Clinical Trial Results:
An Open-Label, Prospective, Pharmacokinetic/Pharmacodynamic and Safety Evaluation of Intravenous Oseltamivir (Tamiflu®) in the Treatment of Infants Less Than One Year of Age With Influenza Infection
Summary
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EudraCT number |
2016-003003-54 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
28 Jan 2013
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Results information
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Results version number |
v1(current) |
This version publication date |
26 Apr 2017
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First version publication date |
26 Apr 2017
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
NP25138
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01053663 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
F. Hoffmann-La Roche AG
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Sponsor organisation address |
Grenzacherstrasse 124, Basel , Switzerland, CH-4070
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Public contact |
Roche Trial Information Hotline, F. Hoffmann-La Roche, +41 616878333, global.trial_information@roche.com
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Scientific contact |
Roche Trial Information Hotline, F.Hoffmann-La Roche, +41 616878333, global.trial_information@roche.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
21 Feb 2013
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Jan 2013
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
This prospective, open-label, pharmacokinetic (PK)/pharmacodynamic (PD) and safety study was designed to define the PK of oseltamivir and oseltamivir carboxylate and evaluate the safety profile following intravenous (IV) administration of oseltamivir phosphate in infants less than 1 year of age with influenza. The study was also planned to evaluate viral load, viral shedding, and to evaluate all isolates for phenotypic and, where necessary, genotypic resistance.
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Protection of trial subjects |
The study was conducted in accordance with the principles of the ''Declaration of Helsinki" and Good Clinical Practice according to the regulations and procedures described in the protocol.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
09 Jan 2011
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 9
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Worldwide total number of subjects |
9
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
1
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Infants and toddlers (28 days-23 months) |
8
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||
Pre-assignment
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Screening 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. | ||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
Arms
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Arm title
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Oseltamivir - All Participants | ||||||||||||||||||
Arm description |
Participants received oseltamivir (Tamiflu) twice daily (every 12 hours) intravenously (IV) over 5 or 6 days for a total of 10 doses. Oseltamivir doses were based on participant’s age. Participants aged 91 to less than (<) 365 days received 3 milligrams per kilogram (mg/kg); participants aged 31 to 90 days received 2.5 mg/kg; and participants aged 0 to 30 days received 2 mg/kg. 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. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Oseltamivir
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Investigational medicinal product code |
RO0640796
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Other name |
Tamiflu®
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Participants received oseltamivir twice daily (every 12 hours) IV over 5 or 6 days for a total of 10 doses. The oseltamivir doses were based on participant’s age.
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Baseline characteristics reporting groups
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Reporting group title |
Oseltamivir - All Participants
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Reporting group description |
Participants received oseltamivir (Tamiflu) twice daily (every 12 hours) intravenously (IV) over 5 or 6 days for a total of 10 doses. Oseltamivir doses were based on participant’s age. Participants aged 91 to less than (<) 365 days received 3 milligrams per kilogram (mg/kg); participants aged 31 to 90 days received 2.5 mg/kg; and participants aged 0 to 30 days received 2 mg/kg. 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. | ||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Oseltamivir: Age 91 to <365 Days
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
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.
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Subject analysis set title |
Oseltamivir: Age 31 to 90 Days
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
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.
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Subject analysis set title |
Oseltamivir: Age 0 to 30 Days
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Subject analysis set type |
Sub-group analysis | ||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
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.
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End points reporting groups
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Reporting group title |
Oseltamivir - All Participants
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Reporting group description |
Participants received oseltamivir (Tamiflu) twice daily (every 12 hours) intravenously (IV) over 5 or 6 days for a total of 10 doses. Oseltamivir doses were based on participant’s age. Participants aged 91 to less than (<) 365 days received 3 milligrams per kilogram (mg/kg); participants aged 31 to 90 days received 2.5 mg/kg; and participants aged 0 to 30 days received 2 mg/kg. 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. | ||
Subject analysis set title |
Oseltamivir: Age 91 to <365 Days
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
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.
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Subject analysis set title |
Oseltamivir: Age 31 to 90 Days
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
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.
