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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Influenza

Intervention / Treatment
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* Drug: Oseltamivir


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oseltamivir: Standard dose<br>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<br>* 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 </= 15 kilograms (kg) body weight participants; 45 mg twice daily for 15 to 23 kg body weight participants; 60 mg twice daily for 23 to 40 kg body weight participants; and 75 mg twice daily for greater than (>) 40 kg body weight participants. Standard dose for infants is 3 mg/kg.<br>* Other names: Tamiflu;|
| Experimental: Oseltamivir: Triple dose<br>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<br>* 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 </= 15 kilograms (kg) body weight participants; 45 mg twice daily for 15 to 23 kg body weight participants; 60 mg twice daily for 23 to 40 kg body weight participants; and 75 mg twice daily for greater than (>) 40 kg body weight participants. Standard dose for infants is 3 mg/kg.<br>* Other names: Tamiflu;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 |