Determination of Levels of Micafungin in Neonates Suffering From Systemic Candidiasis and/or Candida Meningitis

Determination of Plasmatic and CSF Levels of High Doses of Micafungin in Neonates Suffering From Systemic Candidiasis and/or Candida Meningitis

The primary purpose of this study is to evaluate the pharmacokinetic profile of micafungin administered to neonates suffering from systemic candidiasis. This study will also evaluate the proportion of success and of failure of the therapy with micafungin among treated neonates and will identify a conversion factor to relate plasma levels of micafungin into capillary and venous blood measured through blood samples from the heel and from a peripheral vein, collected simultaneously. Safety of micafungin in neonates will also be assessed.

Study Overview

• Status: Completed
• Conditions: Candidiasis, Systemic; Candida Meningitis
• Intervention / Treatment: Drug: Micafungin

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Rome, Italy, 00146
    • Site IT39001
  • Rome, Italy, 00186
    • Site IT39002

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 5 months (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Infection by systemic candidiasis Systemic candidiasis is diagnosed in case of worsening of clinical conditions while on therapy with antibiotics, in case of isolation of candida from at least one sample collected from a normally sterile site (Blood, CSF, Urine, Peritoneal Fluid) and/or from at least two non contiguous sites (tracheal aspirate, gastric aspirate, faeces) and/or positivity to candida through polymerase chain reaction (PCR)(Septifast test), associated with at least one clinical symptom (fever or hypothermia, mottled skin, feeding difficulties, muscular hypotonia or hypertonia, apnoea crisis, bradycardia, tachycardia, hypotension, dyspnea, polypnea, desaturation) and one laboratory symptom (white blood cell [WBC] ≤5000/mm3 or WBC ≥20.000/mm3, immature to total neutrophil ratio [I/T ratio] >2, Platelet count ≤100.000/mm3, C-reactive Protein >0,5 mg/dL, Standard Base Excess >-7 mmol/L, CSF pleocytosis-cells ≥ 6) and/or positivity to test Enzyme Linked Immuno-Sorbent Assay (ELISA) for the mannan antigen (≥125 pg/ml).
• Neonates affected by candida meningitis and/or hydrocephalus due to candida infection and/or bearing external ventricular derivation, until enrollment of at least 4 subjects with this characteristics.
• Parents of neonates, or legal representative, able to consent and comply with protocol requirements.
• Survival expectation not inferior to 3 days.

Exclusion Criteria:

• Acute hepatopathy (ammonium > 200 µg/dL) or chronic hepatopathy.
• Known allergy or hypersensitivity to echinocandins or any of the excipients present in the formulation of the investigational product.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Micafungin; Participants will receive micafungin 8 mg/kg per day via intravenous infusion for approximately 1 hour. Micafungin will be administered for a minimum of 14 days until 1 of the following conditions applied: •Negative results (absence of Candida growth) from at least 2 consecutive blood cultures and/or resolution of clinical and laboratory symptoms and reduction of mannan antigen blood level (< 125 pg/mL) are obtained. •In case of meningitis, hydrocephalus and external ventricular derivation, negative results (absence of Candida growth) from at least 2 consecutive cerebral spinal fluid (CSF) cultures associated with resolution of clinical and laboratory symptoms. •Interruption (including addition or switch to another antifungal agent or dosage change of micafungin) due to demonstration of therapy failure.

Drug: Micafungin; Participants will receive micafungin 8 mg/kg per day via intravenous infusion for approximately 1 hour.; Other Names: Mycamine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of Micafungin in Blood	Concentration will be determined from the pharmacokinetic (PK) blood samples collected via capillary micro-method (draws from the heel).	Predose and after 1, 3, and 8 hours post-dose on one of treatment days from Day 3 to Day 10
Concentration of Micafungin in Cerebral Spinal Fluid (CSF)	Concentration will be determined from the from the CSF samples collected.	Predose and after 1, 3, and 8 hours post-dose on one of treatment days from Day 3 to Day 10

