Clinical trial NCT00391768: Oseltamivir Treatment for Children Less Than 24 Months of Age With Influenza
Official title: A Pharmacokinetic/Pharmacodynamic and Safety Evaluation of Oseltamivir (Tamiflu®) for the Treatment of Children Less Than 24 Months of Age With Confirmed Influenza Infection (CASG 114)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Influenza
Keywords: influenza, oseltamivir, Tamiflu®, antiviral, children, infants
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2006-10-24
Enrollment: 87
Sex: ALL
Maximum age (years): 23
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to learn how to treat influenza in children less than 2 years of age. Tamiflu®, the drug being studied, is approved for treatment of children 1 year of age and older with influenza. Researchers want to learn more about the activity of Tamiflu® in the body to determine a dose of that is safe, well-tolerated, and effective in young children with influenza. Children less than 24 months of age with confirmed influenza will receive Tamiflu® 2 times a day for 5 days. Older participants will be enrolled first and younger children will be enrolled after the safety data is reviewed for older participants. Study procedures include blood samples, swabs from inside the nose, and body and nervous system evaluations. Participants may be involved in study related procedures for up to 37 days.

Detailed description: Oseltamivir is approved for prophylaxis and treatment of children 1 year of age and older with influenza. Influenza treatments for children under the age of 1 year are needed because mortality from influenza is high among this age group, even when there are no underlying medical conditions. Oseltamivir is frequently used off-label in children less than 1 year of age, with no data supporting the doses being used. Given the risk of severe or fatal influenza infection in infants, the lack of repeat dose pharmacokinetic (PK) data in children less than 2, the need for treatments in this population of children, and the fact that oseltamivir is being used off-label in this population, the current study will systematically study the PK and safety of oseltamivir in children less than 2 years of age with confirmed influenza to determine the appropriate dose to be used in these age groups. This data will be critical to pediatricians caring for these potentially gravely ill infants. This study is a prospective, age-stratified PK/pharmacodynamic (PD) and safety evaluation of oseltamivir therapy in children less than 24 months of age with confirmed influenza infection. Participants will be stratified by age into the following enrollment scheme at study initiation: 12-23 months (Cohort I), 9-11 months (Cohort II), 6-8 months (Cohort III), 3-5 months (Cohort IV) and 0-2 months (Cohort V). At study onset, Cohort II and III will be enrolled simultaneously. Cohorts IV and V will be enrolled sequentially by decreasing age groups predicated upon the PK and safety data from the preceding cohort. In the event of a public health emergency, the Data Safety Monitoring Board (DSMB) or Food and Drug Administration (FDA) may authorize the following modifications to the proposed enrollment plan: the opening of younger age cohorts without the full dataset from the next higher age cohort, the re-opening of previously closed cohorts to obtain additional data and/or the over-enrollment of any of the 5 cohorts. The oldest cohort (Cohort I) may be enrolled at any time during the study. The primary study objective is to define the PK of oseltamivir and oseltamivir carboxylate in children with confirmed influenza less than 2 years of age. The oseltamivir dose initially evaluated in Cohort I was the approved dose of 30 mg twice a day (bid). However, the oseltamivir carboxylate area under the curve (AUC)12 values for 5 of the 9 subjects enrolled in Cohort I as of August 5, 2009, were below the lower range utilized for the other cohorts in the study, as was the GM AUC12 for Cohort I as a group \[(2589 nanograms per hour per milliliter (ngxh/mL)\]. As a consequence, the DSMB recommended on August 5, 2009, that the protocol be amended to utilize weight-based dosing of oseltamivir in subjects subsequently enrolled in Cohort I, and to employ the targeted AUC approach used for Cohorts II-V for this cohort as well. Based upon the PK data available as of that date, the initial weight-based dose to be evaluated for Cohort I is 3.5 mg/kg bid. A dose of oseltamivir 3 mg/kg/dose orally bid for 5 days (10 doses) will be administered to the first 9 subjects in each of Cohorts II-III. Additional subjects may be enrolled if the target AUC12 range is not achieved. The proposed dose for subjects enrolled in Cohorts IV and V will be 3 mg/kg/dose orally bid for 5 days (10 doses), although this dose may be adjusted prior to opening Cohort IV or V based on the dose required to achieve the target oseltamivir carboxylate AUC12 range in the previous cohort.

Eligibility criteria: Inclusion Criteria:

* Signed informed consent from parent(s) or legal guardian(s).
* Age:

Cohort I: 12 - 23 mo. Cohort II: 9 - 11 mo. Cohort III: 6 - 8 mo. Cohort IV: 3 - 5 mo. Cohort V: 0 - 2 mo.

* Confirmed laboratory diagnosis of influenza by viral culture or rapid influenza diagnostic test within 96 hours prior to study enrollment.
* Duration of influenza symptoms less than or equal to 96 hours.

