Test design and supervision
In the study of tofacitinib in hospitalized patients with Covid-19 pneumonia (STOP-COVID), we compared tofacitinib to placebo in patients with Covid-19 pneumonia. The trial protocol (available with the full text of this article on NEJM.org) was approved by the institutional ethics committee of the participating sites. The trial was conducted in accordance with the guidelines for good clinical practice and the principles of the Declaration of Helsinki.
The trial was sponsored by Pfizer and was designed and led by a steering committee that included academic researchers and representatives from Pfizer. The test operations and statistical analyzes were carried out by the University Research Organization of the Israelita Albert Einstein Hospital in São Paulo. An independent data and safety oversight committee continuously reviewed unblinded patient safety data during the trial. Pfizer provided the entire trial budget, which covered all trial-related expenses, including, but not limited to, investigator fees, costs related to suppliers of investigational products, and import, insurance, applicable taxes and fees, and financing to support data and security monitoring activities. Advice.
All authors vouch for the accuracy and completeness of the data and the reliability of the trial to the protocol. The trial committee members and participating investigators are listed in the supplemental appendix, available at NEJM.org.
The trial included patients 18 years of age or older who had laboratory-confirmed SARS-CoV-2 infection as determined by the reverse transcriptase-polymerase chain reaction (RT-PCR) assay prior to randomization. , who showed signs of Covid-19 pneumonia on X-ray imaging (computed tomography or chest x-ray), and who had been hospitalized for less than 72 hours. Information regarding the timing of eligible RT-PCR testing in relation to symptom onset is provided in Section S3.1 of the Supplementary Annex. High flow devices were the maximum oxygen carrier allowed for inclusion in the assay.
The main exclusion criteria were the use of non-invasive or invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) on the day of randomization, a history of thrombosis or ongoing thrombosis, known immunosuppression and any ongoing cancer for which the patient was receiving active treatment. Details of the eligibility criteria are provided in section S3.2. Written informed consent was obtained from each patient or the patient’s legally authorized representative if the patient was unable to provide informed consent.
Randomization, interventions and follow-up
Eligible patients were randomized 1: 1 to receive either tofacitinib or placebo. Randomization, with stratification by site, was performed using a centralized, concealed, web-based automated randomization system. Patients received either oral tofacitinib at a dose of 10 mg or placebo twice daily for up to 14 days or until discharge from hospital, whichever came first. If a participant underwent intubation before the end of the 14-day treatment period (or before discharge), they continued to receive tofacitinib or placebo if this was considered clinically appropriate by treating physicians. A reduced dose regimen of 5 mg tofacitinib (or a corresponding placebo) twice daily has been administered to patients with an estimated glomerular filtration rate of less than 50 ml per minute per 1.73 m2 body surface area, in patients with moderate hepatic impairment and in those using a strong CYP3A4 inhibitor or a combination of a moderate CYP3A4 inhibitor and a strong CYP2C19 inhibitor at the same time. The rationale for tofacitinib dosage is provided in section S3.3.
All patients were treated according to local standards of care for Covid-19, which could have included glucocorticoids, antibiotic agents, blood thinners and antiviral agents. The concomitant use of other JAK inhibitors, biologics, strong immunosuppressants, interleukin-1 inhibitors, interleukin-6 inhibitors or strong CYP450 inducers was prohibited. Patients were assessed daily (through day 28) during their hospitalization. Follow-up visits were made on day 14 and day 28 for participants who were discharged before day 14 or 28. The predefined reasons for permanently discontinuing the trial intervention are described in section S3.4.
The primary outcome was death or respiratory failure during the 28-day follow-up. Death or respiratory failure was determined if participants met criteria for category 6 (hospitalization status while receiving non-invasive ventilation or high-flow oxygen ventilation), 7 (status being hospitalized while receiving invasive mechanical ventilation or ECMO), or 8 (death) on the National Institute of Allergy and Infectious Diseases (NIAID) ordinal disease severity scale at eight levels (on a scale of 1 to 8, higher scores indicating more serious condition) (Table S1 in the Supplementary Annex). Patients who entered the trial while receiving oxygen via high flow devices (category 6) were considered to have met the primary endpoint criteria if they were clinically worsening up to to category 7 or 8. The occurrence of the primary outcome was judged by an independent clinical event classification committee, whose members were not aware of group assignments. The protocol and statistical analysis plan used an inverted ordinal scale, which has been inverted in this report to be consistent with previous studies.
Secondary efficacy endpoints were cumulative incidence of death through day 28, NIAID ordinal disease severity scale scores on day 14 and day 28, status of being alive and not. not use mechanical ventilation or ECMO on day 14 and day 28, live and not hospitalized status on day 14 and day 28, recovery (defined as resolution of fever and cough and (absence of ventilation or oxygen therapy), length of stay in hospital and length of stay in intensive care unit (ICU). The occurrence and severity of adverse events were assessed and coded according to the Medical dictionary of regulatory activities, version 23.1. Details of adverse event reporting, including reporting of pre-specified adverse events of particular interest, are described in section S3.5.
We estimated that assigning 260 patients, with randomization performed at a 1: 1 ratio, would provide the trial with 80% power to detect an between-group difference of 15 percentage points in the incidence of primary outcome, assuming that 15% of participants in the tofacitinib group and 30% of those in the placebo group would have an event (death or respiratory failure through day 28). The superiority hypothesis was tested at a two-tailed alpha level of 5%. Efficacy analyzes included all participants who were randomized. Safety analyzes included all participants who were randomized and took at least one dose of tofacitinib or placebo.
Results for the primary efficacy endpoint were analyzed using binary regression with Firth correction, with a test group and antiviral therapy for Covid-19 as covariates, and are expressed as a ratio of risk. Antiviral treatments on day 1 were used in the statistical model. The dichotomous secondary outcomes were analyzed in a manner similar to that used for the primary outcome. The effect of the intervention on death through day 28 is expressed as a hazard ratio derived from Cox regression. For ordinal data, a proportional probability model with adjustment for baseline antiviral therapy was used. An odds ratio less than 1.0 represents clinical improvement assessed on the ordinal scale. The proportionality of the odds was assessed using the Pulkstenis-Robinson method.9 We created Kaplan-Meier survival curves to express the time to onset of the primary outcome, both aggregate and stratified by baseline supplemental oxygen use and onset. of death for 28 days.
As a sensitivity analysis, results for the primary endpoint were analyzed using binary regression with Firth correction, with the use of glucocorticoids and antiviral agents at baseline as covariates. In addition, results for the primary endpoint were analyzed using logistic regression with Firth correction, with adjustment for baseline antiviral therapy. Pre-defined subgroup analyzes were performed based on age, sex, concomitant use of antiviral therapy, concomitant use of glucocorticoids, and time from symptom onset to completion. randomization.
For the primary endpoint, a two-tailed p-value less than 0.05 was considered to indicate statistical significance. 95% confidence intervals were estimated for all endpoints. The widths of the 95% confidence intervals for the secondary outcomes were not adjusted for multiple comparisons, so the intervals should not be used to infer definitive treatment effects. All analyzes were performed using SAS software, version 9.4 (SAS Institute), and R software, version 3.6.3 (R Foundation for Statistical Computing). Further details on the statistical analysis are provided in section S3.6.