Randomized-controlled Trial (RCT) on Combination Antibiotic for Infections Caused by Gram-negative Bacteria
Status:
Withdrawn
Trial end date:
2015-12-01
Target enrollment:
Participant gender:
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.
Phase:
Phase 2/Phase 3
Details
Lead Sponsor:
Tan Tock Seng Hospital
Collaborators:
Changi General Hospital National University Hospital, Singapore Singapore General Hospital
Treatments:
Anti-Bacterial Agents Antibiotics, Antitubercular Colistin Doripenem Polymyxin B Polymyxins