Денис Гордеев Форекс

Study design and participants

This study was an adaptive, phase 3, multicentre, randomised, double-blind trial. The study was done at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain (appendix pp 1–3). Because of the uncertainties of assessing treatment efficacy in COVID pneumonia at the time of study design, the initial protocol allowed adaptations such as modification of the provisional phase 3 endpoints, sample size re-estimation before entering phase 3, or closing a dose group while the study remained blinded. Patients were assessed daily (vital signs were recorded ≥4 times per day from day 1–3, and ≥2 times per day from day 4–29) while hospitalised until discharge, or death, with a final follow-up on day

We enrolled adults (≥18 years) who had been admitted to hospital for laboratory-confirmed SARS-CoV-2 infection in any specimen within 2 weeks before random assignment and with evidence of pneumonia by chest imaging or chest auscultation and no alternative explanation for the clinical presentation. Patients also had to meet criteria for severe disease (defined as administration of supplemental oxygen by nasal cannula, simple face mask, or another similar device) or critical disease (defined as need for supplemental oxygen delivered by non-rebreather mask or high-flow nasal cannula, use of invasive or non-invasive ventilation, or treatment in an intensive care unit).

Patients were excluded from the study if they had, in the investigator's opinion, at least one of the following: a low probability of surviving 48 h or remaining at the investigational site beyond 48 h, dysfunction of two or more organ systems, need for extracorporeal life support, or renal replacement therapy at screening; absolute neutrophil count less than cells per mm³; aspartate aminotransferase or alanine aminotransferase (ALT) exceeding five-times the upper limit of normal at screening; less than 50 platelets per mm³

The protocol was approved by the institutional review boards at each participating hospital and by national ethics committees, as required by local and national regulations. The study was done in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the World Medical Association's Declaration of Helsinki and its amendments. Before participating in the trial, informed consent was obtained from all patients or their legally authorised or appointed representatives, as specified by local law and in compliance with or exceeding ethics committee requirements.

Four amendments were made to the original protocol. Amended protocol 01 (March 26, ) implemented clarifications to the original version. Amended protocol 02 (April 8, ) implemented changes from phase 2 primary and key secondary endpoints to the phase 3 primary and key secondary endpoints and added an option for a second dose. Amended protocol 03 (April 29, ) added an interim analysis when approximately 50% of the total planned number of patients reached day 15, for review by the independent data monitoring committee and unmasked representatives of the sponsor's senior management, who were not involved in study conduct; clarified the extent to which the sponsor could adapt the study following review of an interim report; and removed the use of vasopressors as an exclusion criterion. Amended protocol 04 (June 11, ) closed enrolment into the mg group after senior management review of interim results and subsequent confirmation by review of the independent data monitoring committee, which favoured the mg dose.

Randomisation and masking

Eligible patients were randomly assigned () to one dose of intravenous sarilumab mg, sarilumab mg, or placebo according to a central randomisation scheme using permuted blocks of five and implemented through an interactive response technology. Randomisation was stratified by severity of illness (severe or critical) and use of systemic corticosteroids (yes or no). Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. An unmasked pharmacist was responsible for the preparation and dispensation of all study interventions.

Procedures

Sarilumab mg, sarilumab mg, or placebo were prepared according to instructions provided in the pharmacy manual. After confirming the randomisation number accessed via interactive response technology, the hospital pharmacist added the contents of prefilled syringes of sarilumab mg solution for subcutaneous injection supplied by the sponsor into a specified volume of locally sourced 0·9% sodium chloride solution for intravenous infusion (two syringes for the mg dose, one syringe for the mg dose, and 0·9% sodium chloride solution for the placebo dose) to produce an intravenous bag containing a colourless solution to be administered by masked hospital staff as one intravenous infusion. Patients could have the intravenous infusion stopped for a safety-related issue, in which case they did not continue with dosing. An option for a second dose existed (within the assigned treatment group) within 24–48 h of the first dose, based on the investigator's benefit-risk assessment (amended protocol 02; April 8, ).

Efficacy assessments included a once per day assessment of clinical status until discharge, body temperature (day 1–3 four times a day; day 4–29 twice a day), oxygen administration (day 1–3 four times a day; day 4–29 results recorded as assessed), resting oxygen saturation (SpO₂ day 1–3 four times a day; day 4–29 results recorded as assessed), and National Early Warning Score Safety procedures and assessments included clinical laboratory testing (done locally at each hospital), targeted physical examination, and concomitant medication review. Vital signs were recorded daily until discharge. Surveillance testing for bacterial and fungal infection was done locally, on days 7 and In addition to the positive SARS-CoV-2 result required for inclusion, nasopharyngeal (when feasible) and blood samples were collected at baseline and on days 7, 15, 21, and 29, or on the day of hospital discharge and analysed by the local laboratories and a central laboratory. Serum IL-6 and other biomarkers were analysed in a central laboratory. Blood samples were also taken for measurement of sarilumab concentration. Other than central laboratory results, all clinical data were entered by investigators at each site into an electronic clinical research form and validated remotely by the sponsor's monitoring team.

