A Study of Intravenous Oseltamivir [Tamiflu] in Infants With Influenza

An Open-label, Prospective, Pharmacokinetic/Pharmacodynamic and Safety Evaluation of Intravenous Oseltamivir in the Treatment of Infants Less Than One Year of Age With Influenza Infection

Status

Terminated

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01053663

Enrollment

Registered

2010-01-21

Start date

2011-01-31

Completion date

2013-01-31

Last updated

2016-07-27

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Influenza

Brief summary

This open-label study will assess the pharmacokinetics and safety of oseltamivir \[Tamiflu\] in 3 cohorts of infants, aged 0-30 days, 31-90 days and 91-\<365 days with influenza infection. Patients will receive 10 doses of intravenous oseltamivir \[Tamiflu\] therapy over 5 or 6 days. Optional oral therapy with oseltamivir \[Tamiflu\] may be considered following the intravenous dose associated with pharmacokinetic blood sampling. Evidence of continued virus shedding at day 6 can allow for up to 5 additional days (10 doses) of oral or intravenous administration. Anticipated time on study drug is 5-11 days. Target sample size is \<50 patients.

Interventions

DRUGTamiflu

10 doses over 5 or 6 days of which the first 5 or 6 doses must be intravenous, up to 5 days (10 doses) of additional intravenously or oral treatment if virus shedding continues at day 6

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

No minimum to 365 Days

Healthy volunteers

Inclusion criteria

* Infant patients * Date of birth to date of enrollment is \<1 year * Diagnosis of influenza * Duration of influenza symptoms \</=96 hours prior to first dose * \- Parent/guardian willing to have patient receive intravenous therapy for 3 or 4 days (5 or 6 doses of study drug)

Exclusion criteria

* Date of conception to date of birth + date of birth to enrollment is \<36 weeks * Creatinine clearance \<30 mL/min/1.73m2 * Patients receiving any form of renal replacement therapy at baseline * Clinical evidence of severe hepatic decompensation at the time of enrollment * Patients taking probenecid medication within 1 week prior to study day 1 or during the study

Design outcomes

Primary

Measure	Time frame
Cmax of Oseltamivir and Oseltamivir Carboxylate on Day 4	Pre-dose (Hour 0), 2 and 4 hours post-dose on Day 4
Area Under the Concentration Versus Time Curve From Time Zero to Last Measurable Plasma Concentration (AUClast) of Oseltamivir and Oseltamivir Carboxylate on Day 1	Pre-dose (Hour 0), 2, 3-4, 5-7, and 10-12 hours post-dose on Day 1
AUClast of Oseltamivir and Oseltamivir Carboxylate on Day 2	Pre-dose (Hour 0), 2, 3-4, 5-7, and 10-12 hours post-dose on Day 2
AUClast of Oseltamivir and Oseltamivir Carboxylate on Day 4	Pre-dose (Hour 0), 2 and 4 hours post-dose on Day 4
Maximum Observed Plasma Concentration (Cmax) of Oseltamivir and Oseltamivir Carboxylate on Day 1	Pre-dose (Hour 0), 2, 3-4, 5-7, and 10-12 hours post-dose on Day 1
Cmax of Oseltamivir and Oseltamivir Carboxylate on Day 2	Pre-dose (Hour 0), 2, 3-4, 5-7, and 10-12 hours post-dose on Day 2

Secondary

Measure	Time frame	Description
Last Measurable Plasma Concentration (Clast) of Oseltamivir and Oseltamivir Carboxylate	Pre-dose (Hour 0), 2, 3-4, 5-7, and 10-12 hours post-dose on Day 1 and Day 2, pre-dose (Hour 0), 2 and 4 hours post-dose on Day 4	—
Time of the Last Measurable Plasma Concentration (Tlast) of Oseltamivir and Oseltamivir Carboxylate	Pre-dose (Hour 0), 2, 3-4, 5-7, and 10-12 hours post-dose on Day 1 and Day 2, pre-dose (Hour 0), 2 and 4 hours post-dose on Day 4	—
Number of Participants With Greater Than or Equal to (≥) 5-Fold Change in Neuraminidase Inhibition (NAI) Assay 50 Percent (%) Inhibitory Concentration (IC50) Values	Baseline, Days 1, 3, 4, 6, 15	IC50 was defined as the concentration that causes 50% inhibition of viral activity. IC50 values were calculated using NAI assay. The 5-fold change was calculated as either ≥5 times change in the NAI IC50 visit value from the Reference value at a visit or ≥5 times change in the NAI IC50 Visit value from the Baseline value.
Number of Participants With Oseltamivir Resistance Mutation	Up to Day 30	Resistance was assessed by neuraminidase (NA) and hemagglutinin (HA) genes sequencing analysis, using Reverse Transcription Polymerase Chain Reaction (RT-PCR).
Time to the Maximum Observed Plasma Concentration (Tmax) of Oseltamivir and Oseltamivir Carboxylate	Pre-dose (Hour 0), 2, 3-4, 5-7, and 10-12 hours post-dose on Day 1 and Day 2, pre-dose (Hour 0), 2 and 4 hours post-dose on Day 4	—

Countries

Israel, United States

Participant flow

Pre-assignment details

A total of 2428 participants were prescreened; of which, 2419 failed the prescreening evaluation. The most common reasons for failing the prescreening evaluation included the following: negative influenza diagnosis, not meeting the age criterion, ability to tolerate/absorb oral medication, and inability to comply with the study procedures.

