Anakinra Pilot – a clinical trial to demonstrate safety, feasibility and pharmacokinetics of interleukin 1 receptor antagonist in preterm infants

Abstract

BackgroundBronchopulmonary dysplasia (BPD), its complication pulmonary hypertension (BPD-PH) and preterm brain and gut injury lead to significant morbidity and mortality in infants born extremely prematurely. There is extensive evidence that the pro-inflammatory cytokine interleukin 1 (IL-1) plays a key role in the pathophysiology of these illnesses. Two decades of clinical use in paediatric and adult medicine have established an excellent safety and efficacy record for IL-1 blockade with IL-1 receptor antagonist (IL-1Ra, medication name anakinra). Building on robust pre-clinical evidence, the Anakinra Pilot trial aims to demonstrate safety and feasibility of administering anakinra to preterm infants, and to establish pharmacokinetics in this population. Its ultimate goal is to facilitate large studies that will test whether anakinra can ameliorate early-life inflammation, thus alleviating multiple complications of prematurity.Methods and analysisAnakinra Pilot is an investigator-initiated, single arm, safety and feasibility dose-escalation trial in extremely preterm infants born between 24 weeks 0 days (240) and 276 weeks of gestational age (GA). Enrolled infants will receive anakinra intravenously over the first 21 days after birth, starting in the first 24 h after birth. In the first phase, dosing is 1 mg/kg every 48 h, and dosage will increase to 1.5 mg/kg every 24 h in the second phase. Initial anakinra dosing was determined through population pharmacokinetic model simulations. During the study, there will be a interim analysis to confirm predictions before undertaking dose assessment. Anakinra therapy will be considered safe if the frequency of adverse outcomes/events does not exceed that expected in infants born at 240-276 weeks GA.Clinical Trial Registrationhttps://clinicaltrials.gov/, identifier NCT05280340.

Interleukin-1 Blockers: A Paradigm Shift in the Treatment of Recurrent Pericarditis

“…The accumulated experience with their use in clinical practice dates more than 20 years, with anakinra being the most widely used medication for the longest period of time, while relevant data on goflikicept are scant [ 76 , 84 ]. The most common side effects related to the latter medications consist of skin reactions (erythema) and occasionally pain at the injection site.…”

Sex-Specific Dysconnective Brain Injuries and Neuropsychiatric Conditions such as Autism Spectrum Disorder Caused by Group B Streptococcus-Induced Chorioamnionitis

“…This drug presents a potential strategy for preventing perinatal inflammation in premature infants, which is associated with morbidities such bronchopulmonary dysplasia, pulmonary hypertension, and cerebral diffuse WMI [75]. Briefly, enrolled infants born between 24 weeks 0 days (24 0 ) and 27 6 will receive Anakinra over the first 21 days of birth, and the frequency of adverse outcomes/events will be monitored [74,75]. A systematic review analyzing randomized control trials, observational studies, and case reports shows that IL-1 blockers are safe during human pregnancy with no significant increase in adverse outcomes [75].…”

“…In preclinical models of chorioamnionitis triggered by GBS and LPS, the IL-1 blockade has already demonstrated placenta- and feto-protective effects [ 36 , 73 ]. Of particular interest, a Phase I/IIa study of the drug Anakinra, which is an IL-1Ra analogue, has been underway since February 2022 [ 74 ]. This drug presents a potential strategy for preventing perinatal inflammation in premature infants, which is associated with morbidities such bronchopulmonary dysplasia, pulmonary hypertension, and cerebral diffuse WMI [ 75 ].…”

Neuroprotective therapies in the NICU in preterm infants: present and future (Neonatal Neurocritical Care Series)

“…This includes anakinra, an interleukin 1 receptor antagonist, which is the subject of a safety and feasibility study in preterm infants between 24 and 28 weeks gestation, that aims to decrease the morbidity and mortality of prematurity attributed to inflammation, including bronchopulmonary dysplasia, gut injury and necrotizing enterocolitis, and brain injury. 96 Erythropoietin. Erythropoietin (Epo) is an endogenous growth factor whose primary function is to stimulate erythropoiesis.…”