Resumen

Este estudio incluirá adultos de 18 a 80 años diagnosticados con sepsis debida a una infección bacteriana sospechada o confirmada, dentro de los 7 días posteriores a la admisión hospitalaria, y que también hayan desarrollado lesión renal aguda dentro de las 72 horas del inicio de la sepsis. Los participantes elegibles serán asignados aleatoriamente para recibir AZD4144 o placebo por vía intravenosa una vez al día durante el número de días especificado en el protocolo del estudio clínico. Durante este período de tratamiento, los participantes serán sometidos a monitorización diaria de seguridad, así como a la recolección de muestras de sangre y orina y otras evaluaciones. Después del período de tratamiento, los participantes continuarán siendo monitorizados en cuanto a seguridad y otras evaluaciones durante cada día adicional que permanezcan hospitalizados (si corresponde), así como durante hasta 2 visitas de seguimiento después del alta. El objetivo principal es comparar mediciones específicas de la función renal entre los participantes que reciben AZD4144 y los que reciben placebo.

Descripción detallada

Este es un estudio de fase IIa, aleatorizado, doble ciego, controlado con placebo, multicéntrico, que se realizará en participantes adultos (de 18 a 80 años) con lesión renal aguda asociada a sepsis (LRA-AS). Los participantes elegibles deben tener sepsis secundaria a una infección bacteriana sospechada o confirmada que requiera terapia con vasopresores o inotrópicos, y LRA (estadio KDIGO ≥ 1) dentro de un marco temporal definido desde el inicio de la sepsis. Los participantes serán aleatorizados en una proporción 1:1 para recibir AZD4144 intravenoso o placebo equivalente una vez al día durante un período de tratamiento fijo. El estudio constará de: * Un período de tamizaje. * Un período de tratamiento, durante el cual los participantes recibirán AZD4144 o placebo intravenoso diariamente según los días de dosificación del protocolo. * Un período de seguimiento que incluirá evaluaciones diarias mientras aún estén hospitalizados y hasta dos visitas ambulatorias adicionales en horarios programados después del alta.

Elegibilidad

Edad mínima: 18 YearsEdad máxima: 80 YearsSexo: ALL

Criterios de inclusión

Age ≥ 18 to ≤ 80 years at the time of signing the informed consent.
Participants who are admitted to an ICU.
Diagnosis of sepsis according to criteria defined by The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) based on:
Suspected or confirmed bacterial infection AND
Acute increase of mSOFA score of 2 or more excluding renal component (change in score measured to account for participants that may meet mSOFA criteria from pre-existing organ dysfunction before the onset of infection).
Vasopressor and/or inotrope therapy for sepsis-induced hypotension
Diagnosis of AKI with modified KDIGO Stage ≥ 1 persisting after initial volume resuscitation (30 mL/kg or as clinically indicated per investigator discretion) defined as: Increase in serum creatinine to ≥ 1.5 × baseline (pre-AKI reference).
Outpatient pre-AKI reference eGFR ≥ 30 mL/min/1.73 m2 or admission pre-AKI reference eGFR ≥ 45 mL/min/1.73 m2.
Body weight ≥ 40 kg or ≤ 125 kg.
Female or male, assigned at birth, inclusive of all gender identities.
All FOCBP must have a negative pregnancy test at the Screening visit (Visit 1).
Contraception:
Sexually active fertile male participants with partners of childbearing potential must adhere to the contraception methods detailed in CSP from the time of first administration of study intervention administration until 100 days after the last dose of study intervention.
FOCBP must not be lactating and must agree to use an approved method of highly effective contraception, as detailed in the CSP from the time of first administration of study intervention until 100 days after last dose of study intervention.
Capable of giving signed informed consent (participant or LAR)
Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional genomics initiative research

