Publication: Estudio de la seguridad de la infusión intravenosa en perfusión continua de defibrotide en la prevención y tratamiento del distrés respiratorio y síndrome de liberación de citoquinas en pacientes con COVID-19
Authors
Martínez Mellado, Antonio José
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Escuela Internacional de Doctorado
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Moraleda Jiménez, José María ; Jara Rubio, Rubén
Publisher
Universidad de Murcia
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DOI
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info:eu-repo/semantics/doctoralThesis
Description
Abstract
El objetivo principal fue evaluar la seguridad del defibrotide en perfusión intravenosa continua en pacientes con COVID-19 grave (grados 4, 5 o 6 según la OMS), mediante la comparación de la mortalidad a 30 y 60 días frente a un grupo control, así como su posible influencia en la evolución clínica.
Los objetivos secundarios incluyeron:
Analizar la incidencia de acontecimientos adversos graves y no graves asociados a la infusión de defibrotide.
Evaluar el impacto del tratamiento sobre biomarcadores de gravedad (IL-6, linfocitos, dímero D, PCR, LDH, CPK y ferritina).
Comparar la mejoría radiológica de la neumonía mediante radiografías de tórax entre los pacientes tratados y el grupo control.
Finalmente, como objetivo exploratorio, se valoró el papel de la enfermería y de los coordinadores de ensayos clínicos en la ejecución del estudio durante la pandemia, subrayando su contribución esencial en todas las fases de la investigación.
Metodología
Se diseñó un ensayo clínico fase IIB, multicéntrico, aleatorizado, doble ciego y controlado con placebo, para evaluar la seguridad de la administración de defibrotide en perfusión intravenosa continua durante 15 días en pacientes hospitalizados con COVID-19 en grados clínicos 4, 5 o 6 según la clasificación de la OMS.
Resultados o Conclusiones
El estudio incluyó 150 pacientes en seis hospitales españoles: 100 recibieron defibrotide y 50 placebo. Los criterios de inclusión fueron infección por SARS-CoV-2 confirmada, necesidad de oxigenoterapia e IL-6 >3 veces el valor normal. Se excluyeron pacientes con hemorragia activa, anticoagulación terapéutica o patologías graves concomitantes.
En el objetivo primario, no se encontraron diferencias significativas en la mortalidad a 30 y 60 días entre ambos grupos. Tampoco se observaron diferencias en la duración del ingreso hospitalario ni en la necesidad de soporte vital.
En cuanto a la seguridad, el tratamiento fue bien tolerado, sin toxicidades inesperadas. Las complicaciones hemorrágicas y la hipotensión, efectos adversos esperados, se mantuvieron dentro de límites aceptables, sin casos de anafilaxia. Ningún paciente abandonó por toxicidad.
En el análisis de biomarcadores, el dímero D mostró una reducción ≥50% significativamente mayor en el grupo tratado con defibrotide en los días +7 y +15. La ferritina descendió más en el grupo control en fases iniciales, mientras que la CPK presentó reducciones más relevantes en fases tardías en el grupo defibrotide.
La evolución radiológica reflejó mejoría progresiva en ambos grupos, sin ventajas atribuibles al defibrotide. A día +60, este grupo mostró incluso tendencia a puntuaciones radiológicas más altas.
Como objetivo exploratorio, se destacó la contribución de enfermería en la coordinación del ensayo, seguimiento clínico y recogida sistemática de datos y muestras, lo que permitió la creación de un biobanco en un contexto de gran presión asistencial.
Conclusión: La perfusión continua de defibrotide es segura en pacientes con COVID-19 grave. No se evidenció beneficio clínico en mortalidad ni evolución radiológica, aunque sí impacto en algunos biomarcadores. La ausencia de eficacia podría relacionarse con la pauta continua empleada, frente a la discontinua utilizada en estudios previos con resultados positivos. Su perfil de seguridad y acción multidiana justifican seguir investigando su potencial en COVID-19 y secuelas.
