Acute Respiratory Distress Syndrome (ARDS), Community-Acquired Pneumonia (CAP), Immunoparalysis, Lymphopenia, Sepsis
Conditions
Keywords
Community-Acquired Pneumonia, Severe CAP, Sepsis, Acute Respiratory Distress Syndrome (ARDS), Nogapendekin Alfa Inbakicept (NAI), ANKTIVA, iNKT Cells, Invariant Natural Killer T cells (AgenT-797), Immunotherapy, Immunomodulation, Lymphopenia, Critical Illness, Randomized Controlled Trial, Phase 3
Brief summary
This is a Phase 3, randomized, blinded, and placebo-controlled clinical trial investigating a new combination treatment for critically ill adults who have severe community-acquired pneumonia, especially if they also have sepsis or acute respiratory distress syndrome. The study aims to determine if adding the experimental agents, Nogapendekin Alfa Inbakicept and iNKT cells, to standard medical care can reduce the 28-day all-cause mortality rate compared to standard care alone with a placebo.
Detailed description
This multi-center, randomized, blinded, and placebo-controlled Phase 3 study aims to address the high mortality and complication rates associated with severe community-acquired pneumonia (CAP) in critically ill adults, particularly those experiencing immune deficiency like lymphopenia or immunoparalysis. Current standard treatments for severe CAP focus on infection control and organ support but often do not directly restore the patient's compromised immune function. This trial investigates a novel immunotherapeutic approach using a combination of two agents: 1. Nogapendekin Alfa Inbakicept (NAI): An IL-15 receptor agonist designed to activate natural killer (NK) and CD8+ T-cells, aiming to enhance the body's immune competence. 2. iNKT Cells (invariant natural killer T cells): An allogeneic cell therapy intended to rapidly orchestrate both innate and adaptive immune responses. The central hypothesis is that this combination therapy, when added to standard of care treatments, can reverse immune dysfunction, clear infections, regulate inflammation, and ultimately improve survival and reduce severe complications such as secondary infections and prolonged organ support requirements in this vulnerable patient population. The study will meticulously assess the safety and efficacy of this combined approach, building on promising signals from earlier research.
Interventions
BIOLOGICALNogapendekin alfa inbakicept (NAI)
NAI is a soluble complex consisting of two protein subunits of a human IL-15 variant (nogapendekin alfa) bound with high affinity to a dimeric human IL 15Rα sushi domain/human IgG1 Fc fusion protein (inbakicept).
BIOLOGICALagenT-797
Allogeneic invariant NKT (iNKT) cell therapy - an off-the-shelf cell therapy that can rapidly orchestrate both innate and adaptive immunity.
Sponsors
ImmunityBio, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
This is a double-blind study, meaning that participants, treating physicians, and most study personnel and sponsor staff are unaware of which treatment (active drug or placebo) a participant receives. Blinding is maintained through the use of identical-looking active drugs and placebos.
Intervention model description
This is a parallel assignment study where participants are randomized 1:1 into two distinct arms: an Experimental Arm receiving active study drugs (Nogapendekin Alfa Inbakicept and iNKT cells) plus standard of care, and a Control Arm receiving matching placebos plus standard of care. The study is double-blinded, meaning both participants and treating physicians are unaware of the assigned treatment to maintain objectivity. Blinding is maintained through the use of identical-appearing syringes for NAI/placebo and identical IV bags for iNKT cells/placebo.
Eligibility
Sex/Gender
ALL
Age
18 Years to 105 Years
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 years, adult participants of any gender. 2. Critically ill adults requiring admission to an ICU-unit due to severe community acquired pneumonia. * Severe CAP is defined by the presence of one major criterion or at least three minor criteria: * Major Criteria (any one = severe CAP): * Respiratory failure requiring mechanical ventilation * Septic shock requiring vasopressors to maintain blood pressure * Minor Criteria (≥3 indicates severe CAP): * Tachypnea: Respiratory rate ≥ 30 breaths/min * Hypoxemia: PaO2/FiO2 ratio ≤ 200 * Multilobar infiltrates on chest imaging * Confusion or disorientation (new onset mental status changes) * Uremia: Blood urea nitrogen (BUN) ≥ 20 mg/dL (7.1 mmol/L) * Thrombocytopenia: Platelet count \< 100,000/μL * Hypothermia: Core temperature \< 36.0 °C (96.8 °F) * Hypotension requiring aggressive fluid resuscitation 3. Hospital admission with a diagnosis of CAP within 72 hours. 4. Lymphopenia/ Absolute Lymphocyte Count (ALC): ALC \< 1,500/μL (not secondary due to chemotherapy). 5. Participants already treated by antibiotics (at least one dose since admission to the ICU). 6. Informed consent: Ability to obtain informed consent from participant or legally authorized representative (given the incapacity of many ICU participants, consent via surrogate/Legally Authorized Representative is allowed per ethics approval).
