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Sarilumab versus standard of care for the early treatment of COVID-19 pneumonia in hospitalized patients: SARTRE: a structured summary of a study protocol for a randomised controlled trial.
Caballero Bermejo, Antonio F; Ruiz-Antorán, Belén; Fernández Cruz, Ana; Diago Sempere, Elena; Callejas Díaz, Alejandro; Múñez Rubio, Elena; Avendaño-Solá, Cristina; Ramos Martínez, Antonio; Sancho López, Aránzazu.
  • Caballero Bermejo AF; Clinical Pharmacology Department, Hospital Universitario Puerta de Hierro-Majadahonda, Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana, Madrid, Spain.
  • Ruiz-Antorán B; Clinical Pharmacology Department, Hospital Universitario Puerta de Hierro-Majadahonda, Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana, Madrid, Spain. mariabelen.ruiz@salud.madrid.org.
  • Fernández Cruz A; Infectious Diseases Unit, Internal Medicine Department, Hospital Universitario Puerta de Hierro-Majadahonda, Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana, Madrid, Spain.
  • Diago Sempere E; Clinical Pharmacology Department, Hospital Universitario Puerta de Hierro-Majadahonda, Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana, Madrid, Spain.
  • Callejas Díaz A; Infectious Diseases Unit, Internal Medicine Department, Hospital Universitario Puerta de Hierro-Majadahonda, Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana, Madrid, Spain.
  • Múñez Rubio E; Infectious Diseases Unit, Internal Medicine Department, Hospital Universitario Puerta de Hierro-Majadahonda, Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana, Madrid, Spain.
  • Avendaño-Solá C; Clinical Pharmacology Department, Hospital Universitario Puerta de Hierro-Majadahonda, Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana, Madrid, Spain.
  • Ramos Martínez A; Infectious Diseases Unit, Internal Medicine Department, Hospital Universitario Puerta de Hierro-Majadahonda, Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana, Madrid, Spain.
  • Sancho López A; Clinical Pharmacology Department, Hospital Universitario Puerta de Hierro-Majadahonda, Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana, Madrid, Spain.
Trials ; 21(1): 794, 2020 Sep 16.
Article in English | MEDLINE | ID: covidwho-768595
Semantic information from SemMedBD (by NLM)
1. sarilumab TREATS Pneumonia
Subject
sarilumab
Predicate
TREATS
Object
Pneumonia
2. Pneumonia PROCESS_OF hospitalized patients
Subject
Pneumonia
Predicate
PROCESS_OF
Object
hospitalized patients
3. Blood LOCATION_OF interleukin-6
Subject
Blood
Predicate
LOCATION_OF
Object
interleukin-6
4. Infected PROCESS_OF Patients
Subject
Infected
Predicate
PROCESS_OF
Object
Patients
5. Pneumoni PROCESS_OF C0030705
Subject
Pneumoni
Predicate
PROCESS_OF
Object
C0030705
6. Elevated IL6 PROCESS_OF Patients
Subject
Elevated IL6
Predicate
PROCESS_OF
Object
Patients
7. Adrenal Cortex Hormones TREATS Pneumonia
Subject
Adrenal Cortex Hormones
Predicate
TREATS
Object
Pneumonia
8. CD69 protei ASSOCIATED_WITH C0206061
Subject
CD69 protei
Predicate
ASSOCIATED_WITH
Object
C0206061
9. Therapeutic procedure USES UBXN11
Subject
Therapeutic procedure
Predicate
USES
Object
UBXN11
10. CD69 protei PART_OF C0030705
Subject
CD69 protei
Predicate
PART_OF
Object
C0030705
11. Serum LOCATION_OF Ferritin
Subject
Serum
Predicate
LOCATION_OF
Object
Ferritin
12. Therapeutic immunosuppression USES Antibodies
Subject
Therapeutic immunosuppression
Predicate
USES
Object
Antibodies
13. Pathogenic organism CAUSES Septicemia
Subject
Pathogenic organism
Predicate
CAUSES
Object
Septicemia
14. Hospitals LOCATION_OF Study
Subject
Hospitals
Predicate
LOCATION_OF
Object
Study
15. Adrenal Cortex Hormones ADMINISTERED_TO Patients
Subject
Adrenal Cortex Hormones
Predicate
ADMINISTERED_TO
Object
Patients
16. COVID-19 PROCESS_OF Patients
Subject
COVID-19
Predicate
PROCESS_OF
Object
Patients
17. sarilumab TREATS Pneumonia
Subject
sarilumab
Predicate
TREATS
Object
Pneumonia
18. Pneumonia PROCESS_OF hospitalized patients
Subject
Pneumonia
Predicate
PROCESS_OF
Object
hospitalized patients
19. Blood LOCATION_OF interleukin-6
Subject
Blood
Predicate
LOCATION_OF
Object
interleukin-6
20. Infected PROCESS_OF Patients
Subject
Infected
Predicate
PROCESS_OF
Object
Patients
21. Pneumonia, Interstitial PROCESS_OF Patients
Subject
Pneumonia, Interstitial
Predicate
PROCESS_OF
Object
Patients
22. Elevated IL6 PROCESS_OF Patients
Subject
Elevated IL6
Predicate
PROCESS_OF
Object
Patients
23. Adrenal Cortex Hormones TREATS Pneumonia
Subject
Adrenal Cortex Hormones
Predicate
TREATS
Object
Pneumonia
24. CD69 protein, human|CD69 ASSOCIATED_WITH Pneumonia, Interstitial
Subject
CD69 protein, human|CD69
Predicate
ASSOCIATED_WITH
Object
Pneumonia, Interstitial
25. Therapeutic procedure USES UBXN11
Subject
Therapeutic procedure
Predicate
USES
Object
UBXN11
26. CD69 protein, human|CD69 PART_OF Patients
Subject
CD69 protein, human|CD69
Predicate
PART_OF
Object
Patients
27. Serum LOCATION_OF Ferritin
Subject
Serum
Predicate
LOCATION_OF
Object
Ferritin
28. Therapeutic immunosuppression USES Antibodies
Subject
Therapeutic immunosuppression
Predicate
USES
Object
Antibodies
29. Pathogenic organism CAUSES Septicemia
Subject
Pathogenic organism
Predicate
CAUSES
Object
Septicemia
30. Hospitals LOCATION_OF Study
Subject
Hospitals
Predicate
LOCATION_OF
Object
Study
31. Adrenal Cortex Hormones ADMINISTERED_TO Patients
Subject
Adrenal Cortex Hormones
Predicate
ADMINISTERED_TO
Object
Patients
32. COVID-19 PROCESS_OF Patients
Subject
COVID-19
Predicate
PROCESS_OF
Object
Patients
ABSTRACT

