Early oral stepdown antibiotic therapy versus continuing intravenous therapy for uncomplicated Gram-negative bacteraemia (the INVEST trial): Study protocol for a multicentre, randomised controlled, open-label, phase III, non-inferiority trial

I. Russel Lee, Steven Y.C. Tong, Joshua S. Davis, David L. Paterson, Sharifah F. Syed-Omar, Kwong Ran Peck, Doo Ryeon Chung, Graham S. Cooke, Eshele Anak Libau, Siti Nabilah B.A. Rahman, Mihir P. Gandhi, Luming Shi, Shuwei Zheng, Jenna Chaung, Seow Yen Tan, Shirin Kalimuddin, Sophia Archuleta, David C. Lye

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Abstract

Background: The incidence of Gram-negative bacteraemia is rising globally and remains a major cause of morbidity and mortality. The majority of patients with Gram-negative bacteraemia initially receive intravenous (IV) antibiotic therapy. However, it remains unclear whether patients can step down to oral antibiotics after appropriate clinical response has been observed without compromising outcomes. Compared with IV therapy, oral therapy eliminates the risk of catheter-associated adverse events, enhances patient quality of life and reduces healthcare costs. As current management of Gram-negative bacteraemia entails a duration of IV therapy with limited evidence to guide oral conversion, we aim to evaluate the clinical efficacy and economic impact of early stepdown to oral antibiotics. Methods: This is an international, multicentre, randomised controlled, open-label, phase III, non-inferiority trial. To be eligible, adult participants must be clinically stable / non-critically ill inpatients with uncomplicated Gram-negative bacteraemia. Randomisation to the intervention or standard arms will be performed with 1:1 allocation ratio. Participants randomised to the intervention arm (within 72 h from index blood culture collection) will be immediately switched to an oral fluoroquinolone or trimethoprim-sulfamethoxazole. Participants randomised to the standard arm will continue to receive IV therapy for at least 24 h post-randomisation before clinical re-assessment and decision-making by the treating doctor. The recommended treatment duration is 7 days of active antibiotics (including empiric therapy), although treatment regimen may be longer than 7 days if clinically indicated. Primary outcome is 30-day all-cause mortality, and the key secondary outcome is health economic evaluation, including estimation of total healthcare cost as well as assessment of patient quality of life and number of quality-adjusted life years saved. Assuming a 30-day mortality of 8% in the standard and intervention arms, with 6% non-inferiority margin, the target sample size is 720 participants which provides 80% power with a one-sided 0.025 α-level after adjustment for 5% drop-out. Discussion: A finding of non-inferiority in efficacy of oral fluoroquinolones or trimethoprim-sulfamethoxazole versus IV standard of care antibiotics may hypothetically translate to wider adoption of a more cost-effective treatment strategy with better quality of life outcomes. Trial registration: ClinicalTrials.govNCT05199324. Registered 20 January 2022.

Original languageEnglish
Article number572
Pages (from-to)1-18
Number of pages18
JournalTrials
Volume23
Issue number1
DOIs
Publication statusPublished - Dec 2022
Externally publishedYes

Bibliographical note

Funding Information:
This trial will be managed by Singapore ID Clinical Research Network (SCRN), which was established in 2013 to coordinate multicentre clinical ID research in Singapore and internationally. SCRN is governed by an executive committee comprising clinical investigators from eight public hospitals in Singapore. SCRN is supported by project managers, clinical research fellows and clinical research coordinators based across multiple hospital sites in Singapore. The SCRN team will assist in the execution of multicentre legal agreements; application for EC/IRB and regulatory approvals; local participant enrolment and follow-up; data management, cleaning and analyses; and drafting of reports and manuscripts. At the time of writing (16-Mar-2022), the study’s overall PI is in the progress of forming a Global Trial Steering Committee (GTSC), which will be the key decision-making body for the trial. The roles and responsibilities of the GTSC include, but are not limited to, providing oversight to ensure the trial’s timeline, milestones and key performance indicators are met as well as proper execution of the trial in each of the participating sites in the different countries.

Publisher Copyright:
© 2022, The Author(s).

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