Single- and multiple-ascending dose study of oral lumicitabine in infants and neonates (Study 1)
neutropenia, SAD
ADVERSE EVENTS, RSV INFECTION, NEUTROPENIA
Study 1 was a randomized, double-blind, placebo-controlled, 2-part, phase 1b study to assess the safety, PK and PD of single- and multiple-ascending doses (SAD/MAD) of oral lumicitabine in neonates and infants (aged 1 to 12 months) hospitalized with RSV infection. The starting dose of lumicitabine was selected based on an estimation of human efficacious doses projected to be the lowest potential therapeutic dose from the pediatric PK modeling.In Part 1 (SAD part), infants received a single dose of 1 of 4 ascending dose levels of lumicitabine (1.37 mg/kg, 4.1 mg/kg, 12 mg/kg, and 25 mg/kg) or placebo. Within each dosing cohort, the patients were randomized to receive either lumicitabine or placebo (3:1). Except the neonate cohort, each dosing cohort was further stratified by age (≥1 to <2 months, ≥2 to <6 months and ≥6 to ≤12 months), with planned enrollment of approximately 8 patients in each stratum. An age de-escalation approach was used, such that infants between age ≥6 to ≤12 months were enrolled first, followed by those aged ≥2 to <6 months, and then ≥1 to <2 months. A sentinel group of 3 infants was enrolled initially in each age stratum and randomized (2:1) to receive either lumicitabine or placebo. An Independent Data Monitoring Committee (IDMC) reviewed the safety and PK data for the sentinel group prior to randomization (4:1 lumicitabine or placebo) of the remaining 5 infants in the age stratum. Following this assessment, enrollment in the next age stratum’s sentinel cohort(s) was initiated. Infants received the single oral dose of the study drug after randomization and were evaluated over a 7-day period. Infants discharged prior to day 7 were asked to return as an outpatient for assessment on day 7.The Part 2 (MAD part) commenced after evaluation of the PK and safety data of Part 1 by the IDMC. Each infant received a total of 10 doses which included an initial loading dose (LD) on day 1 followed by 9 maintenance doses (MD) commencing 8 to 18 hours later, administered twice daily. This LD/MD regimen consisted of multiple-ascending doses of lumicitabine (4.1/1.37 mg/kg, 10/2 mg/kg, 30/6 mg/kg, 30/10 mg/kg, 40/20 mg/kg, and 60/40 mg/kg), or placebo. Each dosing cohort was further stratified into 3 age strata (≥1.0 to <2.0 months, ≥2 to <6 months and ≥6 to ≤12 months) and randomized (3:1) to receive either lumicitabine or placebo. The enrollment of neonates (<28 days old) occurred following the IDMC’s evaluation of the safety and PK data in 79 infants aged 1–12 months. The neonates were to be randomized (3:1) to receive either lumicitabine or placebo as 10 mg/kg LD on day 1, followed by 9 MD of 2 mg/kg administered twice daily. Only a single neonate was enrolled; subsequent enrollment of neonates was discontinued following a health authority request to generate more safety data in infants prior to the enrollment of additional neonates.Infants were evaluated over a 28-day period from the time of randomization. All received standard supportive care during the study. Throughout both the SAD and MAD parts of the study, the IDMC reviewed unblinded PK of metabolites (ALS-008112 and ALS-008144) and the safety data on a regular basis and approved each dose escalation decision. Patient safety was monitored by regular assessment of the results of clinical laboratory tests, electrocardiograms, physical examinations, vital signs, and adverse events (AEs). In December 2016, the sponsor voluntarily halted the study due to a serious AE of severe neutropenia. The sponsor conducted a comprehensive review of the hematologic data from the lumicitabine development program. Following review by the IDMC, who determined the benefit-risk remained favorable, the sponsor resumed the study after notification/agreement of Health Authority/ethics committees.