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

Candidemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00761267
• Other study ID #: A8851008
• Secondary ID: 2008-004150-32
• Status: Completed
• Phase: Phase 3
• Start date: February 2009
• Est. completion date: February 2018

Study information

• Verified date: March 2019
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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 information / eligibility

• Status: Completed
• Enrollment: 70
• Est. completion date: February 2018
• Est. primary completion date: February 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Month to 17 Years

Eligibility

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.

Related Conditions & MeSH terms

• Candidemia
• Candidiasis
• Candidiasis, Invasive

Intervention

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.
• 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.

Locations

Country	Name	City	State
Brazil	Hospital de Clinicas da Universidade Federal do Parana	Curitiba	Paraná
Brazil	Hospital Pequeno Principe	Curitiba	PR
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	SP
Brazil	Instituto de Oncologia Pediatrica - Grupo de Apoio ao Adolescente e a Crianca com Cancer	Sao Paulo
Brazil	Instituto PENSI - Pesquisa e Ensino em Saúde Infantil	Sao Paulo	SP
Canada	Stollery Children's Hospital - University of Alberta	Edmonton	Alberta
Greece	Aghia Sophia Childrens Hospital	Athens
Greece	Hippokration Hospital	Thessaloniki
Italy	IRCCS Ospedale Pediatrico Bambino Gesu	Roma	RM
Italy	Universita degli Studi di Roma La Sapienza	Roma	Province OF ROME
Italy	Universitario Ospedaliero IRCCS Ospedale Pediatrico Bambino Gesu	Roma	RM
Korea, Republic of	Asan Medical Center, Department of Pharmacy	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Korea, Republic of	Asan Medical Center	Songpa-gu	Seoul
Russian Federation	Fed. Scientific Center for Pediatric Hematology, Oncology and Immunology of Russian Healthcare Org.	Moscow
Russian Federation	National Cancer Research Center RAMS n.a. N.N. Blokhin; Laboratory Microbiological Diagnostics	Moscow
Spain	Hospital Vall D'Hebron	Barcelona
Taiwan	Chang Gung Children's Hospital	Kwei Shan Town	Taoyuan County
Taiwan	China Medical University Hospital	Taichung
United Kingdom	Nottingham Children's Hospital	Nottingham
United States	University Hospitals of Cleveland Laboratory University Hospitals Case Medical Center	Cleveland	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	Cook Children's Infectious Diseases Clinic	Fort Worth	Texas
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	Infectious Diseases Clinic Cook Children's Medical Center	Fort Worth	Texas
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	University of California - Los Angeles - Ronald Reagan Medical Center	Los Angeles	California
United States	University of California - Los Angeles - Ronald Reagan UCLA Medical Center	Los Angeles	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	Memphis	Tennessee
United States	LeBonheur Children's Hospital- Central Laboratory	Memphis	Tennessee
United States	Pediatric Clinical Research Unit University of Tennessee Health Science Center	Memphis	Tennessee
United States	Pediatric Clinical Research Unit- 7th Floor Lab	Memphis	Tennessee
United States	Pharmacy-University of Tennessee Health Science Center	Memphis	Tennessee
United States	University of Tennessee Health Science Center	Memphis	Tennessee
United States	University of Tennessee Health Science Center, Department of Ophthalmology	Memphis	Tennessee
United States	University of Tennessee Medical Group Pediatrics	Memphis	Tennessee
United States	Miami Children's Hospital	Miami	Florida
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	Children's Hospital & Research Center Oakland (CHRCO)	Oakland	California
United States	Children's Hospital of Orange County	Orange	California
United States	Children's Hospital of Orange County - Inpatient Pharmacy	Orange	California

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Countries where clinical trial is conducted

United States,  Brazil,  Canada,  Greece,  Italy,  Korea, Republic of,  Russian Federation,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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)

External Links

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