Exclusion Criteria:

* Concomitant vomiting illness that would preclude ability to take drug.
* Immunocompromised subject (e.g., malignancy, congenital agammaglobulinemia, HIV).
* Documented renal impairment (e.g., polycystic renal disease, nephrectomy, renal transplantation, renal agenesis, dialysis requirement, renal failure, nephrotic syndrome at any time prior to enrollment, current receipt of diuretic therapy).
* Documented hepatic impairment (e.g., congenital hepatitis, biliary atresia, cholelithiasis).
* Gastrointestinal abnormality which might hinder absorption of an oral medication.
* Current receipt of inotropic drugs (e.g., epinephrine, norepinephrine, dopamine, dobutamine).
* History of seizures.
* Documented congenital malformations of the central nervous system defined at birth (e.g., hydranencephaly, prosencephaly, spina bifida).

Primary outcomes:
measure: Oseltamivir Carboxylate AUC12 (Area Under the Curve).
timeFrame: Day 3 of drug administration
Secondary outcomes:
measure: Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy.
timeFrame: Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 30 plus or minus 3 days.
measure: Number and Characteristics of Adverse Events (AEs) Described as Neurological Events.
timeFrame: Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 30 plus or minus 3 days.
measure: Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade
timeFrame: Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 30 plus or minus 3 days
measure: Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort Leading to Discontinuation of Study Medication
timeFrame: Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 5 plus or minus 1 day
measure: Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC)
timeFrame: Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 30 plus or minus 3 days
measure: Correlation of Clearance of Viral RNA by Culture With Pharmacokinetic Parameters by Cohort
timeFrame: Day to negative viral load for subjects positive at baseline
measure: Correlation of Clearance of Viral RNA by Polymerase Chain Reaction (PCR) to Pharmacokinetic Parameters by Cohort.
timeFrame: From date of enrollment until the date of first documented absence of viral load by culture, assessed up to 10 days after enrollment.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Little Rock
country: United States
facility: Arkansas Children's Hospital - Infectious Diseases
state: Arkansas
city: Long Beach
country: United States
facility: Miller Children's Hospital Long Beach - Bickerstaff Family Center
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital San Diego
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado - Infectious Disease
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center - Sheikh Zayed Campus - Infectious Disease
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida - Shands Children's Hospital
state: Florida
city: Tampa
country: United States
facility: University of South Florida - Tampa General Hospital - Pediatrics
state: Florida
city: Atlanta
country: United States
facility: Emory Children's Center - Pediatric Infectious Diseases
state: Georgia
city: Atlanta
country: United States
facility: Emory University School of Medicine - Emory Children's Center - Pediatric Infectious Diseases
state: Georgia
city: Shreveport
country: United States
facility: Louisiana State University Health Shreveport - Pediatrics
state: Louisiana
city: Jackson
country: United States
facility: University of Mississippi - Children's Infectious Diseases
state: Mississippi
city: Saint Louis
country: United States
facility: Washington University School of Medicine in St. Louis - Center for Clinical Studies
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center - Children's Hospital and Medical Center - Infectious Diseases
state: Nebraska
city: Manhasset
country: United States
facility: Cohen Children's Medical Center - Pediatric Infectious Diseases
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University Hospital - Pediatrics
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center - Infectious Diseases
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Medical Center - Pediatric Infectious Disease
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia - The Center for Pediatric Clinical Effectiveness
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC - General Academic Pediatric
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital - Pediatrics
state: Rhode Island
city: Nashville
country: United States
facility: Vanderbilt University - Pediatric - Infectious Diseases
state: Tennessee
city: Dallas
country: United States
facility: Parkland Memorial Hospital
state: Texas
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Infectious Disease Services
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah - Pediatric Pharmacology Program
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital - Infectious Diseases
state: Washington
city: Edmonton
country: Canada
facility: University of Alberta Hospital - Pediatrics
state: Alberta
city: Toronto
country: Canada
facility: The Hospital for Sick Children - Infectious Diseases
state: Ontario
city: Quebec
country: Canada
facility: Centre Hospitalier de l'Universite Laval/ CHUQ
Study officials:
References:
citation: Kimberlin DW, Acosta EP, Prichard MN, Sanchez PJ, Ampofo K, Lang D, Ashouri N, Vanchiere JA, Abzug MJ, Abughali N, Caserta MT, Englund JA, Sood SK, Spigarelli MG, Bradley JS, Lew J, Michaels MG, Wan W, Cloud G, Jester P, Lakeman FD, Whitley RJ; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Oseltamivir pharmacokinetics, dosing, and resistance among children aged <2 years with influenza. J Infect Dis. 2013 Mar 1;207(5):709-20. doi: 10.1093/infdis/jis765. Epub 2012 Dec 10.