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

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00391768
• Collaborator: (none)
• Enrollment: 87
• Locations: 32
• Arm: 1
• Duration (Months): 39
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Influenza	Drug: oseltamivir (Tamiflu®)	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 87 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pharmacokinetic/Pharmacodynamic and Safety Evaluation of Oseltamivir (Tamiflu®) for the Treatment of Children Less Than 24 Months of Age With Confirmed Influenza Infection (CASG 114)
• Study Start Date: Jan 1, 2007
• Actual Primary Completion Date: Mar 1, 2010
• Actual Study Completion Date: Apr 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: oseltamivir (Tamiflu®)

Drug: 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.

Outcome Measures

Primary Outcome Measures

1. Oseltamivir Carboxylate AUC12 (Area Under the Curve). [Day 3 of drug administration]

   The oseltamivir carboxylate AUC12 was derived from a series of five blood draws over 10 to 12 hours.

Secondary Outcome Measures

1. Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy. [Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 30 plus or minus 3 days.]

   Any event considered associated with drug that occurred post first dose of drug administration that was not present at baseline was considered an AE. Expected flu symptoms were not reported as AEs but were collected separately.

2. Number and Characteristics of Adverse Events (AEs) Described as Neurological Events. [Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 30 plus or minus 3 days.]

   Any neurological event that occurred post first dose of drug administration that was not present at baseline was considered an AE. Expected flu symptoms were not reported as AEs but were collected separately.

3. Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade [Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 30 plus or minus 3 days]

   Any event considered to be related to the study drug that occurred post first dose of drug administration that was not present at baseline was considered an AE. Expected flu symptoms were not reported as AEs but were collected separately. The Division of AIDS Toxicity Tables (DIAIDS) were used to grade the events.

4. Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort Leading to Discontinuation of Study Medication [Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 5 plus or minus 1 day]

   Study drug was administered for 5 days; any event that occurred prior to the last dose of study medication that was considered related to an AE and that caused the subject to stop taking study drug.

5. Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC) [Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 30 plus or minus 3 days]

   Serious Adverse Event (SAE) were classified by MedDRA System Organ Class (SOC). An SAE was reported if it met the following criteria and occurred after the first dose of study medication through the end of the study: death throughout study participation; life threatening; requires inpatient hospitalization or prolongation of existing hospitalization during the period of protocol defined surveillance; results in congenital anomaly or birth defect; results in a persistent or significant disability; and an event considered serious by the PI.

6. Correlation of Clearance of Viral RNA by Culture With Pharmacokinetic Parameters by Cohort [Day to negative viral load for subjects positive at baseline]

   The Spearman coefficient and the p-values were computed between the clearance of Viral RNA and Oseltamivir Carboxylate Area under the curve from 0 to 12 hours (AUC0-12)

7. Correlation of Clearance of Viral RNA by Polymerase Chain Reaction (PCR) to Pharmacokinetic Parameters by Cohort. [From date of enrollment until the date of first documented absence of viral load by culture, assessed up to 10 days after enrollment.]

   The Spearman coefficient and the p-values were computed between the clearance of viral RNA and oseltamivir carboxylate Area Under the Curve from 0 to 12 hours (AUC 0-12)

