Anakinra Pilot 2 - A Study to Optimise Dose and Route of Administration of Anakinra in Preterm Infants (AP2)

A phase 2 randomised, three-arm, parallel-group, dose-ranging trial to determine safety, efficacy and optimal dosing of intravenous anakinra in premature neonates, with subcutaneous pharmacokinetic sub-study.

Study Overview

• Status: Recruiting
• Conditions: Inflammation; Premature Infants; Very Premature Infants
• Intervention / Treatment: Drug: Anakinra (Kineret®)

Detailed Description

Advances in neonatal intensive care have significantly improved the survival rates for extremely premature neonates. Despite this, many survivors develop chronic conditions such as cerebral palsy and chronic lung disease, primarily due to the pro-inflammatory environment common in these patients. Efforts to reduce these conditions using anti-inflammatory glucocorticoids are effective but are hindered by significant adverse effects that outweigh potential benefits for most neonates.

Crucially, not only is inflammation an important driver of morbidities of prematurity, but as shown by the investigators and other research groups, the potent pro-inflammatory cytokine interleukin-1 is a key player.

A phase I/IIa trial of anakinra in extremely premature infants (24 - 27+6 weeks gestational age) demonstrated feasibility of administration intravenous over the first 3 weeks of life, without any acute safety concerns and confirmation of mechanistic pharmacokinetic predictions.

The aims of this phase II dose-ranging trial (Anakinra Pilot 2, AP2) are to:

1. Establish pharmacokinetics, linearity and target concentration attainment over a range of doses, to determine optimal dosing regimen.
2. Assess feasibility and pharmacokinetics of an alternative route of administration (RoA), namely subcutaneous, in week 3 of treatment.
3. Further expand safety & feasibility, as well as perform exploratory pharmacometric dose-exposure-response analysis, against biomarkers and early efficacy endpoints.

The primary outcome is to refine understanding of anakinra population pharmacokinetics in extremely premature neonates, and at 3 different dosing levels, to allow determination of optimal dose for population target concentration attainment in future trials.

In addition, the pharmacokinetics of subcutaneously administered anakinra in extremely premature neonates (from week 3) will be explored. Population pharmacokinetic model development and validation, for intravenous and subcutaneous anakinra in premature neonates over the first 3 weeks of life, to enable dose determination for target concentration attainment.

Model performance and validation will be based on metrics and graphics of model 'goodness-of-fit', precision of parameter estimates (relative standard error & confidence intervals for CL, Vd and Ka) and predictive performance and robustness, per published (PMID: 27884052) and regulatory guidance (FDA guidance on Population Pharmacokinetics (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/population-pharmacokinetics).

Population Pharmacokinetic (PK)/Pharmacodynamic (PD) Modeling will also enable exploratory investigation of the relationship between anakinra dose, concentration-time course in blood, and drug effects, both biomarkers of inflammation and clinical endpoints.

AP2 will recruit 24 infants born 24-28 weeks-GA, randomised to one of 3 dosing arms, 8 infants/arm, stratified to ensure balanced GA-distribution. Participants will otherwise receive standard care.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Marcel F Nold, Prof; Phone Number: +61385723936; Email: marcel.nold@monash.edu
• Study Contact Backup: Name: Claudia Nold, Prof; Phone Number: +61385723936; Email: claudia.nold@hudson.org.au

Study Locations

• Australia
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Recruiting
      • Monash Children's Hospital
      • Contact: Rebecka Atkinson, RN; Phone Number: +61385722713; Email: rebecka.atkinson@hudson.org.au
      • Principal Investigator: Marcel F Nold, Prof
• New Zealand
  • Auckland
    • Grafton, Auckland, New Zealand, 1023
      • Not yet recruiting
      • Starship Children's Hospital
      • Contact: Gergely Toldi, Dr; Phone Number: +64 93670000; Email: gergely.toldi@auckland.ac.nz
      • Principal Investigator: Gergely Toldi, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Born between 24+0 and 28+6 weeks of gestation

