A Phase 3 Study of Micafungin Versus Amphotericin B Deoxycholate in Infants With Invasive Candidiasis

Pediatr Infect Dis J. 2018 Oct;37(10):992-998. doi: 10.1097/INF.0000000000001996.

Abstract

Background: Amphotericin B deoxycholate (AmB-D) is standard of care treatment for neonatal invasive candidiasis (IC). Micafungin (MCA) has broad-spectrum fungicidal activity against Candida spp. We compared the efficacy and safety of intravenous MCA with intravenous AmB-D and assessed the pharmacokinetics of MCA in infants >2-120 days of age with proven IC in a phase 3, randomized, double-blind, multicenter, parallel-group, noninferiority study (NCT00815516).

Methods: Infants were randomized 2:1 to MCA (10 mg/kg/d) or AmB-D (1 mg/kg/d) for ≥21 days. Primary efficacy endpoint was fungal-free survival (FFS) 1 week after last study drug dose. MCA population pharmacokinetics included simulated area under the curve (AUC) at steady state and maximum plasma concentration after 2-hour infusion. AUC pharmacodynamic target exposure was 170 µg·h/mL.

Results: Thirty infants received MCA (n = 20) or AmB-D (n = 10). The trial was terminated early because of slow recruitment. FFS was observed in 12 of 20 [60%; 95% confidence interval (CI): 36%-81%] MCA-group infants and in 7 of 10 (70%; 95% CI: 35%-93%) AmB-D-group infants. The most common treatment-emergent adverse events were anemia [MCA: n = 9 (45%); AmB-D: n = 3 (30%)] and thrombocytopenia [n = 2 (10%) and n = 3 (30%), respectively]. Model-derived mean AUC at steady state for MCA was 399.3 ± 163.9 µg·h/mL (95% prediction interval: 190.3-742.3 µg/mL); steady state and maximum plasma concentration after 2-hour infusion was 31.1 ± 10.5 µg/mL (95% prediction interval: 17.0-49.7 µg/mL). MCA exposures were above the AUC pharmacodynamic target exposure.

Conclusions: Within the study limitations, infants with IC treated with MCA achieved similar FFS compared with AmB-D. Both agents were safe and well tolerated.

Publication types

  • Clinical Trial, Phase III
  • Equivalence Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Amphotericin B / pharmacokinetics
  • Amphotericin B / therapeutic use*
  • Antifungal Agents / pharmacokinetics
  • Antifungal Agents / therapeutic use*
  • Area Under Curve
  • Candida / drug effects
  • Candidiasis, Invasive / blood
  • Candidiasis, Invasive / drug therapy*
  • Deoxycholic Acid / pharmacokinetics
  • Deoxycholic Acid / therapeutic use*
  • Double-Blind Method
  • Drug Combinations
  • Female
  • Hematologic Tests
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Micafungin / pharmacokinetics
  • Micafungin / therapeutic use*
  • Treatment Outcome

Substances

  • Antifungal Agents
  • Drug Combinations
  • Deoxycholic Acid
  • Amphotericin B
  • amphotericin B, deoxycholate drug combination
  • Micafungin

Associated data

  • ClinicalTrials.gov/NCT00815516