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 23 Months
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35117
2	Arkansas Children's Hospital - Infectious Diseases	Little Rock	Arkansas	United States	72202-3500
3	Miller Children's Hospital Long Beach - Bickerstaff Family Center	Long Beach	California	United States	90806-1701
4	Children's Hospital of Orange County	Orange	California	United States	92868-3835
5	Rady Children's Hospital San Diego	San Diego	California	United States	92123-4223
6	Children's Hospital Colorado - Infectious Disease	Aurora	Colorado	United States	80045-7106
7	Children's National Medical Center - Sheikh Zayed Campus - Infectious Disease	Washington	District of Columbia	United States	20010-2916
8	University of Florida - Shands Children's Hospital	Gainesville	Florida	United States	32610-0296
9	University of South Florida - Tampa General Hospital - Pediatrics	Tampa	Florida	United States	33606-3438
10	Emory Children's Center - Pediatric Infectious Diseases	Atlanta	Georgia	United States	30322-1014
11	Emory University School of Medicine - Emory Children's Center - Pediatric Infectious Diseases	Atlanta	Georgia	United States	30322
12	Louisiana State University Health Shreveport - Pediatrics	Shreveport	Louisiana	United States	71103-4228
13	University of Mississippi - Children's Infectious Diseases	Jackson	Mississippi	United States	39216-4505
14	Washington University School of Medicine in St. Louis - Center for Clinical Studies	Saint Louis	Missouri	United States	63110-1010
15	University of Nebraska Medical Center - Children's Hospital and Medical Center - Infectious Diseases	Omaha	Nebraska	United States	68114-4108
16	Cohen Children's Medical Center - Pediatric Infectious Diseases	Manhasset	New York	United States	11030-3816
17	University of Rochester	Rochester	New York	United States	14642
18	SUNY Upstate Medical University Hospital - Pediatrics	Syracuse	New York	United States	13210-2342
19	Cincinnati Children's Hospital Medical Center - Infectious Diseases	Cincinnati	Ohio	United States	45229-3026
20	MetroHealth Medical Center - Pediatric Infectious Disease	Cleveland	Ohio	United States	44109-1998
21	Children's Hospital of Philadelphia - The Center for Pediatric Clinical Effectiveness	Philadelphia	Pennsylvania	United States	19104-3309
22	Children's Hospital of Pittsburgh of UPMC - General Academic Pediatric	Pittsburgh	Pennsylvania	United States	15213-3205
23	Rhode Island Hospital - Pediatrics	Providence	Rhode Island	United States	02903-4923
24	Vanderbilt University - Pediatric - Infectious Diseases	Nashville	Tennessee	United States	37232-0011
25	Parkland Memorial Hospital	Dallas	Texas	United States	75235-7708
26	The University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390-9063
27	Cook Children's Infectious Disease Services	Fort Worth	Texas	United States	76104-2710
28	University of Utah - Pediatric Pharmacology Program	Salt Lake City	Utah	United States	84108-1457
29	Seattle Children's Hospital - Infectious Diseases	Seattle	Washington	United States	98105-3901
30	University of Alberta Hospital - Pediatrics	Edmonton	Alberta	Canada	T6G 2B7
31	The Hospital for Sick Children - Infectious Diseases	Toronto	Ontario	Canada	M5G 1X8
32	Centre Hospitalier de l'Universite Laval/ CHUQ	Quebec		Canada	G1V 4G2

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00391768
• Other Study ID Numbers: 06-0059; N01AI30025C; Roche WP-20749; CASG 114
• First Posted: Oct 24, 2006
• Last Update Posted: May 1, 2013
• Last Verified: Feb 1, 2010

• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): influenza, oseltamivir, Tamiflu®, antiviral, children, infants
• Additional relevant MeSH terms: Influenza, Human; Oseltamivir

Study Results

Participant Flow

Recruitment Details	Patients were recruited from the emergency department, hospital, physician's office or clinical care unit. Children of both sexes and all races were included. The recruitment period was January 2007 through May 2010.

Arm/Group Title	Cohort IA	Cohort IB	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort V
Arm/Group Description	12 - 23 months of age, 30 mg	12 - 23 months of age, 3.5 mg/kg body weight	9 - 11 months of age, 3 mg/kg body weight	9 to 11 months of age, 3.5 mg/kg body weight	6 to 8 months of age, 3 mg/kg body weight	3 to 5 months of age, 3 mg/kg body weight	0 to 2 months of age, 3 mg/kg body weight
Period Title: Overall Study
STARTED	12	3	7	8	24	10	23
COMPLETED	12	3	6	7	22	7	19
NOT COMPLETED	0	0	1	1	2	3	4