Criterios de exclusión

Any clinical evidence which in the investigator's opinion makes it undesirable for the potential participant to enrol in the study.
Known history of Stage 4 or 5 CKD with documented sustained eGFR \< 30 mL/min/1.73 m2 prior to hospital admission.
No serum creatinine results available within 12 months of admission and an eGFR \< 45 mL/min/1.73 m2 at admission.
Sepsis diagnosed \> 7 days after hospital admission (to include from time of outside admission if patient transferred from another healthcare setting).
AKI attributed to causes other than sepsis, including but not limited to compromised renal perfusion-related causes (surgical complication, acute abdominal aortic aneurysm, dissection, renal artery stenosis, etc), glomerular disease, acute interstitial nephritis, and medication toxicity.
Evidence of recovery from AKI prior to randomisation defined as:
A reduction of serum creatinine to less than 1.5 times reference serum creatinine in the last available local SoC laboratory result before randomisation or
A \> 25% reduction in serum creatinine from peak serum creatinine after volume resuscitation prior to randomisation.
Expected survival from sepsis \< 24 hours.
Expected survival \< 90 days due to chronic or pre-existing medical conditions other than SA-AKI
Known history of renal transplant or bilateral nephrectomy.
Permanent incapacitation.
Active cancer or cancer in remission for less than 2 years.
Known history of immunodeficiency disease or currently receiving immunosuppressant therapy for non-sepsis related disease.
Severe burns requiring ICU treatment.
Sepsis attributed to confirmed or presumed fungal or viral infection at time of Screening.
Has advanced chronic liver disease, confirmed by a Child-Pugh score of 10-15 (Class C).
Known history of cerebrovascular accident within the last 90 days.
Known history of heart failure with reduced ejection fraction with documented ejection fraction ≤ 20% before sepsis diagnosis.
Known hypersensitivity to iohexol or known history of severe adverse reaction to iodinated contrast media.
Participants with known medical or psychological condition(s), or who, in the judgement of the investigator, should not participate in the study if they are unlikely to comply with study procedures, restrictions, and requirements.
Current KRT (eg, continuous haemofiltration and haemodialysis/continuous renal replacement therapy, intermittent haemodialysis, and peritoneal dialysis) or planned KRT at randomisation
Currently receiving active treatment for malignancy.
Potential participants will be excluded if they have received a certain class of medication during the weeks before enrollment or are anticipated to require a specific class of medication during the trial duration.
Participants with a known hypersensitivity to AZD4144 or any of the excipients of the product.
Receipt of another IMP within 30 days, 5 half-lives, or the time frame of expected PD effect from most recent dose, whichever is longest.
Previous receipt of AZD4144.
Active or planned treatment of sepsis with an extracorporeal haemoperfusion device.
Participation in any other concurrent ICU study which could impact participant clinical outcomes and confound results of this study to, including but not limited to volume resuscitation, vasopressor, or mechanical ventilation studies.
Presence of anuria (≥ 12 hours) at randomisation.
Any clinically important abnormalities in rhythm, conduction, or morphology of the resting 12-lead ECG, at Screening, as judged by the investigator.
Prolonged QTcF \> 470 ms.
Known history of QT prolongation associated with other medications that required discontinuation of that medication.
Congenital long QT syndrome.
Known history of ST-elevation myocardial infarction or non-ST-elevation myocardial infarction, with or without intervention by percutaneous coronary intervention or coronary artery bypass grafting within the last 90 days.
Ventricular arrhythmia requiring treatment.
Known or presumed latent or active tuberculosis.
Acute pancreatitis with no established source of infection.
Undergoing extracorporeal membrane oxygenation (ECMO) at randomisation.
Neutropenia: ANC \< 1.5 × 109/L.
Admitting diagnosis of rhabdomyolysis.
Admitting diagnosis of trauma with CK \> 15000 U/L.
Presumed nidus of infection in central nervous system.
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
Previous randomisation in the present study.
For females only - currently pregnant (confirmed with positive pregnancy test) or breast-feeding.
First dose of IMP unable to be administered within 36 hours of AKI diagnosis.
Presence of a do-not-resuscitate order.

Intervenciones

drug

AZD4144

Intravenous solution of AZD4144 will be administered to randomised participants according to the treatment arm to which they have been assigned.

drug

Placebo

Intravenous solution of Placebo will be administered to randomised participants according to the treatment arm to which they have been assigned.

Estudio de fase IIa, aleatorizado, doble ciego, controlado con placebo, multicéntrico, para evaluar la eficacia, seguridad y tolerabilidad de AZD4144 en participantes con lesión renal aguda asociada a sepsis (SERENIA)

Resumen

Descripción detallada

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

AZD4144

Placebo

Ubicaciones

Research Site

Research Site

Research Site

Research Site

Patrocinadores

Contactos

AstraZeneca Clinical Study Information Center