Study To Assess Pharmacokinetics, Safety & Efficacy of Anidulafungin When Treating Children With Invasive Candidiasis

A PROSPECTIVE, OPEN-LABEL STUDY TO ASSESS THE PHARMACOKINETICS, SAFETY & EFFICACY OF ANIDULAFUNGIN WHEN USED TO TREAT CHILDREN WITH INVASIVE CANDIDIASIS, INCLUDING CANDIDEMIA

Prospective, open label study to assess the pharmacokinetics, safety & efficacy of anidulafungin when used to treat children (aged 1 month - <18 years) with invasive candidiasis, including candidemia (ICC).

Study Overview

• Status: Completed
• Conditions: Candidemia
• Intervention / Treatment: Drug: Anidulafungin; Drug: Fluconazole

Detailed Description

Prospective, open label study to assess the pharmacokinetics, safety & efficacy of anidulafungin when used to treat children (aged 1 month - < 18 years) with invasive candidiasis, including candidemia (ICC). To participate in the study, at the time of enrollment subjects must (1) have either a confirmed diagnosis of ICC or mycological evidence highly suggestive of Candida sp or (2) in infants 1 month to < 2 years only, be at high risk of candidiasis. All subjects meeting screening criteria receive IV anidulafungin. Subjects will be stratified by age (1 month - < 2 years; 2 years - < 5 years; 5 years - < 18 years). Subjects may be switched to oral fluconazole, provided that the pre-specified criteria are met. Subjects with microbiologically confirmed ICC must have a minimum total treatment duration of 14 days. The maximum allowed treatment duration of anidulafungin is 35 days; the maximum total treatment duration for the study is 49 days. At selected centers, anidulafungin pharmacokinetics will be assessed in the first 6 subjects age 1 month - < 2 years to confirm the recommended dosage regimen. A population PK-PD analysis will be performed in all other enrolled subjects. Subjects will be followed for safety through 6 week FU visit. Efficacy for subjects with confirmed ICC will be assessed at EOIVT, EOT, 2-week FU and 6-week FU visits.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Sao Paulo, Brazil, 04023-062
    • Instituto de Oncologia Pediatrica - Grupo de Apoio ao Adolescente e a Crianca com Cancer
  • PR
    • Curitiba, PR, Brazil, 80250-060
      • Hospital Pequeno Principe
  • Paraná
    • Curitiba, Paraná, Brazil, 80060-900
      • Hospital de Clínicas da Universidade Federal do Paraná
  • SP
    • Sao Paulo, SP, Brazil, 01227-200
      • Hospital Infantil Sabara / Fundacao Jose Luiz Egydio Setubal
    • Sao Paulo, SP, Brazil, 01227-200
      • Instituto PENSI - Pesquisa e Ensino em Saúde Infantil
    • Sao Paulo, SP, Brazil, 04039-001
      • Instituto de Oncologia Pediatrica - Grupo de Apoio ao Adolescente e a Crianca com Cancer
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2R7
      • Stollery Children's Hospital - University of Alberta
• Greece
  • Athens, Greece, 11527
    • Aghia Sophia Childrens Hospital
  • Thessaloniki, Greece, 54642
    • Hippokration Hospital
• Italy
  • Province OF ROME
    • Roma, Province OF ROME, Italy, 00161
      • Università degli Studi di Roma La Sapienza
  • RM
    • Roma, RM, Italy, 00165
      • IRCCS Ospedale Pediatrico Bambino Gesù
    • Roma, RM, Italy, 00165
      • Universitario Ospedaliero IRCCS Ospedale Pediatrico Bambino Gesu
• Korea, Republic of
  • Seoul, Korea, Republic of, 120-752
    • Severance Hospital, Yonsei University Health System
  • Seoul, Korea, Republic of, 138-736
    • Asan Medical Center, Department of Pharmacy
  • Seoul
    • Songpa-gu, Seoul, Korea, Republic of, 138-736
      • Asan Medical Center
• Russian Federation
  • Moscow, Russian Federation, 115478
    • National Cancer Research Center RAMS n.a. N.N. Blokhin; Laboratory Microbiological Diagnostics
  • Moscow, Russian Federation, 117997
    • Fed. Scientific Center for Pediatric Hematology, Oncology and Immunology of Russian Healthcare Org.
• Spain
  • Barcelona, Spain, 08035
    • Hospital Vall d'Hebron
• Taiwan
  • Taichung, Taiwan, 404
    • China Medical University Hospital
  • Taoyuan County
    • Kwei Shan Town, Taoyuan County, Taiwan, 333
      • Chang Gung Children's Hospital
• United Kingdom
  • Nottingham, United Kingdom, NG7 2UH
    • Nottingham Children's Hospital
• United States
  • California
    • Long Beach, California, United States, 90806
      • Miller Children's Hospital Bickerstaff Pediatric Family Center
    • Los Angeles, California, United States, 90095-1752
      • University of California - Los Angeles
    • Los Angeles, California, United States, 90095
      • University of California - Los Angeles - Ronald Reagan Medical Center
    • Los Angeles, California, United States, 90095
      • University of California - Los Angeles - Ronald Reagan UCLA Medical Center
    • Oakland, California, United States, 94609
      • Children's Hospital & Research Center Oakland (CHRCO)
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County - Inpatient Pharmacy
  • Florida
    • Miami, Florida, United States, 33155
      • Miami Children's Hospital
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals of Cleveland Laboratory University Hospitals Case Medical Center
  • Tennessee
    • Memphis, Tennessee, United States, 38103
      • LeBonheur Children's Hospital
    • Memphis, Tennessee, United States, 38105
      • University of Tennessee Health Science Center
    • Memphis, Tennessee, United States, 38103
      • Le Bonheur Children's Hospital - 4th Floor
    • Memphis, Tennessee, United States, 38103
      • Le Bonheur Children's Hospital - 7th Floor lab
    • Memphis, Tennessee, United States, 38103
      • LeBonheur Children's Hospital- Central Laboratory
    • Memphis, Tennessee, United States, 38103
      • Pediatric Clinical Research Unit University of Tennessee Health Science Center
    • Memphis, Tennessee, United States, 38103
      • Pediatric Clinical Research Unit- 7th Floor Lab
    • Memphis, Tennessee, United States, 38103
      • Pharmacy-University of Tennessee Health Science Center
    • Memphis, Tennessee, United States, 38105
      • University of Tennessee Medical Group Pediatrics
    • Memphis, Tennessee, United States, 38163
      • University of Tennessee Health Science Center, Department of Ophthalmology
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Infectious Diseases Clinic
    • Fort Worth, Texas, United States, 76104
      • Infectious Diseases Clinic Cook Children's Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 17 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subject must be either (1) at high risk for candidiasis (1 month - < 2 years ONLY) or (2) have a definitive diagnosis of invasive candidiasis/candidemia (ICC) (All age groups)
• Male and female patients from 1 month to less than 18 years of age.

