| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hyperinflammation and respiratory distress in patients with SARS- CoV-2 |
| Hiperinflamación y la dificultad respiratoria en pacientes con infección por SARS-CoV-2. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hyperinflammation and respiratory distress in patients with SARS- CoV-2 |
| Hiperinflamación y la dificultad respiratoria en pacientes con infección por SARS-CoV-2. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| 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 effect of anakinra in addition to standard treatment on the need for mechanical ventilation in patients with severe COVID-19 and CSS pneumonia. |
| Evaluar el efecto de la anakinra además del tratamiento estándar sobre la necesidad de ventilación mecánica en pacientes con neumonía grave por COVID-19 y CSS |
|
| E.2.2 | Secondary objectives of the trial |
| To assess the effect of anakinra in addition to standard treatment on mortality in patients with severe COVID-19 and CSS pneumonia. |
| Evaluar el efecto de anakinra además del tratamiento estándar sobre la mortalidad en pacientes con neumonía grave por COVID-19 y CSS. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Age 18-80 years.
Severe pneumonia COVID-19 defined as:
o Nasopharyngeal smear with RCP positive for SARS-CoV-2
o X-Rays (or other technique) pulmonary infiltrates compatible with pneumonia.
o 1 or more of the following criteria:
Ambient air oxygen saturation <= 94% measured with a pulse oximeter.
Pa:FiO2 (partial pressure O2/fraction of inspired O2) <=300.
Sa:FiO2 (O2 saturation measured with pulse oximeter/ fraction of inspired O2) <=350.
High suspicion of CSS that could resemble MAS-like: represented by IL-6 values > 40 pg/mL and/or ferritin >500 ug/L and/or PCR > 30 mg/L (rationale: ≥ 5 upper normal limit) and/or LDH >300 UI/L. We have chosen these parameters because they are implemented in all the participating hospitals, they are a reflection of the cytokine storm and they have also been significant in terms of predicting mortality in patients with COVID-19 (9).
Written informed consent. The protocol will be explained to the patient in front of a nurse who will act as a legal witness by signing the document on behalf of the patient. |
Edad 18-80 años.
Neumonía grave COVID-19 definida como:
o frotis nasofaríngeo con PCR positivo para SARS-CoV-2
o Rayos X (u otra técnica) infiltrados pulmonares compatibles con neumonía.
o 1 o más de los siguientes criterios:
Saturación de oxígeno en el aire ambiente <= 94% medido con un oxímetro de pulso.
Pa: FiO2 (presión parcial O2 / fracción de O2 inspirado) <= 300.
Sa: FiO2 (saturación de O2 medida con oxímetro de pulso / fracción de O2 inspirado) <= 350.
Alta sospecha de CSS que podría parecerse a MAS: representado por valores de IL-6> 40 pg / ml y / o ferritina> 500 ug / L y / o PCR> 30 mg / L (justificación: ≥ 5 límite superior normal) y/o LDH >300 UI/L. Hemos elegido estos parámetros porque se implementan en todos los hospitales participantes, son un reflejo de la tormenta de citoquinas y también han sido significativos en términos de predicción de mortalidad en pacientes con COVID-19 (9).
Consentimiento informado por escrito. El protocolo se explicará al paciente frente a una enfermera que actuará como testigo legal al firmar el documento en nombre del paciente. |
|
| E.4 | Principal exclusion criteria |
Need for oro-tracheal intubation and/or invasive mechanical ventilation at the start of the study.
AST/ALT with values greater than 5 times normal levels.
Neutrophils < 1500 cell/mmc.
Platelets < 50.000 cell/mmc.
Sepsis or pneumonia documented by other pathogens than SARS-CoV-2.
Existence of any life-threatening comorbidity or any other medical condition that, in the investigator's opinion, makes the patient unsuitable for inclusion.
Inability to obtain informed consent.
Positivity for HBV, HCV or tuberculin test serology.
Pregnancy.
Use of other previous or concomitant biological treatments. Patients in concomitant treatment with other biologicals that may interfere will be excluded: tocilizumab, canakinumab, TNFalfa inhibitors, JAKiinibs
Severe renal dysfunction (estimated glomerular filtration rate ≤ 30 ml / min / 1.73 m2) or receive continuous renal replacement therapy, hemodialysis or peritoneal dialysis.
