Excluded versus included patients in a randomized controlled trial of infections caused by carbapenem-resistant Gram-negative bacteria: relevance to external validity

Vered Daitch*, Mical Paul, George L. Daikos, Emanuele Durante-Mangoni, Dafna Yahav, Yehuda Carmeli, Yael Dishon Benattar, Anna Skiada, Roberto Andini, Noa Eliakim-Raz, Amir Nutman, Oren Zusman, Anastasia Antoniadou, Giusi Cavezza, Amos Adler, Yaakov Dickstein, Ioannis Pavleas, Rosa Zampino, Roni Bitterman, Hiba ZayyadFidi Koppel, Yael Zak-Doron, Inbar Levi, Tanya Babich, Adi Turjeman, Haim Ben-Zvi, Lena E. Friberg, Johan W. Mouton, Ursula Theuretzbacher, Leonard Leibovici

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Background: Population external validity is the extent to which an experimental study results can be generalized from a specific sample to a defined population. In order to apply the results of a study, we should be able to assess its population external validity. We performed an investigator-initiated randomized controlled trial (RCT) (AIDA study), which compared colistin-meropenem combination therapy to colistin monotherapy in the treatment of patients infected with carbapenem-resistant Gram-negative bacteria. In order to examine the study’s population external validity and to substantiate the use of AIDA study results in clinical practice, we performed a concomitant observational trial. Methods: The study was conducted between October 1st, 2013 and January 31st, 2017 (during the RCTs recruitment period) in Greece, Israel and Italy. Patients included in the observational arm of the study have fulfilled clinical and microbiological inclusion criteria but were excluded from the RCT due to receipt of colistin for > 96 h, refusal to participate, or prior inclusion in the RCT. Non-randomized cases were compared to randomized patients. The primary outcome was clinical failure at 14 days of infection onset. Results: Analysis included 701 patients. Patients were infected mainly with Acinetobacter baumannii [78.2% (548/701)]. The most common reason for exclusion was refusal to participate [62% (183/295)]. Non-randomized and randomized patients were similar in most of the demographic and background parameters, though randomized patients showed minor differences towards a more severe infection. Combination therapy was less common in non-randomized patients [31.9% (53/166) vs. 51.2% (208/406), p = 0.000]. Randomized patients received longer treatment of colistin [13 days (IQR 10–16) vs. 8.5 days (IQR 0–15), p = 0.000]. Univariate analysis showed that non-randomized patients were more inclined to clinical failure on day 14 from infection onset [82% (242/295) vs. 75.5% (307/406), p = 0.042]. After adjusting for other variables, non-inclusion was not an independent risk factor for clinical failure at day 14. Conclusion: The similarity between the observational arm and RCT patients has strengthened our confidence in the population external validity of the AIDA trial. Adding an observational arm to intervention studies can help increase the population external validity and improve implementation of study results in clinical practice. Trial registration: The trial was registered with ClinicalTrials.gov, number NCT01732250 on November 22, 2012.

Original languageEnglish
Article number309
JournalBMC Infectious Diseases
Volume21
Issue number1
DOIs
Publication statusPublished - 31 Mar 2021

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