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Subject analysis set title |
Oseltamivir: Age 0 to 30 Days
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
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.
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End point title |
Area Under the Concentration Versus Time Curve From Time Zero to Last Measurable Plasma Concentration (AUClast) of Oseltamivir and Oseltamivir Carboxylate on Day 1 [1] | ||||||||||||||||||||||||
End point description |
Pharmacokinetic (PK) population included all treated participants who had at least one blood sample evaluable for drug concentration level. Number of subjects analyzed = participants who were evaluable for this outcome. Here, 99999 represent data not estimable due to single participant analyzed.
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End point type |
Primary
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End point timeframe |
Pre-dose (Hour 0), 2, 3-4, 5-7, and 10-12 hours post-dose on Day 1
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this open-label study. |
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Notes [2] - No participant was evaluable for this arm. |
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No statistical analyses for this end point |
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End point title |
AUClast of Oseltamivir and Oseltamivir Carboxylate on Day 2 [3] | ||||||||||||||||||||||||
End point description |
PK population. Number of subjects analyzed = participants who were evaluable for this outcome. Here, 99999 represent data not estimable due to single participant analyzed.
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End point type |
Primary
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End point timeframe |
Pre-dose (Hour 0), 2, 3-4, 5-7, and 10-12 hours post-dose on Day 2
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Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this open-label study. |
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Notes [4] - No participant was evaluable for this arm. |
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No statistical analyses for this end point |
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End point title |
AUClast of Oseltamivir and Oseltamivir Carboxylate on Day 4 [5] | ||||||||||||||||||||||||
End point description |
PK population. Number of subjects analyzed = participants who were evaluable for this outcome. Here, 99999 represent data not estimable due to single participant analyzed.
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End point type |
Primary
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End point timeframe |
Pre-dose (Hour 0), 2 and 4 hours post-dose on Day 4
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Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this open-label study. |
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Notes [6] - No participant was evaluable for this arm. |
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No statistical analyses for this end point |
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End point title |
Maximum Observed Plasma Concentration (Cmax) of Oseltamivir and Oseltamivir Carboxylate on Day 1 [7] | ||||||||||||||||||||||||
End point description |
PK population. Number of subjects analyzed = participants who were evaluable for this outcome. Here, 99999 represent data not estimable due to single participant analyzed.
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End point type |
Primary
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End point timeframe |
Pre-dose (Hour 0), 2, 3-4, 5-7, and 10-12 hours post-dose on Day 1
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Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this open-label study. |
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Notes [8] - No participant was evaluable for this arm. |
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No statistical analyses for this end point |
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End point title |
Cmax of Oseltamivir and Oseltamivir Carboxylate on Day 2 [9] | ||||||||||||||||||||||||
End point description |
PK population. Number of subjects analyzed = participants who were evaluable for this outcome. Here, 99999 represent data not estimable due to single participant analyzed.
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End point type |
Primary
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End point timeframe |
Pre-dose (Hour 0), 2, 3-4, 5-7, and 10-12 hours post-dose on Day 2
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Notes [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this open-label study. |
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Notes [10] - No participant was evaluable for this arm. |
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No statistical analyses for this end point |
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End point title |
Cmax of Oseltamivir and Oseltamivir Carboxylate on Day 4 [11] | ||||||||||||||||||||||||
End point description |
PK population. Number of subjects analyzed = participants who were evaluable for this outcome. Here, 99999 represent data not estimable due to single participant analyzed.
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End point type |
Primary
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End point timeframe |
Pre-dose (Hour 0), 2 and 4 hours post-dose on Day 4
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Notes [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this open-label study. |
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Notes [12] - No participant was evaluable for this arm. |
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No statistical analyses for this end point |
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End point title |
Time to the Maximum Observed Plasma Concentration (Tmax) of Oseltamivir and Oseltamivir Carboxylate | ||||||||||||||||||||||||||||||||||||||||
End point description |
PK population. Number of subjects analyzed = participants who were evaluable for this outcome, n = number of participants evaluable for specified categories. Here, 9999 represent data not available as no participant was evaluable at specified timepoint and 99999 represent data not estimable due to single participant analyzed.
