Oseltamivir Treatment for Children Less Than 24 Months of Age With Influenza

NCT ID: NCT00391768

Last Updated: 2013-05-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 87 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-01-31
• Study Completion Date: 2010-04-30

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.

Conditions

Influenza

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

oseltamivir (Tamiflu®)

Group Type: EXPERIMENTAL

oseltamivir (Tamiflu®)

Intervention Type: DRUG

Oseltamivir is supplied as a white powder blend for constitution to a suspension. It is supplied in 100 ml amber glass bottles with 30 grams of powder for oral suspension, a plastic adapter, a plastic oral dispenser and a plastic measuring cup. Initially subjects in Cohort I received oseltamivir 30 mg orally twice daily for 5 days. The DSMB recommended on 05-Aug-2009 that weight based dosing of oseltamivir for subjects subsequently enrolled in Cohort I. Based on pharmacokinetic data available as of that date, the initial weight-based dose to be evaluated for Cohort I is 3.5 mg/kg twice a day. Cohort II and Cohort III will receive oseltamivir at 3.0 mg/kg/dose orally twice daily for 5 days. Cohorts IV and V will receive 3.0 mg/kg/dose orally twice daily for 5 days, this dose may be adjusted.

Interventions

oseltamivir (Tamiflu®)

Oseltamivir is supplied as a white powder blend for constitution to a suspension. It is supplied in 100 ml amber glass bottles with 30 grams of powder for oral suspension, a plastic adapter, a plastic oral dispenser and a plastic measuring cup. Initially subjects in Cohort I received oseltamivir 30 mg orally twice daily for 5 days. The DSMB recommended on 05-Aug-2009 that weight based dosing of oseltamivir for subjects subsequently enrolled in Cohort I. Based on pharmacokinetic data available as of that date, the initial weight-based dose to be evaluated for Cohort I is 3.5 mg/kg twice a day. Cohort II and Cohort III will receive oseltamivir at 3.0 mg/kg/dose orally twice daily for 5 days. Cohorts IV and V will receive 3.0 mg/kg/dose orally twice daily for 5 days, this dose may be adjusted.

Intervention Type: DRUG

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).

• Maximum Eligible Age: 23 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Arkansas Children's Hospital - Infectious Diseases

Little Rock, Arkansas, United States

Miller Children's Hospital Long Beach - Bickerstaff Family Center

Long Beach, California, United States

Children's Hospital of Orange County

Orange, California, United States

Rady Children's Hospital San Diego

San Diego, California, United States

Children's Hospital Colorado - Infectious Disease

Aurora, Colorado, United States

Children's National Medical Center - Sheikh Zayed Campus - Infectious Disease

Washington D.C., District of Columbia, United States

University of Florida - Shands Children's Hospital

Gainesville, Florida, United States

University of South Florida - Tampa General Hospital - Pediatrics

Tampa, Florida, United States

Emory Children's Center - Pediatric Infectious Diseases

Atlanta, Georgia, United States

Emory University School of Medicine - Emory Children's Center - Pediatric Infectious Diseases

Atlanta, Georgia, United States

Louisiana State University Health Shreveport - Pediatrics

Shreveport, Louisiana, United States

University of Mississippi - Children's Infectious Diseases

Jackson, Mississippi, United States

Washington University School of Medicine in St. Louis - Center for Clinical Studies

St Louis, Missouri, United States

University of Nebraska Medical Center - Children's Hospital and Medical Center - Infectious Diseases

Omaha, Nebraska, United States

Cohen Children's Medical Center - Pediatric Infectious Diseases

Manhasset, New York, United States

University of Rochester

Rochester, New York, United States

SUNY Upstate Medical University Hospital - Pediatrics

Syracuse, New York, United States

Cincinnati Children's Hospital Medical Center - Infectious Diseases

Cincinnati, Ohio, United States

MetroHealth Medical Center - Pediatric Infectious Disease

Cleveland, Ohio, United States

Children's Hospital of Philadelphia - The Center for Pediatric Clinical Effectiveness

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh of UPMC - General Academic Pediatric

Pittsburgh, Pennsylvania, United States

Rhode Island Hospital - Pediatrics

Providence, Rhode Island, United States

Vanderbilt University - Pediatric - Infectious Diseases

Nashville, Tennessee, United States

Parkland Memorial Hospital

Dallas, Texas, United States

The University of Texas Southwestern Medical Center

Dallas, Texas, United States

Cook Children's Infectious Disease Services

Fort Worth, Texas, United States

University of Utah - Pediatric Pharmacology Program

Salt Lake City, Utah, United States

Seattle Children's Hospital - Infectious Diseases

Seattle, Washington, United States

University of Alberta Hospital - Pediatrics

Edmonton, Alberta, Canada

The Hospital for Sick Children - Infectious Diseases

Toronto, Ontario, Canada

Centre Hospitalier de l'Universite Laval/ CHUQ

Québec, Quebec, Canada

Countries

United States; Canada

References

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.

Reference Type: RESULT

PMID: 23230059 (View on PubMed)

Other Identifiers

N01AI30025C

Identifier Type: -

Identifier Source: secondary_id

Roche WP-20749; CASG 114

Identifier Type: -

Identifier Source: secondary_id

N01AI30025

Identifier Type: NIH

Identifier Source: secondary_id

View Link

06-0059

Identifier Type: -

Identifier Source: org_study_id