Efficacy of Proxalutamide in Hospitalized COVID-19 Patients: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Design Clinical Trial
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Abstract
Background
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectivity is mediated by the androgen-promoted protease, transmembrane protease, serine 2 (TMPRSS2). Previously, we have shown that treatment with proxalutamide, a non-steroidal androgen receptor antagonist, accelerates viral clearance and clinical remission in outpatients with coronavirus disease 2019 (COVID-19) compared to placebo. The effects in hospitalized COVID-19 patients were unknown.
Methods
Men and women hospitalized but not requiring mechanical ventilation were randomized (1:1 ratio) to receive 300 mg of proxalutamide per day or placebo for 14 days. The study was conducted at eight sites in the state of Amazonas, Brazil. The primary outcome measure was the clinical status (8-point ordinal scale) at 14-days post-randomization. The primary efficacy endpoint was the 14-day recovery ratio (alive hospital discharge [scores 1, 2]).
Findings
A total of 645 patients were randomized (317 received proxalutamide, 328 placebo) and underwent intention-to-treat analysis. The 14-day median ordinal scale score in the proxalutamide group was 1 (interquartile range [IQR]=1–2) versus 7 (IQR=2–8) for placebo, P<0.001. The 14-day recovery rate was 81.4% for proxalutamide and 35.7% for placebo (recovery ratio, 2.28; 95% CI 1.95–2.66 [P<0.001]). The 28-day all-cause mortality rate was 11.0% for proxalutamide versus 49.4% for placebo (hazard ratio, 0.16; 95% CI 0.11–0.24). The median post-randomization time to recovery was 5 days (IQR=3– 8) for proxalutamide versus 10 days (IQR=6–15) for placebo.
Interpretation
Hospitalized COVID-19 patients not requiring mechanical ventilation receiving proxalutamide had a 128% higher recovery rate than those treated with placebo. All-cause mortality was reduced by 77.7% over 28 days. ( ClinicalTrials.gov number, NCT04728802 ).
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SciScore for 10.1101/2021.06.22.21259318: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable Eligibility criteria: Inclusion criteria: Men and women hospitalized due to COVID-19 with a previously confirmed positive test for SARS-CoV-2 within 7 days prior to randomization. Randomization Trial Design, Setting and Locations: This was a double-blinded, randomized, placebo-controlled, prospective, two-arm trial. Blinding The local investigators who were directly involved with patient care, other healthcare providers, and patients were kept blinded to the group assignments until all patients completed the 28-day post-randomization period and the data was locked. Power Analysis The sample size was calculated to be able to detect a difference of … SciScore for 10.1101/2021.06.22.21259318: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable Eligibility criteria: Inclusion criteria: Men and women hospitalized due to COVID-19 with a previously confirmed positive test for SARS-CoV-2 within 7 days prior to randomization. Randomization Trial Design, Setting and Locations: This was a double-blinded, randomized, placebo-controlled, prospective, two-arm trial. Blinding The local investigators who were directly involved with patient care, other healthcare providers, and patients were kept blinded to the group assignments until all patients completed the 28-day post-randomization period and the data was locked. Power Analysis The sample size was calculated to be able to detect a difference of approximately 14% in the overall recovery rate at 14 days (risk ratio of 1.36) with a power of 90% and a type I error of 5%, over an estimated 39% recovery rate for the placebo group (based on the protocol for NCT04280705 [scenario 4]), and 3.5% non-compliance/cross over for each group. Table 2: Resources
Software and Algorithms Sentences Resources Exclusion criteria included mechanical ventilation at the time of randomization, a history of congestive heart failure class III or IV (New York Heart Association) York Heart Associationsuggested: NoneStata/SE version 16.1 for Mac (StataCorp LLC, College Station, TX, USA) was used to perform all statistical analysis. StataCorpsuggested: (Stata, RRID:SCR_012763)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Important limitations are present in this study. First, the remote locations of many of the study sites created operational difficulties that led to an unbalanced distribution of proxalutamide and placebo amongst sites (details provided in Supplementary Appendix). Minor differences in effects of proxalutamide between sites may have resulted from factors such as local infrastructure and age distribution (Figures S5 and S6). However, the possibility of effect sizes skewing in favor of the proxalutamide group due to its disproportional concentration in the smaller hospitals is unlikely because a similar size effect was observed in subgroup analysis of all hospital sites (Tables S3 and S4). Second, the severity of patients admitted to Amazonas hospitals during the trial did not allow us to test proxalutamide in many hospitalized patients who did not require supplemental oxygen (ordinal score 3). However, we have previously shown that proxalutamide reduced hospitalizations and improved symptom recovery and viral clearance in outpatients with mild-moderate disease.10 Moreover, the subgroup analysis showed patients with baseline scores of 3-5 benefited from proxalutamide. Third, more patients used colchicine in the placebo arm despite randomization. This most likely reflects additional therapeutic interventions associated with longer hospitalization in the placebo group. Colchicine is unlikely, however, to have contributed to increased mortality directly as there is either no effect...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04728802 Completed Proxalutamide Treatment for Hospitalized COVID-19 Patients NCT04280705 Completed Adaptive COVID-19 Treatment Trial (ACTT) 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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