A Pharmacokinetic/Pharmacodynamic Study of Oseltamivir in Immunocompromised Children With Confirmed Influenza Infection

An Open-Label, Randomized, Adaptive, Two-Arm, Multicenter Trial to Evaluate Pharmacokinetics And Pharmacodynamics of Two Doses of Oseltamivir (Tamiflu®) in The Treatment Of Influenza in Immunocompromised Children Less Than 13 Years Of Age, With Confirmed Influenza Infection

This open-label, randomized, adaptive, 2-arm, multicenter study will evaluate the pharmacokinetics and pharmacodynamics of oseltamivir (Tamiflu) in immunocompromised children, less than (<) 13 years of age, with confirmed influenza infection. Participants will be randomized to receive either the standard dose or triple dose of oseltamivir orally daily for a minimum of 5 days and up to 20 days. Infants <1 year of age will be randomized to the standard dose arm only.

Study Overview

• Status: Completed
• Conditions: Influenza
• Intervention / Treatment: Drug: Oseltamivir

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Brussel, Belgium, 1090
    • UZ Brussel
  • Bruxelles, Belgium, 1200
    • Cliniques Universitaires St-Luc
  • Leuven, Belgium, 3000
    • UZ Leuven Gasthuisberg
• Brazil
  • PR
    • Curitiba, PR, Brazil, 81520-060
      • Hospital Erasto Gaertner
  • RS
    • Porto Alegre, RS, Brazil, 90610-000
      • Hospital São Lucas da PUCRS
  • SP
    • Sao Paulo, SP, Brazil, 04023-062
      • Graacc-Grupo de Apoio ao adolescente e a crianca com cancer
    • São Paulo, SP, Brazil, 08270-070
      • Casa de Saude Santa Marcelina
• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L1
      • Children's Hospital of Eastern Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital For Sick Children; Infectious Disease Dept
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • McGill University; Montreal Children's Hospital; Oncology
• Chile
  • Viña del Mar, Chile, 2520000
    • Hospital Dr. Gustavo Fricke
• Colombia
  • Cali, Colombia
    • Centro Medico Imbanaco
  • Cali, Colombia
    • Fundacion Clinica Valle de Lili, Department Rheumatology
• Finland
  • Turku, Finland, 20520
    • Turun Yliopistollinen Keskussairaala
• Germany
  • Berlin, Germany, 13353
    • Charité - Universitätsmedizin Berlin;Klinik für Allgemeine Pädiatrie
  • Frankfurt, Germany, 60590
    • Universitatsklinikum Frankfurt
  • München, Germany, 80337
    • Dr. von Haunersches Kinderspital
  • Münster, Germany, 48149
    • Universitatsklinikum Munster
  • Tübingen, Germany, 72076
    • Universitätsklinikum Tübingen UNI-Klinik für Kinder- und Jugendmedizin
• Greece
  • Athens, Greece, 115 27
    • Childrens Regional Hospital Aglaia Kyriakou
  • Athens, Greece, 11527
    • Aghia Sophia Children's Hospital; Pediatric Rheumatology Unit; 1st Department of Pediatrics
• Israel
  • Haifa, Israel, 31096
    • Rambam Medical Center
  • Jerusalem, Israel, 9112001
    • Hadassah University Hospital - Ein Kerem
  • Petach Tikva, Israel, 49100
    • Schneider Children's Medical Center of Israel; Pediatrics Department
  • Ramat-Gan, Israel, 52621
    • The Chaim Sheba Medical Center; Multiple Sclerosis Center
  • Tel Aviv, Israel, 64239
    • The Dana Children's Hospital
• Italy
  • Lazio
    • Roma, Lazio, Italy, 00165
      • Ospedale Pediatrico Bambino Gesù
  • Lombardia
    • Milano, Lombardia, Italy, 20122
      • Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico; Unità Operativa Complessa Pediatria 1
    • Monza, Lombardia, Italy, 20052
      • ASST DI MONZA; Divisione Malattie Infettive
• Mexico
  • Mexico, Mexico, 04530
    • Instituto Nacional de Pediatria; Departmento de Neurologia
  • Monterrey, Mexico, 64460
    • Hospital Universitario Dr Jose Eleuterio Gonzalez; Universidad Autónoma de Nuevo León
• Poland
  • Gdansk, Poland, 80-214
    • Uniwersyteckie Centrum Kliniczne
  • Olsztyn, Poland, 10-561
    • Children Hospital, Olsztyn; Ward of Pediatric Hematology and Oncology
  • Szczecin, Poland, 71-242
    • Samodzielny Publiczny Szpital Kliniczny nr 1 im. prof.Tadeusza Sokolowskiego
  • Zabrze, Poland, 41-800
    • Medical University of Silesia; Department of Pediatric Hematology and Oncology
• South Africa
  • Cape Town, South Africa, 7500
    • Tygerberg Hospital; Rheumatology
  • Johannesburg, South Africa, 1501
    • WWCT Lakeview Hospital
  • Johannesburg, South Africa, 2013
    • Chris Hani Baragwanath Hospital
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Madrid, Spain, 28009
    • Hospital Infantil Universitario Nino Jesus
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañon
  • Madrid, Spain, 280146
    • Hospital Universitario La Paz
  • Barcelona
    • Esplugues De Llobregas, Barcelona, Spain, 08950
      • Hospital Sant Joan De Deu
• United States
  • California
    • Palo Alto, California, United States, 94304
      • Lucile Packard Child Hosp; Pediatric Pulmonary Division
  • Colorado
    • Aurora, Colorado, United States, 80045
      • The Children's Hospital; Pediatric Infectious Diseases
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • New York
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 12 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female children, <13 years of age
• Rapid influenza diagnostic test (RIDT), polymerase chain reaction (PCR), or viral culture positive for influenza
• Immunocompromised
• Symptoms/signs suggestive of influenza like illness (ILI)
• Less than or equal to (</=) 96 hours between onset of ILI and first dose of study drug

