NAI Plus Standard of Care Compared With Placebo Plus Standard of Care in Critically Ill Adults With Sepsis

This is a randomized, double-blind, placebo-controlled, parallel-assignment Phase 2a study evaluating NAI plus standard of care compared with placebo plus standard of care in critically ill adults with sepsis and persistent lymphopenia. Approximately 50 participants will be randomized in a 1:1 ratio. The first 10 randomized participants will comprise a safety run-in, with approximately 5 participants assigned to each treatment arm. Safety data will be reviewed by the designated safety review committee or DSMB before enrollment of the remaining participants proceeds.

Inclusion criteria

• Age ≥18 years at the time of informed consent.
• Admission to the ICU with sepsis, without septic shock, per Sepsis-3 criteria, operationalized as a SOFA increase of at least 2 points attributable to suspected or confirmed infection.
• ALC ≤1,000 cells/µL in two consecutive measurements separated by at least 12 hours during the 72-hour screening window.
• Documented or strongly suspected bacterial, viral, fungal, or mixed infection with reasonable diagnostic workup initiated.
• Receiving guideline-directed standard of care according to the 2026 Surviving Sepsis Campaign Guidelines.
• Able to receive the first dose of NAI within 72 hours of sepsis recognition, targeted within 12 hours of eligibility confirmation.
• Ability to obtain written informed consent from the participant or legally authorized representative.
• Agreement to practice effective contraception, as applicable, by females of childbearing potential and nonsterile males.

Exclusion criteria

• Severe hepatic failure, including Child-Pugh class C, ALT or AST ≥3 times the ULN with total bilirubin >2 times the ULN, or ALT or AST ≥5 times the ULN.
• Septic shock at screening or at the time of the first dose.
• Active malignancy treated with cytotoxic chemotherapy, radiotherapy, or checkpoint-inhibitor therapy within 30 days before sepsis onset.
• History of solid-organ transplantation.
• Hematopoietic stem-cell transplantation within the prior 100 days.
• Active graft-versus-host disease requiring systemic immunosuppression.
• Known hypersensitivity to NAI, IL-15, recombinant IL-15 receptor-alpha sushi domain, or human IgG1 Fc.
• Pregnancy.
• Breastfeeding.
• Active treatment with another investigational therapy.
• Participation in another interventional clinical trial within 30 days before enrollment.
• A clinical condition or treatment limitation that, in the Investigator's opinion, precludes meaningful participation or follow-up.
• Expected death within 24 hours.
• Comfort-care-only orders that preclude protocol-mandated assessments.