Participants by arm

Arm	Count
Oseltamivir: Age 91 to < 365 Days Participants aged 91 to \<365 days received oseltamivir 3 mg/kg twice daily (every 12 hours) IV over 5 or 6 days for a total of 10 doses. For participants who did not receive all 10 doses IV, treatment could be completed with oral oseltamivir suspension (twice daily). If medically necessary, participants were allowed to receive an additional 10 doses of IV or oral oseltamivir after the initial 10 doses.	7
Oseltamivir: Age 31 to 90 Days Participants aged 31 to 90 days received oseltamivir 2.5 mg/kg twice daily (every 12 hours) IV over 5 or 6 days for a total of 10 doses. For participants who did not receive all 10 doses IV, treatment could be completed with oral oseltamivir suspension (twice daily). If medically necessary, participants were allowed to receive an additional 10 doses of IV or oral oseltamivir after the initial 10 doses.	1
Oseltamivir: Age 0 to 30 Days Participants aged 0 to 30 days received oseltamivir 2 mg/kg twice daily (every 12 hours) IV over 5 or 6 days for a total of 10 doses. For participants who did not receive all 10 doses IV, treatment could be completed with oral oseltamivir suspension (twice daily). If medically necessary, participants were allowed to receive an additional 10 doses of IV or oral oseltamivir after the initial 10 doses.	1
Total	9

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Death	2
Overall Study	Lost to Follow-up	1
Overall Study	Negative Influenza Diagnosis	1
Overall Study	Poor IV Access	1
Overall Study	Transferred to Another Hospital	1

Baseline characteristics

Characteristic	Oseltamivir: Age 91 to < 365 Days	Oseltamivir: Age 31 to 90 Days	Oseltamivir: Age 0 to 30 Days	Total
Age, Continuous	175.0 days STANDARD_DEVIATION 62	41.0 days	23.0 days	143.2 days STANDARD_DEVIATION 82.9
Sex: Female, Male Female	2 Participants	0 Participants	0 Participants	2 Participants
Sex: Female, Male Male	5 Participants	1 Participants	1 Participants	7 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	4 / 7	0 / 1	1 / 1	5 / 9
serious Total, serious adverse events	5 / 7	0 / 1	0 / 1	5 / 9

Outcome results

Primary

Area Under the Concentration Versus Time Curve From Time Zero to Last Measurable Plasma Concentration (AUClast) of Oseltamivir and Oseltamivir Carboxylate on Day 1

Time frame: Pre-dose (Hour 0), 2, 3-4, 5-7, and 10-12 hours post-dose on Day 1

Population: Pharmacokinetic (PK) population included all treated participants who had at least one blood sample evaluable for drug concentration level. Number of participants analyzed = participants who were evaluable for this outcome.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)	Dispersion
Oseltamivir: Age 91 to < 365 Days	Area Under the Concentration Versus Time Curve From Time Zero to Last Measurable Plasma Concentration (AUClast) of Oseltamivir and Oseltamivir Carboxylate on Day 1	Oseltamivir	777 hournanogram/milliliter (hng/mL)	Geometric Coefficient of Variation 162.8
Oseltamivir: Age 91 to < 365 Days	Area Under the Concentration Versus Time Curve From Time Zero to Last Measurable Plasma Concentration (AUClast) of Oseltamivir and Oseltamivir Carboxylate on Day 1	Oseltamivir Carboxylate	5200 hournanogram/milliliter (hng/mL)	Geometric Coefficient of Variation 87.8
Oseltamivir: Age 0 to 30 Days	Area Under the Concentration Versus Time Curve From Time Zero to Last Measurable Plasma Concentration (AUClast) of Oseltamivir and Oseltamivir Carboxylate on Day 1	Oseltamivir	494 hournanogram/milliliter (hng/mL)	—
Oseltamivir: Age 0 to 30 Days	Area Under the Concentration Versus Time Curve From Time Zero to Last Measurable Plasma Concentration (AUClast) of Oseltamivir and Oseltamivir Carboxylate on Day 1	Oseltamivir Carboxylate	7510 hournanogram/milliliter (hng/mL)	—

Primary