Exclusion Criteria:

• Inability of the legal representatives to consent,
• Genetic syndromes,
• Severe cardiac anomalies,
• Substantial pre-/perinatal compromise,
• Congenital diaphragmatic hernia,
• Intrauterine stroke,
• Conditions that could confound trial results
• Imminent death or plan for comfort / palliative care
• Infants born outside the recruiting institutions

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Anakinra dose 1 IV; Anakinra IV for 21 days	Drug: Anakinra (Kineret®); Standard care plus Anakinra for 21 days
Active Comparator: Anakinra dose 1 IV/SC; Anakinra IV for 14 days & SC for 7 days	Drug: Anakinra (Kineret®); Standard care plus Anakinra for 21 days
Active Comparator: Anakinra dose 2 IV; Anakinra IV for 21 days	Drug: Anakinra (Kineret®); Standard care plus Anakinra for 21 days
Active Comparator: Anakinra dose 2 IV/SC; Anakinra IV for 14 days & SC for 7 days	Drug: Anakinra (Kineret®); Standard care plus Anakinra for 21 days
Active Comparator: Anakinra dose 3 IV; Anakinra IV for 21 days	Drug: Anakinra (Kineret®); Standard care plus Anakinra for 21 days
Active Comparator: Anakinra dose 3 IV/SC; Anakinra IV for 14 days & SC for 7 days	Drug: Anakinra (Kineret®); Standard care plus Anakinra for 21 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Population Pharmacokinetics (PopPK) Model of the Clearance of anakinra in extremely premature neonates from birth, during the 3-week treatment period.	Point Estimate of Population Total Clearance (CL) of anakinra will be reported.	From Baseline up to Day 21
Population Pharmacokinetics (PopPK) Model of the Volume of Distribution of anakinra in extremely premature neonates from birth, during the 3-week treatment period.	Point Estimate of Population Volume of Distribution (VD) of anakinra will be reported.	From Baseline up to Day 21
Population Pharmacokinetics (PopPK) Model of the Absorption of Population of subcutaneously administered anakinra in extremely premature neonates from birth, during the 3-week treatment period.	Point Estimate of Population Absorption of subcutaneously administered anakinra will be reported.	Day 14-21