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End point type |
Secondary
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End point timeframe |
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
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No statistical analyses for this end point |
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End point title |
Last Measurable Plasma Concentration (Clast) of Oseltamivir and Oseltamivir Carboxylate | ||||||||||||||||||||||||||||||||||||||||
End point description |
PK population. Number of subjects analyzed = participants who were evaluable for this outcome, n = number of participants evaluable for specified categories. Here, 9999 represent data not available as no participant was evaluable at specified timepoint and 99999 represent data not estimable due to single participant analyzed.
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End point type |
Secondary
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End point timeframe |
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
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No statistical analyses for this end point |
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End point title |
Time of the Last Measurable Plasma Concentration (Tlast) of Oseltamivir and Oseltamivir Carboxylate | ||||||||||||||||||||||||||||||||||||||||
End point description |
PK population. Number of subjects analyzed = participants who were evaluable for this outcome, n = number of participants evaluable for specified categories. Here, 9999 represent data not available as no participant was evaluable at specified timepoint and 99999 represent data not estimable due to single participant analyzed.
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End point type |
Secondary
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End point timeframe |
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
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No statistical analyses for this end point |
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End point title |
Number of Participants With Greater Than or Equal to (>/=) 5−Fold Change in Neuraminidase Inhibition (NAI) Assay 50 Percent (%) Inhibitory Concentration (IC50) Values | ||||||||||||||||||||||||||||||||||||||||
End point description |
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. Safety population included all participants who received at least one dose of IV study medication and had a safety assessment performed after initiation of treatment. Here, number of subjects analyzed = participants evaluable for this outcome measure, and n = participants evaluable for specified time-point, for each arm, respectively. Here, 9999 represent data not available as no participant was evaluable at specified timepoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Days 1, 3, 4, 6, 15
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Notes [13] - No participant was evaluable for this arm. |
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No statistical analyses for this end point |
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End point title |
Number of Participants With Oseltamivir Resistance Mutation | |||||||||||||||
End point description |
Resistance was assessed by neuraminidase (NA) and hemagglutinin (HA) genes sequencing analysis, using Reverse Transcription Polymerase Chain Reaction (RT-PCR). Safety population.
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End point type |
Secondary
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End point timeframe |
Up to Day 30
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Up to Day 30
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Adverse event reporting additional description |
Safety population
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15.1
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Reporting groups
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Reporting group title |
Oseltamivir - All Participants
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Reporting group description |
Participants received oseltamivir (Tamiflu) twice daily (every 12 hours) IV over 5 or 6 days for a total of 10 doses. Oseltamivir doses were based on participant’s age. Participants aged 91 to <365 days received 3 mg/kg; participants aged 31 to 90 days received 2.5 mg/kg; and participants aged 0 to 30 days received 2 mg/kg. 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Oseltamivir: Age 91 to <365 Days
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Reporting group description |
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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Oseltamivir: Age 31 to 90 Days
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Reporting group description |
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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Oseltamivir: Age 0 to 30 Days
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Reporting group description |
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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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08 Apr 2010 |
• Modified the requirements for the IV therapy duration and clarified the study population influenza diagnosis and duration of IV therapy
• Provided an updated Assessments and Procedures schedule
• Specified adverse events grading system |
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14 May 2010 |
• Decreased the required number of IV doses to at least one and clarified that participants could have switched to oral dosing with oseltamivir after IV therapy was no longer medically necessary
• Modified dosing in participants with moderate or severe renal impairment or who required continuous renal replacement therapy
• Revised exclusion criteria and increased the flexibility of PK sampling |
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19 Sep 2011 |
• Clarified the day of treatment completion depending on when dosing was started and whether one or two doses were received on Day 1
• Revised the screening and eligibility text to allow flexibility to include data obtained from standard-of-care procedures prior to obtaining informed consent for study participation
• Revised PK sample collection time-points |
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
Low number of participants enrolled in the study at the time that the study was terminated limits conclusions that can be derived from the study data. |