Baseline Characteristics

Arm/Group Title	Cohort IA	Cohort IB	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort V	Total
Arm/Group Description	12 - 23 months of age, 30 mg	12 - 23 months of age, 3.5 mg/kg body weight	9 - 11 months of age, 3 mg/kg body weight	9 to 11 months of age, 3.5 mg/kg body weight	6 to 8 months of age, 3 mg/kg body weight	3 to 5 months of age, 3 mg/kg body weight	0 to 2 months of age, 3 mg/kg body weight	Total of all reporting groups
Overall Participants	12	3	7	8	24	10	23	87
Age, Customized (Number) [Number]
Number [Participants]	12 100%	3 100%	7 100%	8 100%	24 100%	10 100%	23 100%	87 100%
Sex: Female, Male (Count of Participants)
Female	3 25%	1 33.3%	3 42.9%	6 75%	13 54.2%	2 20%	8 34.8%	36 41.4%
Male	9 75%	2 66.7%	4 57.1%	2 25%	11 45.8%	8 80%	15 65.2%	51 58.6%
Region of Enrollment (participants) [Number]
United States	12 100%	3 100%	7 100%	8 100%	24 100%	10 100%	23 100%	87 100%

Outcome Measures

1. Primary Outcome

Title	Oseltamivir Carboxylate AUC12 (Area Under the Curve).
Description	The oseltamivir carboxylate AUC12 was derived from a series of five blood draws over 10 to 12 hours.
Time Frame	Day 3 of drug administration

Outcome Measure Data

Analysis Population Description

Subjects that received 3 days study drug administration and had successful PK draws on study day 3.

Arm/Group Title	Cohort IA	Cohort IB	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort V
Arm/Group Description	Subjects aged 12 to 23 months of age confirmed to have influenza. These subjects received 30mg of Oseltamivir twice a day times 5 days.	Subjects 12 to 23 months of age confirmed to have influenza and received 3.5 mg/kg of Oseltamivir by mouth twice a day times 5 days.	Subjects 9 to 11 months of age confirmed to have influenza and received 3 mg/kg body weight of Oseltamivir by mouth twice a day times 5 days.	Subjects 9 to 11 months of age confirmed to have influenza and received 3.5 mg/kg body weight of Oseltamivir by mouth twice a day times 5 days.	Subjects 6 to 8 months of age confirmed to have influenza and received 3 mg/kg body weight of Oseltamivir by mouth twice a day times 5 days.	Subjects 3 to 5 months of age confirmed to have influenza and received 3 mg/kg body weight of Oseltamivir by mouth twice a day times 5 days.	Subjects 0 to 2 months of age confirmed to have influenza and received 3 mg/kg body weight of Oseltamivir by mouth twice a day times 5 days.
Measure Participants	10	3	6	7	22	10	19
AUC12 <2660	6 50%	1 33.3%	3 42.9%	0 0%	2 8.3%	0 0%	3 13%
AUC12 > or = 2660 and <7700	4 33.3%	2 66.7%	3 42.9%	7 87.5%	19 79.2%	10 100%	13 56.5%
AUC12 > or =7700	0 0%	0 0%	0 0%	0 0%	1 4.2%	0 0%	3 13%

2. Secondary Outcome

Title	Overall Reported Adverse Events (AEs) Thought to be Associated With Study Therapy.
Description	Any event considered associated with drug that occurred post first dose of drug administration that was not present at baseline was considered an AE. Expected flu symptoms were not reported as AEs but were collected separately.
Time Frame	Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 30 plus or minus 3 days.