OBJECTIVES:

In some patients, acute, life-threatening respiratory injury produced by viruses such as SARS-CoV and other viral pneumonia are associated with an over-exuberant cytokine release. Elevated levels of blood IL-6 had been identified as a one of the risk factors associated with severe COVID-19 disease. Anti-IL6 inhibitors are among the therapeutic armamentarium for preventing the fatal consequences of acute respiratory and multi organ failure in around 20% of the COVID-19 infected patients. At present, their use is prioritized to patients with severe interstitial pneumonia (Brescia-COVID Scale-COVID 2-3) with hyperinflammation as determined by the presence of elevated IL6 and/or d-dimer, or progressive d-dimer increase, in patients who otherwise are subsidiary to ICU admission. However, many uncertainties remain on the actual role of anti-IL6 inhibitors in this setting, and whether current use and timing is the right one. There is the hypothesis that the use of anti-IL6 inhibitors at an earlier state during the hyperinflammatory syndrome would be beneficial and may avoid progressing to ARDS. On the other hand, the standard of care has changed and nowadays the use of corticosteroids has become part of the SOC in the treatment of COVID-19 pneumonia. Our limited experience suggests that better treatment outcomes can be achieved when combining IL6-inhibitors (e.g. sarilumab) with corticosteroids. The aim of the present study is to evaluate if an earlier therapeutic intervention with sarilumab plus SOC (including corticosteroids) may be more effective than current standard of care alone, in preventing progression to respiratory failure in COVID-19 infected patients with interstitial pneumonia. This study will also provide supportive evidence to that provided by currently ongoing studies on the efficacy and safety of sarilumab in this clinical context. TRIAL

DESIGN:

A phase two multi-center randomised controlled trial (RCT) with two parallel arms (11 ratio).

