infections and Mycoses; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Cross Infection; Pneumonia; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases; Iatrogenic Disease; Disease Attributes

Intervention Hierarchy (Ancestors)

Polymyxins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Lipopeptides; Lipids; Antimicrobial Cationic Peptides; Peptides; Amino Acids, Peptides, and Proteins; Antimicrobial Peptides; Pore Forming Cytotoxic Proteins; Membrane Proteins; Proteins; Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• David Lye, MBBS, FRACP

  Tan Tock Seng Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Senior Consultant

Study Record Dates

• First Submitted: May 4, 2014
• First Posted: May 8, 2014
• Study Start: January 1, 2015
• Primary Completion: October 1, 2015
• Study Completion: December 1, 2015
• Last Updated: October 9, 2019

Record last verified: 2019-10

Data Sharing

• IPD Sharing: Will not share

Locations

SG (2)