Doxycycline for the prevention of progression of COVID-19 to severe disease requiring intensive care unit (ICU) admission: A randomized, controlled, open-label, parallel group trial (DOXPREVENT.ICU)
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Abstract
After admission to hospital, COVID-19 progresses in a substantial proportion of patients to critical disease that requires intensive care unit (ICU) admission.
Methods
In a pragmatic, non-blinded trial, 387 patients aged 40–90 years were randomised to receive treatment with SoC plus doxycycline (n = 192) or SoC only (n = 195). The primary outcome was the need for ICU admission as judged by the attending physicians. Three types of analyses were carried out for the primary outcome: “Intention to treat” (ITT) based on randomisation; “Per protocol” (PP), excluding patients not treated according to randomisation; and “As treated” (AT), based on actual treatment received. The trial was undertaken in six hospitals in India with high-quality ICU facilities. An online application serving as the electronic case report form was developed to enable screening, randomisation and collection of outcomes data.
Results
Adherence to treatment per protocol was 95.1%. Among all 387 participants, 77 (19.9%) developed critical disease needing ICU admission. In all three primary outcome analyses, doxycycline was associated with a relative risk reduction (RRR) and absolute risk reduction (ARR): ITT 31.6% RRR, 7.4% ARR (P = 0.063); PP 40.7% RRR, 9.6% ARR (P = 0.017); AT 43.2% RRR, 10.8% ARR (P = 0.007), with numbers needed to treat (NTT) of 13.4 (ITT), 10.4 (PP), and 9.3 (AT), respectively. Doxycycline was well tolerated with not a single patient stopping treatment due to adverse events.
Conclusions
In hospitalized COVID-19 patients, doxycycline, a safe, inexpensive, and widely available antibiotic with anti-inflammatory properties, reduces the need for ICU admission when added to SoC.
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SciScore for 10.1101/2022.01.30.22269685: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The study was approved by the ethics committees at individual study sites and all patients gave their written informed consent.
Consent: The study was approved by the ethics committees at individual study sites and all patients gave their written informed consent.Sex as a biological variable not detected. Randomization Study Design: This was a parallel group, controlled (against standard of care, SoC), randomized trial, including a screening period (0-1 days), 14 days of treatment and 14 days of follow-up by telephone. Blinding not detected. Power Analysis The trial required 80% power to detect a reduction in the risk of needing admission to ICU from 25% to 12.5% using a one-sided … SciScore for 10.1101/2022.01.30.22269685: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The study was approved by the ethics committees at individual study sites and all patients gave their written informed consent.
Consent: The study was approved by the ethics committees at individual study sites and all patients gave their written informed consent.Sex as a biological variable not detected. Randomization Study Design: This was a parallel group, controlled (against standard of care, SoC), randomized trial, including a screening period (0-1 days), 14 days of treatment and 14 days of follow-up by telephone. Blinding not detected. Power Analysis The trial required 80% power to detect a reduction in the risk of needing admission to ICU from 25% to 12.5% using a one-sided significance level of 2.5%. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources In vitro studies: To test and compare the effects of doxycycline, tetracycline and remdesivir on SARS-CoV-2 infection of ACE-2-overexpressing lung-derived cell lines, we carried out a drug screening viability assay on A549-hACE2 cells and MDA-MB-231-hACE2 after infection of with SARS-CoV-2 (MS, OTK). A549-hACE2suggested: RRID:CVCL_A5KB)MDA-MB-231-hACE2suggested: NoneResults from OddPub: Thank you for sharing your code and data.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:The study and the approach we took had its limitations, the main being the absence of the intensity of monitoring that drug trials usually entail. However, as a real-world study, this trial was just as determined and able as the major COVID-19 platform trials to obtain accurate data. We also recognize that we could not undertake the planned interim analyses because of strained communications during the second peak in India, something that may have been easier to cope with had more centres been recruited (meaning less burden per centre) and/or had trial monitors been assigned to each site, albeit raising the cost of the trial. Whilst we were confident about the main outcome (need for ICU admission) and mortality, we were less confident about collecting some of the secondary endpoints, so did not feel it justified to analyse these outputs. We conclude, therefore, that the approach taken, including the use of the eCRF, is less suited for collection of finer study details, although adjustments to improve the functionality of the app should make it possible to collect more complex datasets. In summary, this study has shown that doxycycline prevents progression of COVID-19 to the point where ICU admission is needed. This comes with significant implications for both patients and health services, in particular in countries where, because of limited financial resources, ICU admission is dependent on accessibility and affordability rather than clinical indication. A similar study is ne...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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