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT)

Arm/Group Title	Cohort IA	Cohort IB	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort V
Arm/Group Description	Subjects aged 12 - 23 months of age confirmed to have influenza. These subjects received 30 mg of Oseltamivir twice a day times 5 days.	Subjects aged 12 - 23 months of age confirmed to have influenza. These subjects received 3.5 mg/kg body weight of Oseltamivir twice a day times 5 days.	Subjects aged 9 - 11 months of age confirmed to have influenza. These subjects received 3 mg/kg body weight of Oseltamivir twice a day times 5 days.	Subjects aged 9 - 11 months of age confirmed to have influenza. These subjects received 3.5 mg/kg body weight of Oseltamivir twice a day times 5 days.	Subjects aged 6 - 8 months of age confirmed to have influenza. These subjects received 3 mg/kg body weight of Oseltamivir twice a day times 5 days.	Subjects aged 3 - 5 months of age confirmed to have influenza. These subjects received 3 mg/kg body weight of Oseltamivir twice a day times 5 days	Subjects aged 0 - 2 months of age confirmed to have influenza. These subjects received 3 mg/kg body weight of Oseltamivir twice a day times 5 days
Measure Participants	12	3	7	8	24	10	23
Event - Vomiting	3 25%	0 0%	0 0%	0 0%	2 8.3%	0 0%	0 0%
Event - Dermatitis Diaper	0 0%	0 0%	0 0%	0 0%	1 4.2%	0 0%	0 0%
Event - Rash	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 4.3%

3. Secondary Outcome

Title	Number and Characteristics of Adverse Events (AEs) Described as Neurological Events.
Description	Any neurological event that occurred post first dose of drug administration that was not present at baseline was considered an AE. Expected flu symptoms were not reported as AEs but were collected separately.
Time Frame	Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 30 plus or minus 3 days.

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT)

Arm/Group Title	Cohort IA	Cohort IB	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort V
Arm/Group Description	Subjects aged 12 - 23 months of age confirmed to have influenza. These subjects received 30 mg of Oseltamivir twice a day times 5 days	Subjects aged 12 - 23 months of age confirmed to have influenza. These subjects received 3.5 mg/kg body weight of Oseltamivir twice a day times 5 days	Subjects aged 9 - 11 months of age confirmed to have influenza. These subjects received 3 mg/kg body weight of Oseltamivir twice a day times 5 days	Subjects aged 9 - 11 months of age confirmed to have influenza. These subjects received 3.5 mg/kg body weight of Oseltamivir twice a day times 5 days.	Subjects aged 6 - 8 months of age confirmed to have influenza. These subjects received 3 mg/kg body weight of Oseltamivir twice a day times 5 days	Subjects aged 3 - 5 months of age confirmed to have influenza. These subjects received 3 mg/kg body weight of Oseltamivir twice a day times 5 days	Subjects aged 0 - 2 months of age confirmed to have influenza. These subjects received 3 mg/kg body weight of Oseltamivir twice a day times 5 days
Measure Participants	12	3	7	8	24	10	23
Event - Lethargy	0 0%	0 0%	0 0%	0 0%	1 4.2%	0 0%	0 0%
Event - Tremor	0 0%	1 33.3%	0 0%	0 0%	0 0%	0 0%	0 0%

4. Secondary Outcome

Title	Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort and Toxicity Grade
Description	Any event considered to be related to the study drug that occurred post first dose of drug administration that was not present at baseline was considered an AE. Expected flu symptoms were not reported as AEs but were collected separately. The Division of AIDS Toxicity Tables (DIAIDS) were used to grade the events.
Time Frame	Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 30 plus or minus 3 days

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT)

Arm/Group Title	Cohort IA	Cohort IB	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort V
Arm/Group Description	12 - 23 months of age, 30 mg	12 - 23 months of age, 3.5 mg/kg body weight	9 - 11 months of age, 3 mg/kg body weight	9 to 11 months of age, 3.5 mg/kg body weight	6 to 8 months of age, 3 mg/kg body weight	3 to 5 months of age, 3 mg/kg body weight	0 to 2 months of age, 3 mg/kg body weight
Measure Participants	12	3	7	8	24	10	23
Grade I - Mild	3 25%	0 0%	0 0%	0 0%	3 12.5%	0 0%	1 4.3%
Grade II - Moderate	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Grade III - Severe	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Grade IV - Life-threatening	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Grade V - Death	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