Exclusion Criteria:

• Any patients with allergy to the drug; and any pregnant female or lactating.
• Failed previous antifungal therapy or expected to live < 3 days.
• Patients with documented or suspected Candida meningitis.

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: Anidulafungin IV; All subjects meeting screening criteria will receive IV anidulafungin.

Drug: Anidulafungin; Day 1: loading dose of 3 mg/kg (not to exceed 200 mg) Day 2 onwards: maintain a dose of 1.5 mg/kg (not to exceed 100 mg). Minimum total treatment duration is 14 days. Minimum IV anidulafungin treatment duration is 10 days for subjects with microbiologically confirmed ICC and 5 days for subjects at risk of candidiasis; followed by oral fluconazole 6-12 mg/kg/day (not to exceed 800mg/day). Maximum treatment duration with anidulafungin is 35 days.; Other Names: Eraxis; Drug: Fluconazole; Subjects may be switched to oral fluconazole [6-12 mg/kg/day (not to exceed 800mg/day] provided they meet specified criteria. Maximum total treatment duration is 49 days.; Other Names: Diflucan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 6 weeks after end of treatment (EOT) (up to 91 days) that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs and non-SAEs. EOT visit defined as last day of study treatment (IV or oral).	Baseline up to 6 weeks after EOT (up to 91 days)
Number of Participants With Laboratory Abnormalities	Criteria for laboratory abnormalities: Hematology parameters: red blood cell count: <0.8*lower limit of normal (LLN); reticulocytes count (absolute or percent): <0.5*LLN or greater than (>) 1.5*upper limit of normal (ULN); Platelets: <0.5*LLN or >1.75*ULN; white blood cell count: <0.6*LLN or >1.5*ULN; neutrophils (absolute or percent): <0.8*LLN or >1.2*ULN; basophils (absolute or percent): >1.2*ULN; lymphocytes (absolute or percent): <0.8*LLN or >1.2*ULN; monocytes (absolute or percent): >1.2*ULN. Serum Chemistry parameters: sodium: <0.95*LLN or >1.05*ULN, potassium, chloride, bicarbonate, calcium: <0.9*LLN or >1.1*ULN; magnesium: >1.1*ULN or <0.9*LLN; BUN (blood urea nitrogen): >1.3* ULN, creatinine: >1.3*ULN; aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase : >3.0*ULN ; total bilirubin: >1.5*ULN; albumin: <0.8*LLN or >1.2*ULN and glucose: <0.6*LLN or >1.5*ULN.EOT visit defined as last day of study treatment (IV or oral).	Baseline up to 6 weeks after EOT (up to 91 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Global Response	Global response categorized: success, failure, indeterminate.Success:clinical response(CR) of cure(resolution of sign, symptoms attributed to Candida infection[CI]; no additional systemic/oral antifungal) or improvement (significant but incomplete resolution of signs symptoms of CI; no additional systemic antifungal) and microbiological eradication/presumed eradication(Baseline pathogen not isolated from original site culture/culture data not available for participant with successful outcome).Failure:CR of failure(no significant improvement in signs symptoms/ death due to CI)and/or microbiological failure(persistence/new infection at follow-up/relapse of infection at follow-up). Indeterminate:CR of indeterminate(evaluation not made or failure assessment)and/or microbiological response of indeterminate(Culture data not available for participant with clinical outcome of indeterminate) and neither response was failure.EOT visit:last day of study treatment (IV or oral).	End of intravenous treatment (EOIVT) (maximum of 35 days), EOT (maximum of 49 days), during 2 week follow-up after EOT (up to 63 days) and during 6 week follow-up after EOT (up to 91 days)
Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC24) of Anidulafungin for Pharmacokinetic (PK) Subgroup	Non-compartmental PK analysis was performed on individual plasma anidulafungin concentration-time data collected by serial sampling from participants in the PK sub-study. AUC24 was calculated based on the trapezoidal rule.	Day 2: Just prior to the start of infusion, 2 minutes before the end of infusion, 6, 12 and 24 hours after the start of infusion
Maximum Plasma Concentration (Cmax) of Anidulafungin for Pharmacokinetic (PK) Subgroup	Cmax was obtained directly from the observed concentration data on Day 2.	Day 2: Just prior to the start of infusion, 2 minutes before the end of infusion, 6, 12, and 24 hours after the start of infusion
Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC24) of Polysorbate 80 (PS 80) Following Infusion of Anidulafungin for PK Subgroup	Excipient PS 80 is a solubilizing agent contained in the IV formulation of anidulafungin. The lower limit of quantitation (LLOQ) for all the observations of PS 80 was 5.0 microgram per milliliter (mcg/mL). PK time points were assessed on Day 1, Day 3, Day 5, Day 7 and Day 9. Summarized data for all the time points was reported.	Day 1: 0 to 2 hours post dose; Day 3 and Day 9:pre-dose; Day 5: 0 to 3 hours post dose; Day 7: 6 to 12 hours and 24 hours delayed post-dose