Exclusion criteria
1. Hematologic malignancies (eg, active leukemia and lymphoma, not in remission). 2. Post CAR-T cells therapy or hematopoietic cell transplant for ALL, NHL or Multiple Myeloma less than 3 months prior to enrollment. 3. Participant diagnosed with cytokine release syndrome. 4. Participant receiving colony stimulating factors eg, G-CSF. 5. Clinical history or radiological imaging suggesting aspiration of gastric content. 6. Participant with advanced dementia or prolonged bedridden status. 7. Pregnancy or breastfeeding. 8. High-dose immunosuppressive therapy at baseline: eg, \> 0.5 mg/kg prednisone (or equivalent). Note: Use of low-dose corticosteroids for septic shock or ARDS (eg, dexamethasone 6 mg/day for ARDS) is not an exclusion, as it is standard care such use will be recorded and balanced between arms. 9. Uncontrolled autoimmune or inflammatory disease requiring immunosuppressive therapies (to avoid confounding immune effects or exacerbation). 10. Life expectancy \< 24-48 hours or moribund condition despite care (Investigator judgment that participant will not survive long enough to benefit or be evaluated). 11. Active uncontrolled bleeding or intracerebral hemorrhage (cell therapy infusion could transiently affect hemodynamics or coagulation; exclude if such conditions make the intervention risk unjustifiable). 12. Known hypersensitivity to ingredients used in cell product formulation such as DMSO. 13. Treated by antibiotics for a respiratory infection for more than seven days at the time of hospitalization (except if culture and sensitivities determine a resistant organism to the administered antibiotics). 14. Known active Viral Hepatitis A, B, or C. 15. History of human immunodeficiency virus (HIV) with current CD4+ T-cell count \< 350 cells/µL and/or a detectable HIV viral load. 16. The Investigator believes that participating in the trial is not in the best interest of the participant, or the Investigator considers the participant unsuitable for enrollment (such as due to unpredictable risks or severe co-morbidities).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 28-day all-cause mortality | 30 days after the last dose of study drug | Up to Day 28 from randomization. (Participants lost to follow-up before Day 28 will be censored at their last known date alive; participants alive on Day 28 will be censored at Day 28). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ALC count | From randomization through 28 days following randomization. | Absolute Lymphocyte Count |
| Ventilator-Free days (VFD) through Day 28. | Through 28 days following randomization. | The number of days a participant is free from mechanical ventilation. |
| Number of ICU free days through Day 28. | Through 28 days following randomization. | The number of days a participant is free from being in the Intensive Care Unit. |
| Number of antibiotic free days through Day 28. | Through 28 days following randomization. | The number of days a participant is free from antibiotic treatment. |
| Number of days alive and free of organ support through 28 days. | Through 28 days following randomization. | The number of days a participant is alive and does not require organ support. |
| Time from first administration of study drug to ICU discharge. | From first study drug administration until ICU discharge, assessed up to 90 days; ICU discharge date documented from medical record (participants not discharged by Day 90 censored at Day 90; deaths prior to discharge counted as competing events). | The duration from the first dose of study drug until the participant is discharged from the Intensive Care Unit. |
| Time from first administration of study drug to hospital discharge. | From first study drug administration until hospital discharge, assessed up to 90 days; hospital discharge date documented from medical record (participants not discharged by Day 90 censored at Day 90; deaths prior to discharge counted as competing events | The duration from the first dose of study drug until the participant is discharged from the hospital. |
| Incidence of secondary infections through Day 28 and for the entire study. | From randomization through 90 days following randomization. | The occurrence rate of infections that develop after the start of study treatment. |
| 90-day all-cause mortality. | Through 90 days following randomization. | Death from any cause. |
Contacts
STUDY_DIRECTORJayson Garmizo
ImmunityBio, Inc.
Outcome results
None listed