5. Secondary Outcome

Title	Incidence of Treatment Emergent AEs and Drug Related AEs by Cohort Leading to Discontinuation of Study Medication
Description	Study drug was administered for 5 days; any event that occurred prior to the last dose of study medication that was considered related to an AE and that caused the subject to stop taking study drug.
Time Frame	Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 5 plus or minus 1 day

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort IA	Cohort IB	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort V
Arm/Group Description	12 - 23 months of age, 30 mg	12 - 23 months of age, 3.5 mg/kg body weight	9 - 11 months of age, 3 mg/kg body weight	9 to 11 months of age, 3.5 mg/kg body weight	6 to 8 months of age, 3 mg/kg body weight	3 to 5 months of age, 3 mg/kg body weight	0 to 2 months of age, 3 mg/kg body weight
Measure Participants	12	3	7	8	24	10	23
Number [events]	0	0	1	0	0	0	0

6. Secondary Outcome

Title	Incidence of All Serious Adverse Events by Cohort and System Organ Class (SOC)
Description	Serious Adverse Event (SAE) were classified by MedDRA System Organ Class (SOC). An SAE was reported if it met the following criteria and occurred after the first dose of study medication through the end of the study: death throughout study participation; life threatening; requires inpatient hospitalization or prolongation of existing hospitalization during the period of protocol defined surveillance; results in congenital anomaly or birth defect; results in a persistent or significant disability; and an event considered serious by the PI.
Time Frame	Duration of study, from receipt of the first dose of study drug and continuing through study visit Day 30 plus or minus 3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort IA	Cohort IB	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort V
Arm/Group Description	12 - 23 months of age, 30 mg	12 - 23 months of age, 3.5 mg/kg body weight	9 - 11 months of age, 3 mg/kg body weight	9 to 11 months of age, 3.5 mg/kg body weight	6 to 8 months of age, 3 mg/kg body weight	3 to 5 months of age, 3 mg/kg body weight	0 to 2 months of age, 3 mg/kg body weight
Measure Participants	12	3	7	8	24	10	23
Total	2 16.7%	0 0%	1 14.3%	2 25%	2 8.3%	1 10%	0 0%
General Disorders & Administration Site Conditions	0 0%	0 0%	0 0%	0 0%	1 4.2%	0 0%	0 0%
Immune System Disorders	0 0%	0 0%	1 14.3%	0 0%	0 0%	0 0%	0 0%
Infections and Infestations	2 16.7%	0 0%	0 0%	1 12.5%	1 4.2%	0 0%	0 0%
Investigations	0 0%	0 0%	0 0%	1 12.5%	0 0%	0 0%	0 0%
Respiratory, thoracic & mediastinal disorders	0 0%	0 0%	0 0%	0 0%	0 0%	1 10%	0 0%

7. Secondary Outcome

Title	Correlation of Clearance of Viral RNA by Culture With Pharmacokinetic Parameters by Cohort
Description	The Spearman coefficient and the p-values were computed between the clearance of Viral RNA and Oseltamivir Carboxylate Area under the curve from 0 to 12 hours (AUC0-12)
Time Frame	Day to negative viral load for subjects positive at baseline

Outcome Measure Data

Analysis Population Description

Subjects included in this analysis are those who had positive culture at baseline (day 0) and had a negative culture on one of the following study visit days: Day 3, Day 5 or Day 10. Culture was obtained from a a nasal swab. Subjects also would have had evaluable PK samples on study day 3.