Maximum Plasma Concentration (Cmax) of Polysorbate 80 (PS 80) Following Infusion of Anidulafungin for PK Subgroup	Excipient PS 80 is a solubilizing agent contained in the IV formulation of anidulafungin. The lower limit of quantitation (LLOQ) for all the observations of PS 80 was 5.0 mcg/ml. PK time points were assessed on at Day 1, Day 3, Day 5, Day 7 and Day 9. Summarized data for all the time points was reported.	Day 1: 0 to 2 hours post dose; Day 3 and Day 9:pre-dose; Day 5: 0 to 3 hours post dose; Day 7: 6 to 12 hours delayed post-dose
Estimated Area Under the Plasma Curve Over a 24-Hour Dosing Interval at Steady State (AUC0-24ss) of Anidulafungin	AUC24 values were calculated using the individual parameter estimates obtained from the final population PK model. PK time points were assessed on Days 1-3, Day 5, Day 7, and Day 9. Data for all time points were included in the model.	Sparse Sampling:Day 1:0-2 hr after end of infusion (EOI); Day3&9:pre-dose;Day 5:0-3hr post EOI; Day 7:6-12hr after EOI.For 1st 6 infants:< 2 years:Day 1:2 minutes before EOI; Day 2:pre infusion, 2 minutes before EOI, 6, 12,24 hours after start of infusion
Estimated Minimum Plasma Concentration (Cmin) of Anidulafungin	Cmin values were calculated using the individual parameter estimates obtained from the final population PK model. PK time points were assessed on Days 1-3, Day 5, Day 7, and Day 9. Data for all time points were included in the model.	Sparse Sampling:Day 1:0-2 hr after end of infusion (EOI); Day3&9:pre-dose;Day 5:0-3hr post EOI; Day 7:6-12hr after EOI.For 1st 6 infants:< 2 years:Day 1:2 minutes before EOI; Day 2:pre infusion, 2 minutes before EOI, 6, 12,24 hours after start of infusion
Number of Participants With Greater Than or Equal to 1 Hepatic Adverse Event Categorized on the Basis of Exposure to Anidulafungin (AUC0-24,ss)	The probability of having at least one hepatic adverse event was compared with AUC0-24,ss quantile. Individual parameter estimates from the final PK model were used for estimation of Anidulafungin exposures.	Baseline to End of intravenous treatment (EOIVT) (maximum of 35 days)
Number of Participants With Greater Than or Equal to 1 Gastro-Intestinal (GI) Adverse Event Categorized on the Basis of Exposure to Anidulafungin (AUC0-24,ss)	The probability of having at least one GI adverse event whilst on Anidulafungin treatment was compared with AUC0-24,ss quantile. Individual parameter estimates from the final PK model were used for estimation of Anidulafungin exposures.	Baseline to EOIVT (maximum of 35 days)
Percentage of Participants With Global Response Categorized on the Basis of Exposure to Anidulafungin (AUC0-24,ss)	The probabilities of a global response of success or failure were compared with AUC0-24,ss quantile. Individual parameter estimates from the final PK model were used for estimation of Anidulafungin exposures. For the analysis of this outcome measure, global response was categorized as: success or failure. Success defined as clinical response (CR) of cure (resolution of signs, symptoms attributed to Candida infection [CI]). Failure defined as CR of failure (no significant improvement in signs symptoms/ death due to CI) and/or microbiological failure (persistence/new infection at follow-up/relapse of infection at follow-up).	EOIVT (maximum of 35 days) and EOT (maximum of 49 days)
Percentage of Participants With Relapsed Response	Relapse was defined as any baseline Candida species isolated following eradication (documented or presumed); or culture data not available for a participant with a clinical response of failure after a previous response of success. Clinical response of failure was defined as no significant improvement in signs and symptoms, or death due to the Candida infection. Participants had received at least 3 doses of study medication to be classified as a failure. Clinical response of success was defined as resolution of sign and symptoms attributed to Candida infection occurred with no additional systemic or oral antifungal treatment required to complete the course of therapy. Eradication or presumed eradication: baseline pathogen not isolated from original site culture(s), or culture data are not available for a participant with successful clinical outcome. End of treatment visit defined as last day of study treatment (IV or oral).	During 2 week follow-up after EOT (up to 63 days) and during 6 week follow-up after EOT (up to 91 days)
Percentage of Participants With New Infection	New infection was defined as a participant presenting with clinical failure with the emergence of new Candida species at the original site of infection or at a distant site of infection. Clinical response of failure was defined as no significant improvement in signs and symptoms, or death due to the Candida infection occurred. Participants had received at least 3 doses of study medication to be classified as a failure. End of treatment visit defined as last day of study treatment (IV or oral).	During 2 week follow-up (up to 63 days) and 6 week follow-up (up to 91 days) after EOT
All-Cause Mortality - Number of Participants Who Died During Overall Study Treatment Period and Follow-Up Visits		Overall treatment period (up to 49 days); during 2 week follow-up after EOT (up to 63 days) and during 6 week follow-up after EOT (up to 91 days)