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants with a Response at End of Treatment (EOT) - Success of Therapy (SOT)	For systemic candidiasis (SC) participants, SOT will be determined by survival associated with negative Candida test results of 2 consecutive blood cultures, completed at start of treatment, or resolution of clinical & laboratory symptoms together with reduction of mannan antigen blood level (MABL) (<125 pg/ml). For Candida meningitis (CM), SOT will be determined by survival associated with negative Candida test results of at least 2 consecutive CSF cultures, completed at start of treatment and resolution of clinical and lab symptoms. For hydrocephalus due to Candida infection (CI) and/or external ventricular derivation (EVD), SOT will be determined by survival associated with negative Candida test results of at least 2 consecutive CSF cultures, completed at start of treatment.	Up to day 14
Percentage of Participants with A Response at EOT - Failure of Therapy (FOT)	For SC participants, FOT will be determined by death due to Candida sepsis, by confirmation of persistence of positive Candida test results from 1 blood culture completed by need to add/switch to another antifungal agent (AA) and/or change of micafungin dose for resolution of infection at any time or by the persistence of Candida colonization in different indicated sites associated with persistence of clinical and lab symptoms and with high (MABL) (≥ 125 pg/ml). For CM, FOT will be determined by death due to CM, by persistence of CI from confirmation of positive CSF culture or by need to add/switch to another AA or dose change of micafungin for resolution of CI at any time. For hydrocephalus due to CI and/or EVD, FOT will be determined by death due to CI, by need to add/switch to another AA or dose change of micafungin for resolution of CI at any time or by persistence of CI from confirmation of positive CSF culture.	Up to day 14
Number of Participants with Adverse Events (AEs)	An adverse event (AE) will be defined as any untoward medical occurrence in a participant administered a study drug or who will undergo study procedures which may not necessarily have a causal relationship with this treatment. This includes abnormal laboratory tests, vital signs, electrocardiogram data or physical examinations that are defined as AEs if the abnormality will induce clinical signs or symptoms, require active intervention, interruption or discontinuation of study drug or may be clinically significant in the investigator's opinion. The following standard with 3 grades will be used to measure the severity of AEs, including abnormal clinical laboratory values: ● Mild: No disruption of normal daily activities ● Moderate: Affected normal daily activities ● Severe: Inability to perform daily activities. A treatment-emergent adverse event (TEAE) will be defined as an AE observed after starting administration of the test drug/comparative drug.	From the first dose of study drug administration up 72 hours after the last dose, up to 17 days
Comparison of Capillary and Venous Plasma Concentrations of Micafungin	Micafungin concentrations will be determined from the PK blood samples collected via both capillary micro-method (draws from the heel) and venous methods.	Predose and after 1, 3, and 8 hours post-dose on one of treatment days from Day 3 to Day 10

Collaborators and Investigators

• Sponsor: Astellas Pharma Global Development, Inc.
• Collaborators: IRCCS, Ospedale Pediatrico Bambino Gesu

Publications and helpful links

General Publications

• Auriti C, Goffredo BM, Ronchetti MP, Piersigilli F, Cairoli S, Bersani I, Dotta A, Bagolan P, Pai MP. High-Dose Micafungin in Neonates and Young Infants with Invasive Candidiasis: Results of a Phase 2 Study. Antimicrob Agents Chemother. 2021 Mar 18;65(4):e02494-20. doi: 10.1128/AAC.02494-20. Print 2021 Mar 18.

Helpful Links

• Link to Results on the Astellas Clinical Study Results website

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 30, 2015
• Primary Completion (ACTUAL): April 10, 2018
• Study Completion (ACTUAL): April 10, 2018

Study Registration Dates

• First Submitted: January 9, 2018
• First Submitted That Met QC Criteria: January 29, 2018
• First Posted (ACTUAL): February 5, 2018

Study Record Updates

• Last Update Posted (ACTUAL): April 18, 2019
• Last Update Submitted That Met QC Criteria: April 15, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: micafungin; Mycamine; candida meningitis; candidiasis, systemic
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Infections; Bacterial Infections and Mycoses; Mycoses; Candidiasis; Meningitis; Anti-Infective Agents; Antifungal Agents; Micafungin
• Other Study ID Numbers: 9463-CL-6001; 2014-003087-20 (EUDRACT_NUMBER); 800_OPBG_2014 (OTHER: Ospedale Pediatrico Bambino Gesu Clinical & Research Center)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Access to anonymized individual participant level data will not be provided for this trial as it meets one or more of the exceptions described on www.clinicalstudydatarequest.com under "Sponsor Specific Details for Astellas."

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No