Outcomes

The primary efficacy endpoint was time from baseline to clinical improvement of two or more points on a seven-point ordinal scale, with numerical values defined as follows: (1) death; (2) admitted to hospital, on invasive mechanical ventilation or extracorporeal membrane oxygenation; (3) admitted to hospital, on non-invasive ventilation or high-flow oxygen devices; (4) admitted to hospital, requiring supplemental oxygen; (5) admitted to hospital, not requiring supplemental oxygen, requiring ongoing medical care (COVIDrelated or otherwise); (6) admitted to hospital, not requiring supplemental oxygen, no longer requiring ongoing medical care; and (7) discharged from hospital. Discharge before day 29 was considered as a two-point improvement. The key secondary efficacy endpoint was the proportion of patients alive at day

The original phase 2 primary endpoint was the time to resolution of fever for at least 48 h without antipyretics or until discharge (original protocol; March 18, ). However, the unanticipated rapid rate of enrolment made the plan to use the phase 2 analysis to select phase 3 efficacy endpoints unfeasible. As a result, the primary and key secondary endpoints for phase 3, as described above, were adopted a priori in amended protocol 02 (April 8, ).

Other secondary efficacy endpoints included differences in time-to-event endpoints by treatment (eg, time to improvement of one or more points on the seven-point scale, fever resolution, or discharge from hospital), score changes at specific timepoints (eg, proportion with a one-point improvement or worsening), and event durations (eg, mechanical ventilation, hospital stay).

Safety was assessed by investigator reports of adverse events, serious adverse events, adverse events of special interest (infusion-related reactions; hypersensitivity reactions; absolute neutrophil count < cells per mm³ with or without concurrent invasive infection; increase in ALT of at least three-times the upper limit of normal if normal at baseline or more than three-times the upper limit of normal and at least two-times more than the baseline concentration if abnormal at baseline; invasive bacterial or fungal infections of clinical significance with confirmed diagnosis based on the investigator's assessment with appropriate diagnostic tests and consultations; symptomatic overdose),15

• Founder, Chairman of the Board of Directors in Libertex Group. Founder and Rector till of International Investment and trading Academy. Author of "Play the stock market is easy?!", "FOREX CLUB — win-win revolution".
  
• Founder, Member of the Board of Directors in Libertex Group.
• Founder, Member of the Board of Directors in BBR Bank.
  
• Director of Change One Life Charitable Foundation in
  

• Sergei Bezrukov and Anna Matison
  

  Sergey Bezrukov - National artist of Russia, Anna Matison - playwriter
  
• Russian theater and movie actress
  
• Child top model, designer
  

• Founder and Chairman of Board of Directors online-platform for export of Russian manufacturers' goods eunic-brussels.eu
  
• Head of Sales department in Google
• Chairman of Board of Directors in RuDIVE Group
  

• Head of information and education projects
• Head of ProFamily project
  

• I want to say thank you so much! I found my little son thanks to the video profile on your website. Our kid has been with us for more than a year. And this video is a memory. Special thanks to Ekaterina for her responsiveness.
  
• I want to thank you all from our big (already) family! We arrived safely home. We arrived only yesterday, but if feels like we have never being apart!) Without your foundation it would never happen, we would never meet our child! Thank you personally for the fact that you just answered all the questions that immediately! Thank you very much!!!
  
• I'd like to express our particular gratitude on behalf of our family. This week, we adopted and brought our girl home from Irkutsk oblast thanks to seeing her video profile. With her previously only having such an official-looking photo, like from the state databank, she could hardly expect to find parents in the near future. We certainly would never have met that wonderful child. It's a very long way to Irkutsk oblast and I don't think that many people would want to make the decision to go there having only one photo of the child, especially a such a poor and unnatural one.
• This is a wonderful project and such a necessary one. It's very important to know that, in case of emergency you can ask for help and that you can always secure a stress-free hour or two to take care of your own affairs. Besides, it's often impossible to solve some problems in the presence of a child/children. Of course, if you have grandparents, you might not need this service so much, but I, for example, don't have any grandparents, and for that reason, in a lot of cases this project is a real salvation for me.