Arm/Group Title	Cohort IA	Cohort IB	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort V
Arm/Group Description	Subjects aged 12 to 23 months of age confirmed to have influenza. These subjects received 30mg of Oseltamivir twice a day times 5 days.	Subjects 12 to 23 months of age confirmed to have influenza and received 3.5 mg/kg of Oseltamivir by mouth twice a day times 5 days.	Subjects 9 to 11 months of age confirmed to have influenza and received 3 mg/kg body weight of Oseltamivir by mouth twice a day times 5 days.	Subjects 9 to 11 months of age confirmed to have influenza and received 3.5 mg/kg body weight of Oseltamivir by mouth twice a day times 5 days.	Subjects 6 to 8 months of age confirmed to have influenza and received 3 mg/kg body weight of Oseltamivir by mouth twice a day times 5 days.	Subjects 3 to 5 months of age confirmed to have influenza and received 3 mg/kg body weight of Oseltamivir by mouth twice a day times 5 days.	Subjects 0 to 2 months of age confirmed to have influenza and received 3 mg/kg body weight of Oseltamivir by mouth twice a day times 5 days.
Measure Participants	8	2	4	5	12	8	18
Number [Spearman coefficient]	0.67	NA	0.40	0.62	0.09	0.30	0.01

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort IA
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.07
	Comments
	Method	Spearman Correlation
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cohort IIA
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.60
	Comments
	Method	Spearman Correlation
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cohort IIB
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.27
	Comments
	Method	Spearman Correlation
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Cohort III
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.77
	Comments
	Method	Spearman Correlation
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Cohort IV
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.47
	Comments
	Method	Spearman Correlation
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Cohort V
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.96
	Comments
	Method	Spearman Correlation
	Comments

8. Secondary Outcome

Title	Correlation of Clearance of Viral RNA by Polymerase Chain Reaction (PCR) to Pharmacokinetic Parameters by Cohort.
Description	The Spearman coefficient and the p-values were computed between the clearance of viral RNA and oseltamivir carboxylate Area Under the Curve from 0 to 12 hours (AUC 0-12)
Time Frame	From date of enrollment until the date of first documented absence of viral load by culture, assessed up to 10 days after enrollment.

Outcome Measure Data

Analysis Population Description

Subjects included in this analysis are those who had viral loads at baseline (day 0) and had a non-detectable viral load on one of the following study visit days: day 3, day 5, or day 10. Virus was obtained from a nasal swab. Subjects also would have had evaluable PK samples on study day 3.

Arm/Group Title	Cohort IA	Cohort IB	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort V
Arm/Group Description	12 - 23 months of age, 30 mg	12 - 23 months of age, 3.5 mg/kg body weight	9 - 11 months of age, 3 mg/kg body weight	9 to 11 months of age, 3.5 mg/kg body weight	6 to 8 months of age, 3 mg/kg body weight	3 to 5 months of age, 3 mg/kg body weight	0 to 2 months of age, 3 mg/kg body weight
Measure Participants	10	2	4	5	16	8	18
AUC0-12 (hr*ng/mL) unit: Spearman Coefficient	0.57	NA	0.21	0.90	0.28	0.04	0.07
AUC0-12 (hr*ng/mL) unit: P value	0.08	NA	0.79	0.04	0.30	0.93	0.77