The primary objective was to evaluate the safety of continuous intravenous infusion of defibrotide in patients with severe COVID-19 (WHO grades 4, 5, or 6), by comparing mortality at days 30 and 60 against a control group, as well as its potential influence on clinical outcomes. Secondary objectives included: Analyzing the incidence of serious and non-serious adverse events associated with defibrotide infusion. Assessing the impact of treatment on severity biomarkers (IL-6, lymphocytes, D-dimer, CRP, LDH, CPK, and ferritin). Comparing radiological improvement of pneumonia on chest X-rays between patients treated with defibrotide and the control group. Finally, as an exploratory objective, the role of nursing and clinical trial coordinators in the execution of the study during the pandemic was assessed, highlighting their essential contribution across all phases of research. Methodology A multicenter, randomized, double-blind, placebo-controlled phase IIB clinical trial was designed to evaluate the safety of continuous intravenous infusion of defibrotide for 15 days in hospitalized patients with COVID-19 classified as WHO grades 4, 5, or 6. Results or Conclusions The study included 150 patients across six Spanish hospitals: 100 received defibrotide and 50 received placebo. Inclusion criteria were confirmed SARS-CoV-2 infection, oxygen therapy requirement, and IL-6 >3 times the upper normal limit. Patients with active bleeding, therapeutic anticoagulation, or severe concomitant conditions were excluded. For the primary endpoint, no significant differences in mortality at days 30 and 60 were observed between groups. No differences were found in hospital length of stay or need for life support. Regarding safety, treatment was well tolerated with no unexpected toxicities. Hemorrhagic complications and hypotension, expected adverse events, remained within acceptable limits, and no cases of anaphylaxis occurred. No patient discontinued due to toxicity. In biomarker analysis, D-dimer showed a significantly greater ≥50% reduction in the defibrotide group at days 7 and 15. Ferritin decreased more in the control group during early phases, while CPK showed more relevant late reductions in the defibrotide group. Radiological progression reflected gradual improvement in both groups, with no attributable benefit of defibrotide. By day 60, the defibrotide group even showed a trend toward higher radiological scores. As an exploratory outcome, the essential contribution of nursing was highlighted in coordinating the trial, clinical monitoring, and systematic collection of data and biological samples, which enabled the creation of a biobank under high clinical workload conditions. Conclusion: Continuous intravenous infusion of defibrotide is safe in patients with severe COVID-19. No clinical benefit was demonstrated in mortality or radiological progression, although effects were observed in certain biomarkers. The absence of efficacy may be related to the continuous infusion regimen, compared with the intermittent dosing used in previous positive studies. Its favorable safety profile and multi-targeted action justify further research into its potential role in COVID-19 and its sequelae.
The primary objective was to evaluate the safety of continuous intravenous infusion of defibrotide in patients with severe COVID-19 (WHO grades 4, 5, or 6), by comparing mortality at days 30 and 60 against a control group, as well as its potential influence on clinical outcomes. Secondary objectives included: Analyzing the incidence of serious and non-serious adverse events associated with defibrotide infusion. Assessing the impact of treatment on severity biomarkers (IL-6, lymphocytes, D-dimer, CRP, LDH, CPK, and ferritin). Comparing radiological improvement of pneumonia on chest X-rays between patients treated with defibrotide and the control group. Finally, as an exploratory objective, the role of nursing and clinical trial coordinators in the execution of the study during the pandemic was assessed, highlighting their essential contribution across all phases of research. Methodology A multicenter, randomized, double-blind, placebo-controlled phase IIB clinical trial was designed to evaluate the safety of continuous intravenous infusion of defibrotide for 15 days in hospitalized patients with COVID-19 classified as WHO grades 4, 5, or 6. Results or Conclusions The study included 150 patients across six Spanish hospitals: 100 received defibrotide and 50 received placebo. Inclusion criteria were confirmed SARS-CoV-2 infection, oxygen therapy requirement, and IL-6 >3 times the upper normal limit. Patients with active bleeding, therapeutic anticoagulation, or severe concomitant conditions were excluded. For the primary endpoint, no significant differences in mortality at days 30 and 60 were observed between groups. No differences were found in hospital length of stay or need for life support. Regarding safety, treatment was well tolerated with no unexpected toxicities. Hemorrhagic complications and hypotension, expected adverse events, remained within acceptable limits, and no cases of anaphylaxis occurred. No patient discontinued due to toxicity. In biomarker analysis, D-dimer showed a significantly greater ≥50% reduction in the defibrotide group at days 7 and 15. Ferritin decreased more in the control group during early phases, while CPK showed more relevant late reductions in the defibrotide group. Radiological progression reflected gradual improvement in both groups, with no attributable benefit of defibrotide. By day 60, the defibrotide group even showed a trend toward higher radiological scores. As an exploratory outcome, the essential contribution of nursing was highlighted in coordinating the trial, clinical monitoring, and systematic collection of data and biological samples, which enabled the creation of a biobank under high clinical workload conditions. Conclusion: Continuous intravenous infusion of defibrotide is safe in patients with severe COVID-19. No clinical benefit was demonstrated in mortality or radiological progression, although effects were observed in certain biomarkers. The absence of efficacy may be related to the continuous infusion regimen, compared with the intermittent dosing used in previous positive studies. Its favorable safety profile and multi-targeted action justify further research into its potential role in COVID-19 and its sequelae.
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