Uncontrolled hypertension (sitting systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg).
Administration of plasma from convalescent patients who have recovered from SARS-CoV-2 infection.
History of hypersensitivity or allergy to any component of the study drug.
Enrollment in another concurrent intervention clinical trial, or intake of an investigational medication within three months or 5 half-lives prior to inclusion in this study, if deemed to interfere with the objectives of this study as assessed by the investigator.
Predictable inability to cooperate with given instructions or study procedures. |
Necesidad de intubación oro-traqueal y / o ventilación mecánica invasiva al inicio del estudio.
AST / ALT con valores superiores a 5 veces los niveles normales.
Neutrófilos < 1500 células / mmc.
Plaquetas <50,000 células / mmc.
Sepsis o neumonía documentada por otros patógenos distintos del SARS-CoV-2.
Existencia de cualquier comorbilidad que ponga en peligro la vida o cualquier otra afección médica que, en opinión del investigador, haga que el paciente no sea apto para su inclusión.
Incapacidad para obtener el consentimiento informado.
Positividad para serología de prueba de VHB, VHC o tuberculina.
Embarazo.
Uso de otros tratamientos biológicos previos o concomitantes. Los pacientes en tratamiento concomitante con otros productos biológicos que puedan interferir serán excluidos: tocilizumab, canakinumab, inhibidores de TNFalfa, JAKiinibs
Disfunción renal severa (tasa de filtración glomerular estimada ≤ 30 ml / min / 1.73 m2) o recibir terapia de reemplazo renal continuo, hemodiálisis o diálisis peritoneal.
Hipertensión no controlada (presión arterial sistólica sentada> 180 mmHg o presión arterial diastólica> 110 mmHg).
Administración de plasma de pacientes convalecientes que se han recuperado de la infección por SARS-CoV-2.
Antecedentes de hipersensibilidad o alergia a cualquier componente del fármaco del estudio.
La inscripción en otro ensayo clínico de intervención concurrente, o la ingesta de un medicamento en investigación dentro de los tres meses o 5 vidas medias antes de la inclusión en este estudio, si se considera que interfiere con los objetivos de este estudio según lo evaluado por el investigador.
Incapacidad predecible para cooperar con las instrucciones dadas o los procedimientos de estudio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Treatment success, defined as number of patients not requiring mechanical ventilation by Day 15.
Number of patients not requiring mechanical ventilation (day 28). Time to mechanical ventilation (days)
Time to oxygen saturation normalization
Stay in ICU and hospitalization (days) |
Éxito del tratamiento, definido como el número de pacientes que no requieren ventilación mecánica para el día 15.
Número de pacientes que no requieren ventilación mecánica (día 28).
Tiempo de ventilación mecánica (días)
Tiempo para la normalización de la saturación de oxígeno.
Estancia en UCI y hospitalización (días) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Total mortality rate (day 28)
Mortality 48 hours, 7 days, in ICU and hospital
Viral clearance / viral shedding
Frequency and severity of AEs:
o Treatment-emergent severe fatal and life-threatening serious adverse events (SAEs).
o Adverse events leading to premature discontinuation of study treatment.
o Anaphylactic/anaphylactoid reactions.
o Anakinra treatment group: Severe neutropenia.
o Treatment-emergent laboratory abnormalities. |
Tasa de mortalidad total (día 28)
Mortalidad 48 horas, 7 días, en UCI y hospital.
Eliminación viral / diseminación viral
Frecuencia y gravedad de los AA:
o Eventos adversos graves (SAE) fatales graves y potencialmente mortales emergentes del tratamiento.
o Eventos adversos que conducen a la interrupción prematura del tratamiento del estudio.
o Reacciones anafilácticas / anafilactoides.
o Grupo de tratamiento con Anakinra: neutropenia severa.
o Anomalías de laboratorio emergentes del tratamiento. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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) | Yes |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| SIN ANAKINRA |
| WITHOUT ANAKINRA |
|
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| 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 | Yes |
| 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
|
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | |
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