Study to Compare the Efficacy and Safety of Micafungin Versus Conventional Amphotericin B for the Treatment of Neonatal Candidiasis

Study Overview
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Brief Summary
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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.

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

Official Title
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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

Conditions
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Candidiasis

Intervention / Treatment
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* Drug: micafungin
* Drug: amphotericin B deoxycholate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 48 Hours
Maximum Age: 120 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Micafungin<br>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<br>* Administered by intravenous infusion<br>* Other names: FK463;|
| Active Comparator: Amphotericin B deoxycholate<br>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<br>* Administered by intravenous infusion<br>* Other names: Amphotericin B for injection;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neonate, candidiasis, candida, candidemia, Micafungin, Mycamine, amphotericin B deoxycholate