A Study of Auxora in Patients With AKI and Injurious Lung "Crosstalk"

Phase 2TerminatedNCT06374797

CalciMedica, Inc.122 enrolled

Overview

Approximately 150 patients with acute kidney injury (AKI) associated with acute hypoxemic respiratory failure (AHRF) will be randomized at up to 40 sites. Patients will be randomly assigned to either Auxora or matching placebo. Study drug infusions will occur every 24 hours for five consecutive days for a total of five infusions.

This double blind, randomized, placebo-controlled study will evaluate the efficacy, safety, and tolerability of Auxora in patients with severe AKI who have associated AHRF. The definition of AKI and the stages of AKI will be based on the classification system proposed by the Acute Kidney Injury Working Group of Kidney Disease: Improving Global Outcomes (KDIGO) and incorporate both serum creatinine and urine volume criteria. AHRF will be defined as a P/F ≤ 300 that has been determined by either an arterial blood gas or imputed from the oxygen saturation (SpO2) recorded using pulse oximetry and is being treated with high flow nasal cannula with minimum flow rate ≥ 30 liters/min, or non-invasive mechanical ventilation, or invasive mechanical ventilation. Approximately 150 patients with severe AKI, defined as having developed either stage 2 or 3 AKI at the time of consent, who have associated AHRF will be randomized 1:1 into either the Auxora or placebo group using a computer-generated randomization scheme accessed through an interactive voice/web response system (IXRS). Randomization will be stratified by the use of invasive mechanical ventilation and by Stage 3 AKI. Patients who are randomized to the Auxora group will receive 1.25 mL/kg (2.0 mg/kg of zegocractin) IV over 4 hours at 0 hours and then 1.0 mL/kg (1.6 mg/kg of zegocractin) IV over 4 hours at 24, 48, 72, and 96 hours for a total of 5 doses. Patients who are randomized to the placebo group will receive 1.25 mL/kg IV over 4 hours at 0 hours and then 1.0 mL/kg IV over 4 hours at 24, 48, 72, and 96 hours for a total of 5 doses. Placebo will be a matching emulsion without the active pharmaceutical ingredient zegocractin. The sponsor, investigators, pharmacists, and patients will be blinded to the assigned group. The Start of First Infusion of Study Drug (SFISD) should occur no more than 24 hours of the patient or legally authorized representative (LAR) providing informed consent. A study physician or appropriately trained delegate will perform study-specific hospital assessments immediately prior to the SFISD, and then every 24 hours after the SFISD until 720 hours (Day 30), or until discharge if earlier. All patients, including those that are discharged from the hospital to home, or to a skilled nursing facility, or to an extended care facility, will be assessed at Day 90. All AKI should be managed according to the KDIGO 2012 guidelines which recommends maintaining adequate organ perfusion, avoiding volume overload, avoiding hyperglycemia, discontinuing nephrotoxic agents, and adjusting dosing of renally excreted medications. AHRF/acute respiratory distress syndrome (ARDS) should be managed according to the 2023 European Society of Intensive Care Medicine (ESICM) major recommendations.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

122

Conditions

Acute Kidney Injury

Interventions

AuxoraDRUG

1.25 mL/kg (2.0 mg/kg of zegocractin) intravenously (IV) over 4 hours at 0 hours, and then 1.0 mL/kg (1.6 mg/kg of zegocractin) IV over 4 hours at 24, 48, 72 and 96 hours for a total of 5 doses.

