| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with confirmed COVID-19 infection and criteria for mild-moderate pneumonia (CURB-65 ≤1 i SatO2 ≥90%, MEWS score less than 3) and IL6 values of 20 pg / ml, will be randomly assigned to a sarilumab treatment group or another group receiving treatment according to the current therapeutic protocol of the PSMAR. |
| Los pacientes con infección confirmada COVID-19 y con criterios de neumonía leve-moderada (CURB-65 ≤1 i SatO2 ≥90%, MEWS score menor de 3) y valores de IL6 de 20 pg/ml, se les asignará aleatoriamente a un grupo de tratamiento con sarilumab o a otro grupo que reciba tratamiento según el protocolo terapéutico vigente del PSMAR. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with mild or moderate neumonia with COVID19 infection |
| Pacientes con neumonia leve o moderada e infección COVID19 |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10035737 |
| E.1.2 | Term | Pneumonia viral |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the efficacy and safety of early treatment of sarilumab, added to standard treatment, in patients hospitalized for mild-moderate COVID-19 pneumonia, with criteria of a CURB 65 less than or equal to 1, oxygen saturation equal to or greater than 90%, MEWS less than 3 and with IL6 greater than 20 pg / mL. |
| Evaluar la eficacia y seguridad de salirumab añadido al tratamiento estándar de manera precoz en pacientes ingresados por neumonía leve-moderada por COVID-19, con criterios de un CURB 65 menor o igual a 1, saturación de oxígeno igual o superior a 90%, MEWS menos de 3 y con IL6 mayor de 20 pg/mL. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate:
-Clinical status of patients on days 7 and 14 later than the treatment initiation.
-Proportion of patients discharged on day 14
-28-day mortality rate
-Proportion of patients who required mechanical ventilation and days of duration
-Days of hospital stay of patients who have survived to 28 days
-Time since start of treatment to death of the patient
-Possible serious adverse events related to sarilumab and possible causes of discontinuation of sarilumab treatment
to analyze:
-type of medications received during admission and days since onset of symptoms to starting glucocorticoids
-the evolution of prognostic factors: IL6, D-dimer, ferritin, calprotectin |
Determinar:
-Estado clínico de los pacientes a día 7 y 14 de iniciar el tratamiento.
-Proporción de pacientes dados de alta a día 14
-Tasa de mortalidad a los 28 días
-Proporción de pacientes que precisaron ventilación mecánica y días de duración
-Días de estancia hospitalaria de los pacientes que han sobrevivido a los 28 días
-Tiempo transcurrido desde inicio de tratamiento hasta muerte del paciente
-Evaluar posibles eventos adversos graves relacionados con sarilumab y posibles causas de interrupción de tratamiento con sarilumab
-Analizar medicaciones recibidas durante ingreso y días transcurridos desde inicio de síntomas a inicio de glucocorticoides
-Analizar la evolución de los factores pronósticos: IL6, Dímero D, ferritina, calprotectina |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- more than18 years
- diagnostic confirmation of COVID19 infection (PCR) and radiological diagnosis of pneumonia
- MEWS less than 3 and CURB 65 less than or equal to 1, IL6 greater than or equal to 20 pg / mL. |
– mayores de 18 años
- confirmación diagnóstica de infección por COVID19 (PCR) y diagnóstico radiológico de neumonía
- MEWS menor de 3 y CURB 65 menor o igual que 1, IL6 mayor o igual de 20 pg/mL. |
|
| E.4 | Principal exclusion criteria |
- AST / ALT> 5 X LSN
- neutrophils <500 cell / mm3
- lymphocytes <400 cell
- Platelets <50,000 cell / mm3
- creatinine clearance (CCL) <30 mL / min
- Documented sepsis and active infection by other pathogens other than COVID-19
- presence of comorbidities that may lead to a poor prognosis according to clinical criteria
- Complicated diverticulitis or intestinal perforation
- Ongoing skin infection (eg uncontrolled pyodermitis with antibiotic treatment)
- anti rejection immunosuppressive therapy
- Other biological treatments
- At the investigator's discretion, survival less than 48 hours from screening
- Treatment with anti-IL 6, anti-IL-6R antagonists or with Janus kinase inhibitors (JAKi) in the last 30 days or plans to receive during the study period
- Current treatment with conventional synthetic disease modifying antirheumatic drugs (DMARDs) / immunosuppressive agents
- History of current systemic or localized autoimmune or inflammatory diseases, other than rheumatoid arthritis
- Known active tuberculosis (TB), history of incompletely treated TB, suspected or known extrapulmonary TB, suspected or known systemic bacterial or fungal infections
- Patients who have received immunosuppressive antibody therapy in the last 5 months, including intravenous immunoglobulin, or who plan to receive it during the study period.
- Participation in any clinical research study evaluating a research product or therapy (PI) within 3 months and less than 5 PI half-lives before the screening visit (The use of remdisivir in the context of a compassionate use remdisivir one-arm is allowed)
- Pregnancy
- hypersensitivity to Sarilumab and / or to some of its excipients.
