Bacteremia Clinical Trial
— XDR-GNBOfficial 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)
Verified date | October 2019 |
Source | Tan Tock Seng Hospital |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Withdrawn |
Enrollment | 0 |
Est. completion date | December 2015 |
Est. primary completion date | October 2015 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 21 Years to 90 Years |
Eligibility |
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. |
Country | Name | City | State |
---|---|---|---|
Singapore | National University Hospital | Singapore | |
Singapore | Singapore General Hospital | Singapore |
Lead Sponsor | Collaborator |
---|---|
Tan Tock Seng Hospital | Changi General Hospital, National University Hospital, Singapore, Singapore General Hospital |
Singapore,
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. Review. — View Citation
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. — View Citation
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. — View Citation
Koh TH, Khoo CT, Wijaya L, Leong HN, Lo YL, Lim LC, Koh TY. Global spread of New Delhi metallo-ß-lactamase 1. Lancet Infect Dis. 2010 Dec;10(12):828. doi: 10.1016/S1473-3099(10)70274-7. — View Citation
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. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Treatment related or non-related adverse events and emergence of of secondary infections caused by new multidrug-resistant bacteria or fungi | Safety outcomes: 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. Emergence of secondary infections caused by new multidrug-resistant bacteria or fungi within 30 days from starting study treatment. |
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) | |
Primary | 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 | Microbiological clearance | Microbiological clearance assessed on Day 3 and 7 | On Day 3 and 7 | |
Secondary | Time to defervescence | Time to first occurence of defervescence throughout the entire study period, censored at Day 30 or date of discharge, if fever is still present. | Censored at Day 30 | |
Secondary | Duration of stay in ICU | Duration of first ICU stay for subjects managed in the ICU throughout entire study period (until Day 30). | Censored at Day 30 | |
Secondary | Clinical improvement | 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. | Day 3 | |
Secondary | Clinical progression | 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. | Day 30 |
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