DOOR analysis strategy can be successfully applied to infectious disease RCTs
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Key takeaways:
- A DOOR analysis strategy can be adapted and successfully applied to HABP/VABP randomized controlled trials.
- Using DOOR could create a better understanding of the risks and benefits of novel therapeutics.
Desirability of outcome ranking, or DOOR, can be adapted and used successfully in hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia clinical trials, researchers reported.
“In the spring of 2020, the Antibacterial Resistance Leadership Group (ARLG) created a multidisciplinary DOOR Task Force with the goal of developing DOOR endpoints that could be tailored to common infectious diseases and used in registrational trials testing novel antibiotics,” Jessica Howard-Anderson, MD MSc, assistant professor at Emory University School of Medicine and associate hospital epidemiologist at Emory University Hospital Midtown, told Healio.
She explained that the DOOR endpoint is a patient-centered measure that incorporates both the risk and the benefits of a new therapeutic or intervention and allows for a more comprehensive understanding.
“As a first step to our overall goal, we aimed to see if a DOOR endpoint could be retrospectively applied to completed [randomized controlled trials (RCTs)] for new antibiotics,” Howard-Anderson said. “We initially had success in doing this for complicated urinary tract infection. We then moved on to apply the DOOR endpoint to hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) trials. We were fortunate to partner with Pfizer and Merck, who shared deidentified data, in kind, from the ZEPHyR and VITAL trials, respectively.”
To assess a DOOR endpoint, the ARLG DOOR Task Force created an infectious diseases DOOR endpoint that was customized for HABP/VABP, which incorporated infectious complications, serious adverse events, and mortality.
The researchers then applied the endpoint to two previously completed, large RCTs for HABP/VABP. Additionally, they used data from ZEPHyR — which compared vancomycin with linezolid — and VITAL — which compared linezolid with tedizolid — and evaluated the DOOR distribution and probability.
In total, 448 participants were included in the modified intention-to-treat (mITT) population for ZEPHyR and 718 participants were included in the mITT population for VITAL. Overall, the HABP/VABP DOOR anyalysis demonstrated similar overall clinical outcomes between treatment groups in both trials.
Specifically, the analysis showed that the probability that a patient treated with linezolid would have a more desirable outcome than a participant treated with vancomycin was 50.2% (95% CI, 45.1%-55.3%) in the ZEPHyR trial. In VITAL, the probability that a patient treated with tedizolid would have a more desirable outcome than a participant treated with linezolid was 48.7% (95% CI, 44.8%-52.6%).
The researchers added that because DOOR can be considered a composite outcome, it was important to also analyze the individual components of DOOR. In doing so, they found that there was no difference between treatment arms in any of the individual DOOR components — absence of clinical response, infectious complications, serious adverse events (SAEs), or death — in ZEPHyR.
In VITAL, however, participants in the tedizolid group had a “less desirable” outcome when considering clinical response (probability = 46.3%; 95% CI, 42.8%-49.9%). They added, though, that this was balanced by patients in the tedizolid group having a more favorable outcome when soley assessing SAEs (probability = 52.3%; 95% CI, 48.7%-55.9%).
“The HABP/VABP DOOR is designed to be patient centered, encompassing more than a single assessment of clinical efficacy or mortality, and includes issues that may arise throughout a patient’s follow-up or recovery,” Howard-Anderson said. “The DOOR endpoint provides clinicians and patients with more detailed information than typically presented in clinical trials and can help with risk-benefit and shared decision-making between patients and physicians. We believe DOOR should be prospectively included in future HABP/VABP trials.”
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