E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 evaluate in-hospital mortality or mechanical ventilation in the Intensive Care Unit (ICU), or need for a rescue dose of tocilizumab in patients with confirmed infection by COVID-19 in treatment with hydroxychloroquine and azithromycin combined or non-tocilizumab. |
Evaluar la mortalidad intrahospitalaria o ventilación mecánica en la Unidad de Cuidados Intensivos (UCI), o necesidad de dosis de rescate de tocilizumab en los pacientes con infección confirmada por COVID-19 en tratamiento con hidroxicloroquina y azitromicina combinado o no tocilizumab. |
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E.2.2 | Secondary objectives of the trial |
To assess the clinical efficacy of tocilizumab in COVID-19 infection compared to the control arm by:
Clinical severity: Patient score according to the WHO 7-point ordinal scale National Early Warning Score (NEWS) Oxygen therapy Mechanic ventilation Hospitalization Mortality at 15, 30 and 90 days
To assess the safety of the intervention 30 days after treatment compared to the control arm.
To assess the safety of the intervention at 90 days of treatment compared to the control arm. - Cumulative incidence of serious adverse effects (SAEs). - Cumulative incidence of grade 3 and 4 adverse effects (AEs). - Discontinuation or suspension of treatment for any reason. - Changes in the white blood cell count, hemoglobin, platelets, creatinine, glucose, total bilirubin, AST, ALT, GGT, LDH, C-reactive protein, D-dimer, troponin, ferritin, fibrinogen, KL-6 during follow-up. |
Evaluar la eficacia clínica del tocilizumab en la infección por COVID-19 comparado con la rama control mediante:
Severidad clínica: Puntuación del paciente según la escala ordinal de 7 puntos de la OMS National Early Warning Score (NEWS) Oxigenoterapia Ventilación mecánica Hospitalización Mortalidad a los 15, 30 y 90 días
Evaluar la seguridad de la intervención a los 30 días del tratamiento comparado con la rama control.
Evaluar la seguridad de la intervención a los 90 días de tratamiento comparado con la rama control. - Incidencia acumulativa de efectos adversos graves (SAEs). - Incidencia acumulativa de efectos adversos grado 3 y 4 (AEs). - Discontinuación o suspensión del tratamiento por cualquier razón. - Cambios en el recuento leucocitario, hemoglobina, plaquetas, creatinina, glucosa, bilirrubina total, AST, ALT, GGT, LDH, proteína C reactiva, dímero D, troponina, ferritina, fibrinógeno, KL-6 durante el seguimiento. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject (or authorized legal representative) who can provide written informed consent before beginning any study procedure. 2. Understand and agree to abide by the study procedures. 3. Adult ≥18 years of age at the time of inclusion in the study. 4. Confirmation of SARS-CoV-2 infection by a microbiological test performed before randomization, no longer than 72 hours. 5. Gravity 3-4 according to the WHO 7-point ordinal scale: - Severity 3. Hospitalized, which does not require supplemental oxygen - Severity 4. Hospitalized, requiring supplemental oxygen |
1. Sujeto (o representante legal autorizado) que pueda proporcionar un consentimiento informado por escrito antes de iniciar cualquier procedimiento del estudio. 2. Entienda y acepte cumplir los procedimientos del estudio. 3. Adulto ≥18 años de edad en el momento de inclusión en el estudio. 4. Confirmación de la infección por SARS-CoV-2 mediante una prueba microbiológica realizada antes de la aleatorización, no mayor a 72 horas. 5. Gravedad 3-4 según la escala ordinal de 7 puntos de la OMS: - Gravedad 3. Hospitalizado, que no requiere oxígeno suplementario - Gravedad 4. Hospitalizado, que requiere oxígeno suplementario |
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E.4 | Principal exclusion criteria |
1. ALT / AST> 5 times the normal limit 2. Stage 4 chronic kidney disease (GFR <30) or requiring dialysis. 3. Presence of comorbidities that imply a poor prognosis (according to clinical judgment). 4. Advanced dementia. 5. Pregnancy or breastfeeding. 6. Forecast of transfer to another center in the 12 hours at the beginning of the study. 7. Allergy to study medication. 8. Serious or active bacterial infections or documented sepsis by pathogens other than SARS-CoV-2. 9. Streptococcus pneumoniae antigenuria positive before study start. 10. Neutropenia <500 / mm3. 11. Plateletpenia <100,000 / mm3. 12. History of diverticulosis. 13. Ongoing skin infection (eg, pyodermitis). 14. Transplanted patient under immunosuppressive treatment. 15. Previous evidence of latent untreated tuberculosis. |
1. ALT/AST >5 veces el límite normal 2. Enfermedad renal crónica estadio 4 (FG<30) o que requiera diálisis. 3. Presencia de comorbilidades que impliquen mal pronóstico (según juicio clínico). 4. Demencia avanzada. 5. Embarazo o lactancia materna. 6. Previsión de traslado a otro centro en las 12 horas al inicio del estudio. 7. Alergia a la medicación de estudio. 8. Infecciones bacterianas activas o graves o sepsis documentada por otros patógenos diferentes de SARS-CoV-2. 9. Antigenuria de Streptococcus pneumoniae positivo antes de inicio del estudio. 10. Neutropenia <500/mm3. 11. Plaquetopenia <100.000/mm3. 12. Historia de diverticulosis. 13. Infección cutánea en curso (por ejemplo, piodermitis). 14. Paciente trasplantado en tratamiento inmunosupresor. 15. Evidencia previa de tuberculosis latente no tratada. |
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E.5 End points |
E.5.1 | Primary end point(s) |
In-hospital mortality or need for mechanical ventilation in the Intensive Care Unit. |
Mortalidad intrahospitalaria o necesidad de ventilación mecánica en la Unidad de Cuidados Intensivos. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
During hospitalization |
Durante la hospitalización |
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E.5.2 | Secondary end point(s) |
- Status of the ordinal scale evaluated on days 3, 5, 12, 15 and 30. - Evaluate the NEWS scale on days 3, 5, 12, 15 and 30. - Duration of oxygen therapy. - Duration of mechanical ventilation (if applicable). - Duration of hospitalization. - Date and cause of death (if applicable). - Grade 3 and 4 adverse effects. - SAEs. - Leukocyte count, hemoglobin, platelets, creatinine, glucose, total bilirubin, AST, ALT, GGT, LDH, C-reactive protein, D-dimer, troponin, KL-6, ferritin, fibrinogen on days 1, 3, 5, 12 ( while hospitalization lasts) and 30 (if possible or if you are still admitted). |
- Estado de la escala ordinal evaluado en los días 3, 5, 12, 15 y 30. - Evaluar la escala NEWS en los días 3, 5, 12, 15 y 30. - Duración de la oxigenoterapia. - Duración de la ventilación mecánica (si aplica). - Duración de la hospitalización. - Fecha y causa de la muerte (si aplica). - Efectos adversos grado 3 y 4. - SAEs. - Recuento leucocitario, hemoglobina, plaquetas, creatinina, glucosa, bilirrubina total, AST, ALT, GGT, LDH, proteína C reactiva, dímero D, troponina, KL-6, ferritina, fibrinógeno en los días 1, 3, 5, 12 (mientras dure la hospitalización) y 30 (si es posible realizarla o está todavía ingresado). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
3, 5, 12, 15 and 30 days |
3, 5, 12, 15 y 30 días |
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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 | Yes |
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) | No |
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 | Yes |
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
| 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 | 3 |
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
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LVLS |
Última visita del último sujeto |
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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 | 6 |
E.8.9.1 | In the Member State concerned days | |