Adverse Events

Time Frame	Adverse/Serious adverse events were collected from Day 1 to Day 30 of protocol
Arm/Group Title	Cohort IA		Cohort IB		Cohort IIA		Cohort IIB		Cohort III		Cohort IV		Cohort V
Arm/Group Description	12 - 23 months of age, 30 mg		12 - 23 months of age, 3.5 mg/kg body weight		9 - 11 months of age, 3 mg/kg body weight		9 to 11 months of age, 3.5 mg/kg body weight		6 to 8 months of age, 3 mg/kg body weight		3 to 5 months of age, 3 mg/kg body weight		0 to 2 months of age, 3 mg/kg body weight
All Cause Mortality
	Cohort IA		Cohort IB		Cohort IIA		Cohort IIB		Cohort III		Cohort IV		Cohort V
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Cohort IA		Cohort IB		Cohort IIA		Cohort IIB		Cohort III		Cohort IV		Cohort V
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/12 (16.7%)		0/3 (0%)		1/7 (14.3%)		2/8 (25%)		2/24 (8.3%)		1/10 (10%)		0/23 (0%)
General disorders
Pyrexia	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	1/24 (4.2%)	1	0/10 (0%)	0	0/23 (0%)	0
Immune system disorders
Hypersensitivity	0/12 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/8 (0%)	0	0/24 (0%)	0	0/10 (0%)	0	0/23 (0%)	0
Infections and infestations
Influenza	1/12 (8.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	1/24 (4.2%)	1	0/10 (0%)	0	0/23 (0%)	0
Pnuemonia	1/12 (8.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	0/24 (0%)	0	0/10 (0%)	0	0/23 (0%)	0
Viral upper respiratory tract infection	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/8 (12.5%)	1	0/24 (0%)	0	0/10 (0%)	0	0/23 (0%)	0
Investigations
Oxygen saturation decreased	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/8 (12.5%)	1	0/24 (0%)	0	0/10 (0%)	0	0/23 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory distress	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	0/24 (0%)	0	1/10 (10%)	1	0/23 (0%)	0
Other (Not Including Serious) Adverse Events
	Cohort IA		Cohort IB		Cohort IIA		Cohort IIB		Cohort III		Cohort IV		Cohort V
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/12 (66.7%)		1/3 (33.3%)		3/7 (42.9%)		6/8 (75%)		18/24 (75%)		3/10 (30%)		14/23 (60.9%)
Blood and lymphatic system disorders
Neutropenia	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	2/24 (8.3%)	2	0/10 (0%)	0	0/23 (0%)	0
Cardiac disorders
Tachycardia	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/8 (12.5%)	1	0/24 (0%)	0	0/10 (0%)	0	0/23 (0%)	0
Ear and labyrinth disorders
Tympanic membrane perforation	0/12 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/8 (0%)	0	0/24 (0%)	0	0/10 (0%)	0	0/23 (0%)	0
Eye disorders
Conjunctivitis	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	1/24 (4.2%)	1	0/10 (0%)	0	0/23 (0%)	0
Gastrointestinal disorders
Anal fissure	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	0/24 (0%)	0	0/10 (0%)	0	1/23 (4.3%)	1
Constipation	0/12 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/8 (0%)	0	1/24 (4.2%)	1	0/10 (0%)	0	0/23 (0%)	0
Diarrhoea	2/12 (16.7%)	2	0/3 (0%)	0	1/7 (14.3%)	1	0/8 (0%)	0	1/24 (4.2%)	1	0/10 (0%)	0	4/23 (17.4%)	4
Flatulence	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	1/24 (4.2%)	1	0/10 (0%)	0	0/23 (0%)	0
Haematochezia	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	0/24 (0%)	0	0/10 (0%)	0	1/23 (4.3%)	1
Teething	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	1/24 (4.2%)	1	0/10 (0%)	0	0/23 (0%)	0
Vomiting	3/12 (25%)	4	0/3 (0%)	0	0/7 (0%)	0	1/8 (12.5%)	1	4/24 (16.7%)	4	0/10 (0%)	0	0/23 (0%)	0
General disorders
Injection site pain	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	0/24 (0%)	0	0/10 (0%)	0	1/23 (4.3%)	1
Pyrexia	1/12 (8.3%)	1	0/3 (0%)	0	1/7 (14.3%)	1	0/8 (0%)	0	2/24 (8.3%)	2	0/10 (0%)	0	1/23 (4.3%)	1
Infections and infestations
Candida nappy rash	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	0/24 (0%)	0	0/10 (0%)	0	1/23 (4.3%)	1
Candidiasis	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	0/24 (0%)	0	0/10 (0%)	0	1/23 (4.3%)	1
Conjunctivitis bacterial	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	1/24 (4.2%)	1	0/10 (0%)	0	0/23 (0%)	0
