Study To Assess Pharmacokinetics, Safety & Efficacy of Anidulafungin When Treating Children With Invasive Candidiasis
- Registration Number
- NCT00761267
- Lead Sponsor
- Pfizer
- Brief Summary
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).
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 70
- 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.
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Anidulafungin IV Fluconazole All subjects meeting screening criteria will receive IV anidulafungin. Anidulafungin IV Anidulafungin All subjects meeting screening criteria will receive IV anidulafungin.
- Primary Outcome Measures
Name Time Method Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Baseline up to 6 weeks after EOT (up to 91 days) 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).
Number of Participants With Laboratory Abnormalities Baseline up to 6 weeks after EOT (up to 91 days) 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).
- Secondary Outcome Measures
Name Time Method 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 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 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.
Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC24) of Anidulafungin for Pharmacokinetic (PK) Subgroup 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 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.
Estimated Minimum Plasma Concentration (Cmin) of Anidulafungin 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 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.
Number of Participants With Global Response 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) 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).
Maximum Plasma Concentration (Cmax) of Polysorbate 80 (PS 80) Following Infusion of Anidulafungin for PK Subgroup 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 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.
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) Baseline to EOIVT (maximum of 35 days) 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.
Maximum Plasma Concentration (Cmax) of Anidulafungin for Pharmacokinetic (PK) Subgroup 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 Cmax was obtained directly from the observed concentration data on Day 2.
Number of Participants With Greater Than or Equal to 1 Hepatic Adverse Event Categorized on the Basis of Exposure to Anidulafungin (AUC0-24,ss) Baseline to End of intravenous treatment (EOIVT) (maximum of 35 days) 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.
Percentage of Participants With Global Response Categorized on the Basis of Exposure to Anidulafungin (AUC0-24,ss) EOIVT (maximum of 35 days) and EOT (maximum of 49 days) 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).
Estimated Area Under the Plasma Curve Over a 24-Hour Dosing Interval at Steady State (AUC0-24ss) of Anidulafungin 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 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.
Percentage of Participants With New Infection During 2 week follow-up (up to 63 days) and 6 week follow-up (up to 91 days) after EOT 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).
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) Percentage of Participants With Relapsed Response During 2 week follow-up after EOT (up to 63 days) and during 6 week follow-up after EOT (up to 91 days) 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).
Trial Locations
- Locations (44)
Hospital Pequeno Principe
🇧🇷Curitiba, PR, Brazil
Asan Medical Center
🇰🇷Songpa-gu, Seoul, Korea, Republic of
University of California - Los Angeles - Ronald Reagan UCLA Medical Center
🇺🇸Los Angeles, California, United States
Infectious Diseases Clinic Cook Children's Medical Center
🇺🇸Fort Worth, Texas, United States
Nottingham Children's Hospital
🇬🇧Nottingham, United Kingdom
Cook Children's Medical Center
🇺🇸Fort Worth, Texas, United States
Instituto PENSI - Pesquisa e Ensino em Saúde Infantil
🇧🇷Sao Paulo, SP, Brazil
Stollery Children's Hospital - University of Alberta
🇨🇦Edmonton, Alberta, Canada
Hospital Vall D'Hebron
🇪🇸Barcelona, Spain
Aghia Sophia Childrens Hospital
🇬🇷Athens, Greece
Children's Hospital of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
IRCCS Ospedale Pediatrico Bambino Gesu
🇮🇹Roma, RM, Italy
Severance Hospital, Yonsei University Health System
🇰🇷Seoul, Korea, Republic of
Fed. Scientific Center for Pediatric Hematology, Oncology and Immunology of Russian Healthcare Org.
🇷🇺Moscow, Russian Federation
Asan Medical Center, Department of Pharmacy
🇰🇷Seoul, Korea, Republic of
Universita degli Studi di Roma La Sapienza
🇮🇹Roma, Province OF ROME, Italy
Universitario Ospedaliero IRCCS Ospedale Pediatrico Bambino Gesu
🇮🇹Roma, RM, Italy
University of California - Los Angeles - Ronald Reagan Medical Center
🇺🇸Los Angeles, California, United States
Miller Children's Hospital Bickerstaff Pediatric Family Center
🇺🇸Long Beach, California, United States
University of California - Los Angeles
🇺🇸Los Angeles, California, United States
Children's Hospital & Research Center Oakland (CHRCO)
🇺🇸Oakland, California, United States
Children's Hospital of Orange County - Inpatient Pharmacy
🇺🇸Orange, California, United States
Le Bonheur Children's Hospital - 4th Floor
🇺🇸Memphis, Tennessee, United States
Le Bonheur Children's Hospital - 7th Floor lab
🇺🇸Memphis, Tennessee, United States
LeBonheur Children's Hospital- Central Laboratory
🇺🇸Memphis, Tennessee, United States
Cook Children's Infectious Diseases Clinic
🇺🇸Fort Worth, Texas, United States
Pediatric Clinical Research Unit University of Tennessee Health Science Center
🇺🇸Memphis, Tennessee, United States
Children's Hospital of Orange County
🇺🇸Orange, California, United States
China Medical University Hospital
🇨🇳Taichung, Taiwan
Pharmacy-University of Tennessee Health Science Center
🇺🇸Memphis, Tennessee, United States
Hippokration Hospital
🇬🇷Thessaloniki, Greece
LeBonheur Children's Hospital
🇺🇸Memphis, Tennessee, United States
Chang Gung Children's Hospital
🇨🇳Kwei Shan Town, Taoyuan County, Taiwan
Pediatric Clinical Research Unit- 7th Floor Lab
🇺🇸Memphis, Tennessee, United States
University of Tennessee Health Science Center
🇺🇸Memphis, Tennessee, United States
National Cancer Research Center RAMS n.a. N.N. Blokhin; Laboratory Microbiological Diagnostics
🇷🇺Moscow, Russian Federation
Hospital de Clinicas da Universidade Federal do Parana
🇧🇷Curitiba, Paraná, Brazil
Hospital Infantil Sabara / Fundacao Jose Luiz Egydio Setubal
🇧🇷Sao Paulo, SP, Brazil
Instituto de Oncologia Pediatrica - Grupo de Apoio ao Adolescente e a Crianca com Cancer
🇧🇷Sao Paulo, Brazil
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
University Hospitals of Cleveland Laboratory University Hospitals Case Medical Center
🇺🇸Cleveland, Ohio, United States
Miami Children's Hospital
🇺🇸Miami, Florida, United States
University of Tennessee Medical Group Pediatrics
🇺🇸Memphis, Tennessee, United States
University of Tennessee Health Science Center, Department of Ophthalmology
🇺🇸Memphis, Tennessee, United States