PlaceboDRUG

1.25 mL/kg IV over 4 hours at 0 hours and then 1.0 mL/kg IV over 4 hours at 24, 48, 72, and 96 hours for a total of 5 doses.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. The patient is ≥ 18 years of age. 2. The patient has developed Stage 2 or Stage 3 AKI. 3. The patient has a documented partial pressure of oxygen \[Pa02\]/fraction of inspired oxygen \[FiO2\] (P/F) ≤ 300 in the prior 24 hours, either imputed from SpO2 or obtained from an arterial blood gas, that is not explained by cardiogenic pulmonary edema or volume overload 4. The patient is being treated with either high flow nasal cannula with minimum flow rate ≥ 30 liters/min, or non-invasive mechanical ventilation, or invasive mechanical ventilation at time of randomization. 5. A female patient of childbearing potential who is sexually active with a male partner is willing to practice acceptable methods of birth control for 30 days after the last dose of study drug. 6. A male patient who is sexually active with a female partner of childbearing potential is willing to practice acceptable methods of birth control for 30 days after the last dose of study drug. A male patient must not donate sperm for 30 days after the last dose of study drug. 7. The patient is willing and able to, or has a legally authorized representative (LAR) who is willing and able to, provide informed consent to participate and to cooperate with all aspects of the protocol. Exclusion Criteria: 1. The patient has a do not intubate directive. 2. The patient has chronic lung disease that requires supplemental non-invasive oxygen as an outpatient or home mechanical ventilation. The use of non-invasive mechanical ventilation to treat obstructive sleep apnea is not an exclusion. 3. The patient has been hospitalized in the ICU for more than 10 days. 4. The patient has been receiving invasive mechanical ventilation for \> 120 hours. 5. The patient is receiving extracorporeal membrane oxygen (ECMO). 6. The patient has started or is planned to start kidney replacement therapy (KRT) before randomization. 7. The patient has a serum triglyceride level ≥ 500 mg/dL. 8. The patient has a direct bilirubin level \>3.0 mg/dL or both a direct bilirubin level ≥ 2.0 mg/dL and an international normalized ratio (INR) ≥ 1.7. 9. AKI is suspected to be secondary to: renal artery or renal vein thrombosis; hepato-renal syndrome; cholesterol emboli syndrome; acute glomerulonephritis; vasculitis; acute allergic interstitial nephritis; intrarenal or extrarenal urinary tract obstruction; use of immune checkpoint inhibitor. 10. The patient has a known history of an organ transplant. 11. The patient has a known history of HIV infection. 12. The patient has known history of hepatitis B infection. 13. The patient is currently receiving chemotherapy. 14. The patient is currently receiving immunosuppressive medications 15. The patient is known to be pregnant or is currently nursing. 16. The patient is allergic to eggs. 17. The patient is currently participating in another study of an investigational drug

Locations (33)

Outcomes

Primary Outcomes

Days alive, ventilator-free and kidney replacement therapy (KRT)-free from SFISD through Day 30

The primary efficacy analysis will apply the win ratio method and the Finkelstein-Schoenfeld method to the primary endpoints. The win ratio method allocates all Auxora and placebo pairs to the components that comprise the primary endpoint in a hierarchical fashion. Categories (a) and (c) represent Auxora wins based on all-cause mortality and days ventilator-free and KRT-free. Similarly, categories (b) and (d) represent placebo wins. Category (e) represents ties. (a) Death on placebo, but alive on Auxora at day 30 (b) Death on Auxora, but alive on placebo at day 30 (e) Death on placebo and death on Auxora at day 30 If alive on placebo and alive on Auxora at day 30: (c) Greater number of days alive, ventilator-free and KRT-free on Auxora (d) Greater number of days alive, ventilator-free and KRT-free on Placebo (e) Equal number of days alive, ventilator-free and KRT-free We will calculate the overall win ratio by adding (a) + (c) and dividing it by the sum of (b) + (d).

Time frame: SFISD through Day 30

Secondary Outcomes

Major adverse kidney event (MAKE) 90-1: ≥25% decline in estimated glomerular filtration rate (eGFR) from baseline, incident KRT, and all-cause mortality at 90 days

Time frame: At Day 90

MAKE 90-2: ≥35% decline in eGFR from baseline, incident KRT, and all-cause mortality at 90 days

Time frame: At Day 90

Proportion of patients alive at Day 30

Time frame: At Day 30

Proportion of patients alive at Day 90

Time frame: Day 90

Days alive and ventilator-free from start of first infusion of study drug (SFISD) through Day 30

Time frame: SFISD through Day 30

Data from ClinicalTrials.gov

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