Study to Compare the Efficacy and Safety of Micafungin Versus Conventional Amphotericin B for the Treatment of Neonatal Candidiasis (MAGIC-2)

A Phase 3, Randomized, Double-Blind, Multi-Center Study to Compare the Efficacy and Safety of Micafungin Versus Amphotericin B Deoxycholate for the Treatment of Neonatal Candidiasis

The study will evaluate how effective and how safe the drug micafungin is when compared to the drug amphotericin B deoxycholate in treating neonates and young infants with certain fungal infections.

Study Overview

• Status: Terminated
• Conditions: Candidiasis
• Intervention / Treatment: Drug: micafungin; Drug: amphotericin B deoxycholate

Detailed Description

Neonates and young infants will be stratified by estimated gestational age and by world region

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30150-221
      • Irmandade da Santa Casa de Misericórdia de Belo Horizonte
  • Sao Paulo
    • São José do Rio Preto, Sao Paulo, Brazil, 15090-000
      • Hospital de Base da Faculdade de Medicina
• Bulgaria
  • Sofia, Bulgaria, 1606
    • Spec Hospital for Active Treatment of Children Diseases
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster Children's Hospital
• Colombia
  • Antioque
    • Medellin, Antioque, Colombia, 574
      • Hospital Pablo Tobon Uribe
• Greece
  • Patras, Greece, 26504
    • University Hospital of Patras
• Hungary
  • Budapest, Hungary, 8200
    • Semmelweis Egyetem
• Israel
  • Jerusalem, Israel, 91120
    • Hadassah University Hospital Ein Kerem
• Philippines
  • Manila, Philippines
    • Philippine General Hospital
• Romania
  • Cluj-Napoca, Romania, 400006
    • Emergency County Clinical Hospital
• Turkey
  • Adana, Turkey, 1330
    • Cukurova University Medical Faculty
• Ukraine
  • Odesa, Ukraine, 65031
    • Municipal Institution "Odesa Regional Children's Hospital"
• United States
  • California
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • UMDNJ/Robert Wood Johnson Medical School
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
    • Raleigh, North Carolina, United States, 27610
      • WakeMed Health and Hospitals
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 days to 3 months (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Infant greater than 48 hours of life after birth up to day of life 120 at the time of culture acquisition
• Diagnosis of proven invasive candidiasis within 4 days prior to study start
• Subject's parent or legal guardian agrees not to allow subject to participate in another study with another investigational drug while on treatment.

Exclusion Criteria:

• Infant with any history of a hypersensitivity or severe vasomotor reaction to any echinocandin or systemic amphotericin B product
• Infant who has received more than 48 hours of systemic antifungal therapy prior to the first dose of study drug
• Infant who has a breakthrough systemic fungal infection while receiving amphotericin B product or an echinocandin as prophylaxis
• Infant who has failed prior systemic antifungal therapy for this episode of invasive candidiasis
• Infant who is co-infected with a non-Candida fungal organism
• Infant whose positive yeast cultures are solely from an indwelling bladder catheter (unless obtained at the time the indwelling catheter was placed) or sputum.
• Infant previously enrolled in this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Micafungin; Infants received micafungin at a dose of 10 mg/kg per day by intravenous infusion for a minimum of 21 days to a maximum of 28 days for infants without end-organ dissemination or for a maximum of 42 days for infants with end-organ dissemination.	Drug: micafungin; Administered by intravenous infusion; Other Names: Mycamine; FK463
ACTIVE_COMPARATOR: Amphotericin B deoxycholate; Infants received amphotericin B deoxycholate (CAB) at a dose of 1.0 mg/kg per day by intravenous infusion for a minimum of 21 days to a maximum of 28 days for infants without end-organ dissemination or for a maximum of 42 days for infants with end-organ dissemination.	Drug: amphotericin B deoxycholate; Administered by intravenous infusion; Other Names: Fungizone; Conventional amphotericin B (CAB); Amphotericin B for injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fungal-free Survival	Fungal-free survival was assessed by an independent data review panel (DRP). Fungal-free survival is defined as the percentage of participants alive at one week following the last dose of study drug with a mycological response of eradication and no requirement for alternative systemic antifungal therapy for continued treatment. Eradication was defined as culture or histologically documented absence of the infecting Candida species from all positive normally sterile sites during therapy, documented by 2 negative samples, drawn at least 24 hours apart, or for Candida meningitis and/or candiduria, 1 negative culture.	One week after the last dose of study drug (maximum of 49 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Mycological Clearance of Invasive Candidiasis	Time to mycological clearance of invasive candidiasis is defined as the time from first dose to the day of mycological eradication for baseline invasive candidiasis infection. Eradication was defined as a culture or histologically documented absence of the infecting Candida species from all positive normally sterile sites during therapy, documented by 2 negative samples, drawn at least 24 hours apart, or for for Candida meningitis and/or candiduria, 1 negative culture. Infants without eradication during the treatment period and who survived were censored at one day after the end of treatment. Infants without eradication who died before completing the treatment period or were lost to follow-up during the treatment were censored at their death or last contact day.	From first dose up to 30 days after the last dose of study drug (maximum of 72 days)
Fungal-free Survival at End of Study Drug Therapy in Infants With End-organ Dissemination	Fungal-free survival was assessed by an independent data review panel (DRP). Fungal-free survival is defined as the percentage of participants alive at the end of study drug therapy with a mycological response of eradication based upon the DRP assessment and no requirement for alternative systemic antifungal therapy for continued treatment.	The end of study drug therapy; maximum of 42 days
Fungal-free Survival One Week After Last Dose of Study Drug in Infants With End-organ Dissemination	Fungal-free survival was assessed by an independent data review panel (DRP). Fungal-free survival is defined as the percentage of participants alive one week after last dose of study drug with a mycological response of eradication based upon the DRP assessment and no requirement for alternative systemic antifungal therapy for continued treatment.	One week after the last dose of study drug (maximum of 49 days)
Percentage of Participants With Emergent Fungal Infections	An emergent fungal infection is defined as; An invasive fungal infection which is detected at any time during the study that is a non-Candida organism, or; An invasive fungal infection which is detected during the treatment or post-treatment period with a Candida species identified other than those detected at Baseline. If this occurred within 96 hours of the first dose of study drug, the infection was considered part of the final diagnosis of enrolling infection and not an emergent infection.	Up to 30 days after the last dose of study drug (maximum of 72 days)
Percentage of Participants With Recurrent Fungal Infections	A recurrent infection is defined as a systemic fungal infection in an infant with eradication at the end of study drug therapy, who developed positive blood cultures or a mycologically confirmed deep-seated Candida infection, with the same species as the enrolling infection.	Up to 30 days after the last dose of study drug (maximum of 72 days)
Time to Positive Clinical Response	Time to a positive clinical response is defined as the time from the first dose to the day during the treatment period that a positive clinical response (defined as a complete response or partial response) is observed for the first time, assessed by the Investigator. Complete Response is defined as the resolution of all attributable signs related to fungal infection, if present at baseline and Partial Response is defined as improvement in attributable signs related to the fungal infection, if present at baseline. Infants without positive responses and who survived were censored at one day post the end of treatment. Infants without positive responses who died before completing the treatment period, or were lost to follow-up during the treatment were censored at their death or last contact day.	From first dose up to 30 days after the last dose of study drug (maximum of 72 days)
Clinical Response at the End of Study Drug Therapy	Clinical response assessments were based on the following definitions and assessed by the DRP: Complete Response: Resolution of all attributable signs related to fungal infection, if present at baseline.; Partial Response: Improvement in attributable signs related to the fungal infection, if present at baseline.; Stabilization: Minor improvement or no change in attributable signs related to the fungal infection, if present at baseline, and infant continued on therapy without deterioration.; Progression: Deterioration in attributable signs related to the fungal infection, if present at baseline; or if death occurred presumably related to a fungal infection.	Baseline and end of study drug therapy; maximum of 42 days
Clinical Response One Week After Last Dose of Study Drug	Clinical response assessments were based on the following definitions and assessed by the DRP: Complete Response: Resolution of all attributable signs related to fungal infection, if present at baseline.; Partial Response: Improvement in attributable signs related to the fungal infection, if present at baseline.; Stabilization: Minor improvement or no change in attributable signs related to the fungal infection, if present at baseline, and infant continued on therapy without deterioration.; Progression: Deterioration in attributable signs related to the fungal infection, if present at baseline; or if death occurred presumably related to a fungal infection.	Baseline and one week after the last dose of study drug (maximum of 49 days)
Mycological Response at End of Study Drug Therapy	Mycological response assessments were based on the following definitions and assessed by the DRP: Eradication: Culture or histologically documented absence of the infecting Candida species from all positive normally sterile sites during therapy, documented by 2 negative samples, drawn at least 24 h apart; for Candida meningitis and/or candiduria, 1 negative culture.; Persistence: Continued isolation or histological documentation from a normally sterile site.	End of study drug therapy; maximum of 42 days
Mycological Response One Week After Last Dose of Study Drug	Mycological response assessments were based on the following definitions and assessed by the DRP: Eradication: Culture or histologically documented absence of the infecting Candida species from all positive normally sterile sites during therapy, documented by 2 negative samples, drawn at least 24 h apart; for Candida meningitis and/or candiduria, 1 negative culture.; Persistence: Continued isolation or histological documentation from a normally sterile site.	One week after the last dose of study drug (maximum of 49 days)
Follow-up Status for Infants With End-organ Assessments	End-organ dissemination was assessed through abdominal ultrasound and/or computed tomography (CT), echocardiogram, head imaging and retinal exam. Each specific finding, documented by 1 of these techniques, was evaluated as follows: Improvement: Improvement in size, number or density of identified lesions. Complete response was not expected but may have been documented.; Stabilization: Minor improvement or no change in size, number or density of identified lesions.; Worsening: Increase in size or number of identified lesions.	Baseline and 30 days after the last dose of study drug (maximum of 72 days)
Plasma Micafungin Concentration		15 minutes post intravenous infusion (IV), 4-8 hours post IV and 15-24 hours post IV