- Any finding of the physical examination and / or history of any disease that, in the opinion of the study investigator, may confuse the study results or represent an additional risk for the patient due to their participation in the study. |
- AST/ALT > 5 X LSN
- neutrófilos < 500 cell/mm3
- linfocitos < 400 cell
- Plaquetas < 50.000 cell/ mm3
- aclaramiento de creatinina(CCL) < 30 mL/min
- Sepsis documentada I infecció activa por otros patógenos que no sean COVID-19
- presencia de comobidilidad que pueda comportar mal pronóstico según criterio clínico
- Diverticulitis complicada o perforación intestinal
- Infección cutánea en curso (p.e piodermitis no controlada con tratamiento antibiótico)
- terapia inmunosupresor anti rechazo
- Otros tratamientos biológicos
- A criterio del investigador, supervivencia menor de 48 horas desde el screening
- Tratamiento con anti-IL 6, antagonistas anti-IL-6R o con inhibidores de Janus quinasa (JAKi) en los últimos 30 días o planes para recibir durante el período de estudio
- Tratamiento actual con fármacos antirreumáticos modificadores de la enfermedad sintéticos convencionales (FARME) / agentes inmunosupresores
- Antecedentes de enfermedades sistémicas o localizadas autoinmunitarias o inflamatorias actuales, distintas de la artritis reumatoide
- Tuberculosis activa (TB) conocida, antecedentes de TB incompletamente tratada, TB extrapulmonar sospechada o conocida, infecciones bacterianas o fúngicas sistémicas sospechadas o conocidas
- Pacientes que han recibido terapia de anticuerpos inmunosupresores en los últimos 5 meses, incluida la inmunoglobulina intravenosa o que planean recibirla durante el período de estudio.
- Participación en cualquier estudio de investigación clínica que evalúe un producto o terapia de investigación (IP) dentro de los 3 meses y menos de 5 vidas medias de IP antes de la visita de selección (El uso de remdisivir en el contexto de un protocolo de uso compasivo remdisivir de un solo brazo es permitido)
- Embarazo
- hipersensibilidad a Sarilumab y/o a algunos de sus excipientes.
- Cualquier hallazgo del examen físico y / o antecedentes de cualquier enfermedad que, en opinión del investigador del estudio, pueda confundir los resultados del estudio o representar un riesgo adicional para el paciente por su participación en el estudio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Time to clinical improvement, defined as the time from randomization to a two-point improvement (from randomization status) on an ordinal scale of seven categories or hospital discharge, whichever occurs first.
The seven-category ordinal scale consisted of the following categories: 1, not hospitalized with resumption of normal activities; 2, not hospitalized, but unable to resume normal activities; 3, hospitalized, not requiring supplemental oxygen; 4, hospitalized, requiring supplemental oxygen; 5, hospitalized, requiring nasal high-flow oxygen therapy, noninvasive mechanical ventilation, or both; 6, hospitalized, requiring ECMO, invasive mechanical ventilation, or both; and 7, death. |
Tiempo hasta la mejoría clínica, definido como el tiempo desde la aleatorización hasta una mejora de dos puntos (desde el estado de la aleatorización) en una escala ordinal de siete categorías o alta hospitalaria, lo que ocurriera primero.
La escala presenta las siguientes categorías:
1, no hospitalizado con la reanudación de las actividades normales;
2, no hospitalizado, pero incapaz de reanudar las actividades normales;
3, hospitalizado, que no requiere oxígeno suplementario;
4, hospitalizado, que requiere oxígeno suplementario;
5, hospitalizado, que requiere oxigenoterapia nasal de alto flujo, ventilación mecánica no invasiva, o ambas;
6, hospitalizado, que requiere ECMO, ventilación mecánica invasiva, o ambos; y
7, muerte |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Clinical status evaluated with the ordinal scale of seven categories on days 7 and 14
- 28-day mortality
- Mechanical ventilation (yes / no)
- Duration of mechanical ventilation
- Duration of hospitalization of those who survive (discharge date will be recorded, which is recorded in the report in the patient's medical history)
- time (in days) from the start of treatment until death.
- medication during the study period: vasopressors, renal replacement therapy, non-invasive mechanical ventilation, invasive mechanical ventilation, ECMO, antibiotics, glucocorticoids, others.
- Days from the beginning of the disease to the start of corticosteroid use
- Days of corticosteroid treatment.
- Interleukin 6 basal, at 12 hours, 24 hours, 48 hours, at 72 and at 7 days
- Baseline D-dimer, at 12 hours, 24 hours, 48 hours, at 72 and 7 days
Security variables:
- Adverse events that occurred during treatment,
- Grade 3 and grade 4 serious adverse events
- Serious and unexpected adverse reactions.
- Causes of premature interruption of treatment. |
- Estado clínico evaluado con la escala ordinal de siete categorías en los días 7 y 14
- Mortalidad a los 28 días
- Ventilación mecánica (sí/no)
- Duración de ventilación mecánica
- Duración de la hospitalización de los que sobreviven (se registrará fecha de alta que queda registrada en el informe que consta en la historia clínica del paciente)
- tiempo (en días) desde el inicio del tratamiento hasta muerte.
- medicación durante el período de estudio: vasopresores, terapia de reemplazamiento renal, ventilación mecánica no invasiva, ventilación mecánica invasiva, ECMO, antibióticos, glucocorticoides, otros.
- Días desde el inicio de la enfermedad hasta el inicio de uso de corticoides
- Días de tratamiento de corticoides.
- Interleucina 6 basal, a las 12 horas, 24 horas, 48 horas, a las 72 y a los 7 días
- Dímero D basal, a las 12 horas, 24 horas, 48 horas, a las 72 y a los 7 días
-
Variables de seguridad:
- Eventos adversos que ocurrieron durante el tratamiento,
- Eventos adversos graves grado 3 y grado 4
- Reacciones adversas graves e inesperadas.
- Causas de interrupción prematura del tratamiento. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
clinical status at, 7, 14 and 28 days
laboratory variables: at 12 hours, 24 hours, 48 hours, at 72 and 7 days |
variables relacionadas con el estado clínico a los 7, 14 y 28 días
variables de test de laboratorio: a las 12, 24, 48, 72 horas y 7 días. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| the last visit of the last subject undergoing the trial |
| la última visita del último paciente en activo en el ensayo |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
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