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of bronchopulmonary dysplasia	Early efficacy endpoints (exploratory): incidence of bronchopulmonary dysplasia, in comparison to contemporary unit and national statistics.	4 months.
Hammersmith infant neurological examination	Early efficacy endpoint (exploratory): Hammersmith infant neurological examination; performed at 3-4 months of corrected age, in comparison to contemporary unit and national statistics.	6 months
Incidence of intracranial/intraventricular haemorrhage and peri-ventricular leukomalacia.	Early efficacy endpoint (exploratory): incidence of intracranial/intraventricular haemorrhage and peri-ventricular leukomalacia, in comparison to contemporary unit and national statistics.	4 months
Safety of anakinra in extremely premature neonates.	Safety of anakinra IV and SC in premature neonates, at 3 dosing levels, measured as incidence of safety endpoints in particular late-onset sepsis and necrotizing enterocolitis (compared with contemporary unit and national statistics) as well as neutropenia, thrombocytopenia, acute kidney injury, drug-induced liver injury (per Hy's Law).	4 weeks
Individual Total Clearance (CL) of anakinra in extremely premature neonates.	Average of individual model-derived estimates of CL will be reported.	From Baseline up to Day 21.
Individual Volume of Distribution (VD) of anakinra in extremely premature neonates.	Average of individual model-derived estimates of VD will be reported.	Baseline to Day 21.
Individual Absorption Rate Constant (Ka) of subcutaneously administered anakinra in extremely premature neonates.	Average of individual model-derived estimates of Ka will be reported.	Day 14-21.
Individual Maximum Serum Concentration (Cmax) of anakinra.	Average of individual model-derived estimates of Cmax will be reported.	Baseline to Day 21.
Individual Area Under the Concentration-time Curve Within a Dosing Interval (AUCtau) of anakinra.	Average of individual model-derived estimates of AUCtau will be reported.	Baseline to D21.
Individual Model - derived Ctrough Concentrations of anakinra.	Average of individual model-derived Ctrough concentrations of anakinra will be reported.	Baseline to D21.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility of 3 weeks of anakinra administration to extremely premature neonates from birth, both intravenously and subcutaneously.	Feasibility of anakinra IV and SC in premature neonates, at 3 dosing levels, measured as succesful completion of intervention treatment course, including subcutaneous dosing.	1 month
Influence of anakinra on microbiome.	Monitoring for lung and gut microbiome changes during the treatment course by collection and analysis of bronchoalveolar lavage fluid (in intubated infants), nasopharyngeal swabs, and stool.	3 weeks
Pharmacokinetic (PK)/Pharmacodynamic (PD) Model of the Effect of anakinra Systemic Exposure on clinical endpoints.	Point Estimate of population IC50 of anakinra associated with a reduction in incidence of early efficacy endpoints (exploratory), including bronchopulmonary dysplasia, intracranial/intraventricular haemorrhage & peri-ventricular leukomalacia, and Hammersmith infant neurological examination; performed at 3-4 months of corrected age.	4 months
Pharmacokinetic (PK)/Pharmacodynamic (PD) Model of the Effect of anakinra Systemic Exposure on biomarkers of the inflammatory cascade.	Point Estimate of population IC50 of anakinra, i.e. the drug concentration required to produce 50% of maximal inhibition of the IL-1-driven inflammatory cascade. Biomarkers investigated will include cellular proteomic biomarkers of inflammatory activity and inhibition, including lymphoid and myeloid cell polarisation and activation as well as responsiveness to stimulants such as lipopolysaccharide (LPS) and PMA/ionomycin during the treatment course.	4 Months.
Pharmacokinetic (PK)/Pharmacodynamic (PD) Model of the Effect of anakinra Systemic Exposure on adverse effects.	Point Estimate of population EC50 of anakinra, i.e. the drug concentration associated with exploratory safety endpoints including late-onset sepsis, necrotizing enterocolitis, neutropenia, thrombocytopenia, acute kidney injury, drug-induced liver injury (per Hy's Law).	Baseline to Day 21.

Collaborators and Investigators

• Sponsor: Monash Medical Centre
• Collaborators: Monash University; Starship Children's Hospital of New Zealand; Hudson Institute of Medical Research; Liggins Institute
• Investigators: Principal Investigator: Claudia Nold, Prof, Hudson Institute of Medical Research; Principal Investigator: Marcel F Nold, Prof, Monash Health/ Monash University/ Hudson Institute of Medical Research; Principal Investigator: Rod Hunt, Prof, Monash Health / Monash University; Principal Investigator: Robert Galinsky, Dr, Hudson Institute of Medical Research; Principal Investigator: Gergely Toldi, Dr, Starship Children's Hospital / Liggins Institute; Principal Investigator: Carl Kirkpatrick, Prof, Monash University; Principal Investigator: David Metz, Dr, Monash Health / Royal Children's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 27, 2025
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: April 7, 2025
• First Submitted That Met QC Criteria: November 19, 2025
• First Posted (Actual): November 28, 2025

Study Record Updates

• Last Update Posted (Actual): November 28, 2025
• Last Update Submitted That Met QC Criteria: November 19, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: bronchopulmonary dysplasia; anakinra; diffuse white matter injury; very premature infants
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Female Urogenital Diseases and Pregnancy Complications; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Respiratory Tract Diseases; Lung Diseases; Infant, Premature, Diseases; Infant, Newborn, Diseases; Lung Injury; Ventilator-Induced Lung Injury; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Premature Birth; Inflammation; Bronchopulmonary Dysplasia; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Intercellular Signaling Peptides and Proteins; Cytokines; Interleukin 1 Receptor Antagonist Protein
• Other Study ID Numbers: RES 24-0000-885A

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No