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Roilides E, Carlesse F, Tawadrous M, Leister-Tebbe H, Conte U, Raber S, Swanson R, Yan JL, Aram JA, Queiroz-Telles F; Anidulafungin A8851008 Pediatric Study Group. Safety, Efficacy and Pharmacokinetics of Anidulafungin in Patients 1 Month to <2 Years of Age With Invasive Candidiasis, Including Candidemia. Pediatr Infect Dis J. 2020 Apr;39(4):305-309. doi: 10.1097/INF.0000000000002568.
• Roilides E, Carlesse F, Leister-Tebbe H, Conte U, Yan JL, Liu P, Tawadrous M, Aram JA, Queiroz-Telles F; Anidulafungin A8851008 Pediatric Study Group. A Prospective, Open-label Study to Assess the Safety, Tolerability and Efficacy of Anidulafungin in the Treatment of Invasive Candidiasis in Children 2 to <18 Years of Age. Pediatr Infect Dis J. 2019 Mar;38(3):275-279. doi: 10.1097/INF.0000000000002237.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 1, 2009
• Primary Completion (ACTUAL): February 1, 2018
• Study Completion (ACTUAL): February 1, 2018

Study Registration Dates

• First Submitted: September 25, 2008
• First Submitted That Met QC Criteria: September 26, 2008
• First Posted (ESTIMATE): September 29, 2008

Study Record Updates

• Last Update Posted (ACTUAL): April 4, 2019
• Last Update Submitted That Met QC Criteria: March 19, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: pediatrics; candidemia; safety; invasive candidiasis; Anidulafungin
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Bacterial Infections and Mycoses; Sepsis; Mycoses; Invasive Fungal Infections; Fungemia; Candidiasis; Candidemia; Candidiasis, Invasive; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Anidulafungin; Fluconazole
• Other Study ID Numbers: A8851008; 2008-004150-32 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Drug and device information, study documents

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