Collaborators and Investigators

• Sponsor: Astellas Pharma Global Development, Inc.

Publications and helpful links

General Publications

• Benjamin DK Jr, Kaufman DA, Hope WW, Smith PB, Arrieta A, Manzoni P, Kovanda LL, Lademacher C, Isaacson B, Jednachowski D, Wu C, Kaibara A, Walsh TJ. 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. Erratum In: Pediatr Infect Dis J. 2018 Nov;37(11):1198.

Helpful Links

• Link to results on Astellas Clinical Study Results Web site

Study record dates

Study Major Dates

• Study Start: February 1, 2013
• Primary Completion (ACTUAL): December 1, 2014
• Study Completion (ACTUAL): December 1, 2014

Study Registration Dates

• First Submitted: December 27, 2008
• First Submitted That Met QC Criteria: December 27, 2008
• First Posted (ESTIMATE): December 30, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): November 4, 2015
• Last Update Submitted That Met QC Criteria: October 12, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: Micafungin; candidiasis; candidemia; candida; Neonate; Mycamine; amphotericin B deoxycholate
• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Mycoses; Candidiasis; Anti-Infective Agents; Gastrointestinal Agents; Anti-Bacterial Agents; Antifungal Agents; Antiprotozoal Agents; Antiparasitic Agents; Amebicides; Cholagogues and Choleretics; Micafungin; Deoxycholic Acid; Amphotericin B; Liposomal amphotericin B; Amphotericin B, deoxycholate drug combination
• Other Study ID Numbers: 9463-CL-2303; 2012-000780-24 (EUDRACT_NUMBER)