Exclusion Criteria:

• Clinical evidence of severe hepatic impairment
• Infants with post-menstrual age (PMA) <36 weeks
• Clinical evidence of significant renal impairment
• Allergy to oseltamivir or excipients
• Hereditary fructose intolerance
• Received anti-viral treatment with activity against influenza (for example amantadine, rimantadine, oseltamivir, laninamivir, peramivir, zanamivir, and ribavirin) or probenecid medication within 2 weeks prior to randomization

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oseltamivir: Standard dose; Participants will receive standard dose of oseltamivir capsules or suspension orally for 5 to maximum of 20 days depending on weight. Infants <1 year of age will receive oseltamivir at a dose of 3 milligrams per kilogram (mg/kg).	Drug: Oseltamivir; Participants will receive standard dose (30 to 75 milligrams [mg]) or triple standard dose (90 to 225 mg) of oseltamivir orally daily for up to maximum of 20 days. Standard dose of oseltamivir according to weight (except infants): 30 mg twice daily for ) 40 kg body weight participants. Standard dose for infants is 3 mg/kg.; Other Names: Tamiflu
Experimental: Oseltamivir: Triple dose; Participants will receive three times the standard dose of oseltamivir capsules or suspension orally for 5 to maximum of 20 days depending on weight and age. Infants <1 year will receive standard dose at 3 mg/kg.	Drug: Oseltamivir; Participants will receive standard dose (30 to 75 milligrams [mg]) or triple standard dose (90 to 225 mg) of oseltamivir orally daily for up to maximum of 20 days. Standard dose of oseltamivir according to weight (except infants): 30 mg twice daily for ) 40 kg body weight participants. Standard dose for infants is 3 mg/kg.; Other Names: Tamiflu