PARTICIPANTS:

They will be hospitalized patients, of at least 18 years of age, with severe COVID-19 who have positive RT-PCR test and have radiographic evidence of pulmonary infiltrates by imaging or rales/crackles on exam and SpO2 ≤ 94% on room air that requires supplemental oxygen. Patients must present elevation of inflammatory parameters (IL-6 > 40 pg/mL or d-dimer >1.0 mcg/ml) or, alternatively, progressive worsening in at least two of these inflammatory parameters in the prior 24-48h CRP, LDH, serum ferritin, lymphopenia, or d-dimer. EXCLUSION CRITERIA high oxygen requirements (including face mask with reservoir, non-invasive mechanical ventilation or high flow nasal cannula, or mechanical ventilation), admission to ICU, pregnancy or lactation, allergy or hypersensitivity to sarilumab or corticoesteroids, immunosuppressive antibody therapy within the past 5 months, AST/ALT values > 10 x ULN, neutropenia (< 0.5 x 109/L), severe thrombocytopenia (< 50 x 109/L), sepsis caused by an alternative pathogen, diverticulitis with risk of perforation or ongoing infectious dermatitis. The study will be conducted in several hospitals in Spain. INTERVENTION AND COMPARATOR Patients randomised to the experimental arm will receive sarilumab + methylprednisolone plus SOC for COVID-19. Patients included in the control arm will receive methylprednisolone plus SOC for COVID-19. Corticosteroids will be given to all patients at a 1mg/kg/d of methylprednisolone for at least 3 days. Clinical follow-up visits will be performed at 3, 5, and 15 days after treatment randomization. Patients in the control group (SOC group without sarilumab) progressing to Brescia- COVID 2-3 plus inflammatory markers, will be given the option to be rescued with sarilumab at the same doses and, in that case, be included in an open-label phase and be followed up for additional weeks (with visits at 3, 7 and 15 days after sarilumab rescue administration). Patients randomly assigned to sarilumab therapy at baseline progressing to Brescia-COVID 2-3 will be rescued according to local clinical practice protocols. A final follow-up visit will be conducted for all patients at day 29 from randomization, regardless of initial treatment assignment. MAIN

OUTCOMES:

Primary end point is the proportion of patients progressing to either severe respiratory failure (Brescia-COVID ≥2), ICU admission, or death. RANDOMIZATION Randomization codes were produced by means of the PROC PLAN of the SAS system, with a 11 assignment ratio, stratifying by centre and using blocks multiple of 2 elements. The randomization schedule will be managed through the eCRF in a concealed manner. BLINDING (MASKING) All study drugs will be administered as open label. No blinding methods will be used in this trial. NUMBERS TO BE RANDOMISED (SIMPLE SIZE) The target sample size will be 200 COVID-19 patients, who will be allocated randomly to control arm (100) and treatment arm (100). TRIAL STATUS Protocol Code SARTRE Protocol Date May 05th 2020. Version 2.0 The study has been approved by the Spanish Competent Authority (AEMPS) as a low intervention clinical trial. Start of recruitment August, 2020 End of recruitment May, 2021 TRIAL REGISTRATION Identifier EudraCT Number 2020-002037-15 ; Registration date 26 May 2020. FULL PROTOCOL The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Pneumonia, Viral / Coronavirus Infections / Pandemics / Antibodies, Monoclonal, Humanized / Betacoronavirus / Cytokine Release Syndrome Type of study: Controlled clinical trial / Diagnostic study / Etiology study / Clinical Practice Guide / Observational study / Prognostic study / Randomized controlled trials / Risk factors Limits: Adult / Female / Humans / Male Language: English Journal: Trials Journal subject: Medicine / Therapeutics Year: 2020 Document Type: Article Affiliation country: S13063-020-04633-3

Full text: Available Collection: International databases Database: MEDLINE Main subject: Pneumonia, Viral / Coronavirus Infections / Pandemics / Antibodies, Monoclonal, Humanized / Betacoronavirus / Cytokine Release Syndrome Type of study: Controlled clinical trial / Diagnostic study / Etiology study / Clinical Practice Guide / Observational study / Prognostic study / Randomized controlled trials / Risk factors Limits: Adult / Female / Humans / Male Language: English Journal: Trials Journal subject: Medicine / Therapeutics Year: 2020 Document Type: Article Affiliation country: S13063-020-04633-3