Croup infectious	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	1/24 (4.2%)	1	0/10 (0%)	0	0/23 (0%)	0
Gastroenteritis	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	0/24 (0%)	0	0/10 (0%)	0	1/23 (4.3%)	1
Nasopharyngitis	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	1/24 (4.2%)	1	0/10 (0%)	0	0/23 (0%)	0
Otitis media	0/12 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	1/8 (12.5%)	1	4/24 (16.7%)	4	1/10 (10%)	1	0/23 (0%)	0
Pharyngitis streptococcal	1/12 (8.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	0/24 (0%)	0	0/10 (0%)	0	0/23 (0%)	0
Pneumonia	1/12 (8.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	0/24 (0%)	0	0/10 (0%)	0	0/23 (0%)	0
Roseola	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	1/24 (4.2%)	1	0/10 (0%)	0	0/23 (0%)	0
Sinusitis	0/12 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/8 (0%)	0	0/24 (0%)	0	0/10 (0%)	0	0/23 (0%)	0
Skin infection	1/12 (8.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	0/24 (0%)	0	0/10 (0%)	0	0/23 (0%)	0
Tracheitis	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/8 (12.5%)	2	0/24 (0%)	0	0/10 (0%)	0	0/23 (0%)	0
Upper respiratory tract infection	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	2/24 (8.3%)	2	0/10 (0%)	0	1/23 (4.3%)	1
Urinary tract infection	1/12 (8.3%)	1	0/3 (0%)	0	1/7 (14.3%)	1	0/8 (0%)	0	1/24 (4.2%)	1	0/10 (0%)	0	1/23 (4.3%)	1
Viral infection	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/8 (12.5%)	1	0/24 (0%)	0	0/10 (0%)	0	0/23 (0%)	0
Viral upper respiratory tract infection	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/8 (12.5%)	1	0/24 (0%)	0	0/10 (0%)	0	0/23 (0%)	0
Investigations
Oxygen saturation decreased	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/8 (12.5%)	1	0/24 (0%)	0	0/10 (0%)	0	0/23 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	1/24 (4.2%)	1	0/10 (0%)	0	0/23 (0%)	0
Fluid retention	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/8 (12.5%)	1	0/24 (0%)	0	0/10 (0%)	0	0/23 (0%)	0
Nervous system disorders
Lethargy	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	1/24 (4.2%)	1	0/10 (0%)	0	0/23 (0%)	0
Tremor	0/12 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/8 (0%)	0	0/24 (0%)	0	0/10 (0%)	0	0/23 (0%)	0
Psychiatric disorders
Staring	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	1/24 (4.2%)	1	0/10 (0%)	0	0/23 (0%)	0
Renal and urinary disorders
Urine odour abnormal	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	1/24 (4.2%)	1	0/10 (0%)	0	0/23 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/12 (8.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	1/24 (4.2%)	1	0/10 (0%)	0	0/23 (0%)	0
Dyspnoea	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	1/24 (4.2%)	1	0/10 (0%)	0	0/23 (0%)	0
Rhonchi	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	0/24 (0%)	0	1/10 (10%)	1	0/23 (0%)	0
Wheezing	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	1/24 (4.2%)	1	0/10 (0%)	0	0/23 (0%)	0
Skin and subcutaneous tissue disorders
Dermatitis contact	0/12 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/8 (0%)	0	0/24 (0%)	0	0/10 (0%)	0	0/23 (0%)	0
Dermatitis diaper	2/12 (16.7%)	3	0/3 (0%)	0	1/7 (14.3%)	1	1/8 (12.5%)	1	3/24 (12.5%)	3	1/10 (10%)	1	3/23 (13%)	3
Erythema	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	2/24 (8.3%)	3	0/10 (0%)	0	0/23 (0%)	0
Rash	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	2/24 (8.3%)	2	0/10 (0%)	0	2/23 (8.7%)	2
Rash erythematous	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	0/24 (0%)	0	0/10 (0%)	0	1/23 (4.3%)	1
Rash generalised	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	0/24 (0%)	0	0/10 (0%)	0	1/23 (4.3%)	1
Rash macular	0/12 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	1/24 (4.2%)	1	0/10 (0%)	0	0/23 (0%)	0
Urticaria	1/12 (8.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/8 (0%)	0	0/24 (0%)	0	0/10 (0%)	0	0/23 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.