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Steady State Area Under the Concentration-Time Curve From Time 0 to 12 Hours (AUC0-12) of Oseltamivir	Pre-dose (within 30 minutes prior to administration), 1.5, 4, 8 hours post-dose on Days 3 or 4
Steady State AUC0-12 of Oseltamivir Carboxylate	Pre-dose (within 30 minutes prior to administration), 1.5, 4, 8 hours post-dose on Days 3 or 4
Maximum Plasma Concentration (Cmax) of Oseltamivir	Pre-dose (within 30 minutes prior to administration), 1.5, 4, 8 hours post-dose on Days 3 or 4
Cmax of Oseltamivir Carboxylate	Pre-dose (within 30 minutes prior to administration), 1.5, 4, 8 hours post-dose on Days 3 or 4
Trough Plasma Concentration (Ctrough) of Oseltamivir	Pre-dose (within 30 minutes prior to administration) on Days 3 or 4
Ctrough of Oseltamivir Carboxylate	Pre-dose (within 30 minutes prior to administration) on Days 3 or 4
Time to Cessation of Viral Shedding, as Assessed by Polymerase Chain Reaction (PCR) or Culture Testing	From randomization to negative PCR/culture test result (up to Day 50)

Secondary Outcome Measures

Outcome Measure	Time Frame
Time to Resolution of Influenza Symptoms (including fever),, as Assessed by Canadian Acute Respiratory Infections Scale (CARIFS)	From randomization to resolution of all influenza symptoms (up to Day 50)
Number of Participants With Adverse Events	Baseline up to Day 50
Number of Participants With Influenza Associated Complications	Baseline up to Day 50
Number of Participants With Viral Resistance	Baseline up to Day 50
Half-life (t1/2) of Oseltamivir	Pre-dose (within 30 minutes prior to administration), 1.5, 4, 8 hours post-dose on Days 3 or 4
t1/2 of Oseltamivir Carboxylate	Pre-dose (within 30 minutes prior to administration), 1.5, 4, 8 hours post-dose on Days 3 or 4
Time to Maximum Concentration (Tmax) of Oseltamivir	Pre-dose (within 30 minutes prior to administration), 1.5, 4, 8 hours post-dose on Days 3 or 4
Tmax of Oseltamivir Carboxylate	Pre-dose (within 30 minutes prior to administration), 1.5, 4, 8 hours post-dose on Days 3 or 4
Elimination Rate Constant (Ke) of Oseltamivir	Pre-dose (within 30 minutes prior to administration), 1.5, 4, 8 hours post-dose on Days 3 or 4
Ke of Oseltamivir Carboxylate	Pre-dose (within 30 minutes prior to administration), 1.5, 4, 8 hours post-dose on Days 3 or 4
Apparent Volume of Distribution (V/F) of Oseltamivir	Pre-dose (within 30 minutes prior to administration), 1.5, 4, 8 hours post-dose on Days 3 or 4
V/F of Oseltamivir Carboxylate	Pre-dose (within 30 minutes prior to administration), 1.5, 4, 8 hours post-dose on Days 3 or 4
Apparent Clearance (CL/F) of Oseltamivir	Pre-dose (within 30 minutes prior to administration), 1.5, 4, 8 hours post-dose on Days 3 or 4
CL/F of Oseltamivir Carboxylate	Pre-dose (within 30 minutes prior to administration), 1.5, 4, 8 hours post-dose on Days 3 or 4
Time to Last Measurable Concentration (Tlast) of Oseltamivir	Pre-dose (within 30 minutes prior to administration), 1.5, 4, 8 hours post-dose on Days 3 or 4
Tlast of Oseltamivir Carboxylate	Pre-dose (within 30 minutes prior to administration), 1.5, 4, 8 hours post-dose on Days 3 or 4
Last Measurable Concentration (Clast) of Oseltamivir	Pre-dose (within 30 minutes prior to administration), 1.5, 4, 8 hours post-dose on Days 3 or 4
Clast of Oseltamivir Carboxylate	Pre-dose (within 30 minutes prior to administration), 1.5, 4, 8 hours post-dose on Days 3 or 4

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): January 22, 2014
• Primary Completion (Actual): June 17, 2018
• Study Completion (Actual): June 17, 2018

Study Registration Dates

• First Submitted: October 25, 2012
• First Submitted That Met QC Criteria: October 25, 2012
• First Posted (Estimate): October 29, 2012

Study Record Updates

• Last Update Posted (Actual): October 16, 2018
• Last Update Submitted That Met QC Criteria: October 15, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Oseltamivir
• Other Study ID Numbers: NV25719; 2012-002633-11 (EudraCT Number)