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A Pharmacokinetic/Pharmacodynamic (PK/PD) and Safety Evaluation of Oseltamivir [Tamiflu] in the Treatment of Infants 0 to <12 Months of Age With Confirmed Flu Infection

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ClinicalTrials.gov Identifier: NCT00988325
Recruitment Status : Completed
First Posted : October 2, 2009
Results First Posted : March 20, 2017
Last Update Posted : March 20, 2017
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE September 30, 2009
First Posted Date  ICMJE October 2, 2009
Results First Submitted Date  ICMJE February 18, 2016
Results First Posted Date  ICMJE March 20, 2017
Last Update Posted Date March 20, 2017
Study Start Date  ICMJE January 2011
Actual Primary Completion Date April 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 30, 2017)
  • Steady-state Area Under the Plasma Concentration Versus Time Curve From Time Zero to 12 Hours of Oseltamivir and Oseltamivir Carboxylate [ Time Frame: 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 3 if two doses taken on Day 1 or 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 4 if one dose taken on Day 1 ]
    Oseltamivir carboxylate is active metabolite of oseltamivir. AUC0-12 was estimated for oseltamivir and oseltamivir carboxylate by linear trapezoidal rule
  • Steady-state Maximum Observed Plasma Concentration of Oseltamivir and Oseltamivir Carboxylate [ Time Frame: 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 3 if two doses taken on Day 1 or 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 4 if one dose taken on Day 1 ]
    Oseltamivir carboxylate is an active metabolite of oseltamivir. Cmax was estimated for both oseltamivir and Oseltamivir carboxylate by non-compartmental analysis.
  • Steady-state Minimum Observed Plasma Concentration of Oseltamivir and Oseltamivir Carboxylate [ Time Frame: 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 3 if two doses taken on Day 1 or 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 4 if one dose taken on Day 1 ]
    Oseltamivir carboxylate is active metabolite of oseltamivir. Cmin was estimated for both oseltamivir and oseltamivir carboxylate by non-compartmental analysis
Original Primary Outcome Measures  ICMJE
 (submitted: September 30, 2009)
The steady-state pharmacokinetic parameters AUC0-12 and Cmax of oseltamivir and oseltamivir carboxylate. [ Time Frame: Until study discontinuation ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 30, 2017)
  • Time to the Maximum Observed Plasma Concentration of Oseltamivir and Oseltamivir Carboxylate [ Time Frame: 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 3 if two doses taken on Day 1 or 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 4 if one dose taken on Day 1 ]
    Oseltamivir carboxylate is an active metabolite of oseltamivir.Tmax was estimated using non-compartmental methods
  • Apparent Elimination Half Life of Oseltamivir and Oseltamivir Carboxylate [ Time Frame: 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 3 if two doses taken on Day 1 or 15 minutes pre-dose; 1 hour +/-15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 4 if one dose taken on Day 1 ]
    Elimination half-life is defined as the time required for elimination of a drug to half its plasma concentration and was computed using non-compartmental method
  • Apparent First-order Elimination Rate Constant of Oseltamivir and Oseltamivir Carboxylate [ Time Frame: 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 3 if two doses taken on Day 1 or 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 4 if one dose taken on Day 1 ]
    Oseltamivir carboxylate is active metabolite of oseltamivir.The apparent first-order elimination rate constant (Lambda Z) was determined by linear regression analysis of terminal data points. A minimum of 3 data points were used for lambda Z estimation. By reporting tool convention, if n<3, no summary statistics were calculated
  • Total Plasma Clearance as a Function of Bioavailability and Apparent Plasma Clearance of the Metabolite as a Function of Bioavailability (CLm/F) of Oseltamivir and Oseltamivir Carboxylate [ Time Frame: 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 3 if two doses taken on Day 1 or 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 4 if one dose taken on Day 1 ]
    Oseltamivir carboxylate is active metabolite of oseltamivir. CL/F was calculated as dose/AUCinf, where AUCinf represents the area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity
  • The Volume of Distribution as a Function of Bioavailability of Oseltamivir and Oseltamivir Carboxylate [ Time Frame: 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 3 if two doses taken on Day 1 or 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 4 if one dose taken on Day 1 ]
    Oseltamivir carboxylate is active metabolite of oseltamivir. V/F is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.
  • Clast of Oseltamivir and Oseltamivir Carboxylate [ Time Frame: 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 3 if two doses taken on Day 1 or 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 4 if one dose taken on Day 1 ]
    The last measurable plasma concentration of oseltamivir and oseltamivir carboxylate was the last quantifiable concentration of oseltamivir or oseltamivir carboxylate, respectively.
  • Time of the Last Measurable Plasma Concentration for Oseltamivir and Oseltamivir Carboxylate [ Time Frame: 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 3 if two doses taken on Day 1 or 15 minutes pre-dose; 1 hour +/- 15 minutes, 2-3, 5-7, 10-12 hours post-dose on Day 4 if one dose taken on Day 1 ]
    Oseltamivir carboxylate is an active metabolite of oseltamivir.
  • Number of Participants With Change From Baseline in Neurological Assessment Scores [ Time Frame: Baseline (Day 1); Day 3 for who received two does on Day 1 or Day 4 for who received one dose on Day 1; Day 6, Day 11, Day 18, Day 30 ]
    Neurological assessment was performed to assess the mental state of the participants through two scales: Infant face scale and Glasgow coma scale. Each scale consists of 3 subscales: eye opening (ranging 1 to 4), verbal response (ranging 1 to 5), and motor responses (ranging 1 to 6). The final score is the sum of these ranges and is scored between 3 and 15. 3 being the worst, and 15 the best. Change from baseline is change of final score post-baseline minus the final score at baseline.
  • Median Time to Cessation of Viral Shedding in Participants With Positive Culture at Baseline [ Time Frame: Days 1, 3 or 4, 6, 11, 18, and 30 ]
    Median time to cessation of viral shedding was calculated for all patients with positive by culture / by polymerase chain reaction (PCR) at baseline using all data points between the start of the treatment and the 1st time point of negative culture without subsequent positive culture results. These time-to event analyses were only performed for the viral titre.
  • Number of Participants With Virus Shedding by Virus Type [ Time Frame: Baseline (Day 1), Day3/4, Day 6, Day 11, Day 18+/-2 days, Day 30+/-2 days ]
    The viral titer was measured by culture and reported in log10 (50% tissue culture infective dose [TCID50]). The viral load was analyzed by PCR and reported as log10 particles/mL. The number of patients positive for viral shedding by virus sub-type was measured on specified days from baseline to last visit on Day 30.
  • Time to Resolution of Fever in Participants With Fever at the Baseline [ Time Frame: Days 1 to 11; Day 18; Day 30 ]
    This was performed for all participants who had fever at baseline. Fever is defined as body temperature >37.0 degree Celsius. Rectal temperature is converted by subtracting 1 degree Celsius. Time to Resolution of Fever was defined as the time from the initiation of treatment to first time the afebrile state was reached and maintained for at least 21.5 hours, where afebrile state was defined as axillary temperature ≤ 37 degree Celsius.
  • Percentage of Participants With Decline of Body Temperature to the Afebrile State [ Time Frame: Baseline (Day 1), Day3/4, Day 6, Day 11, Day 18+/-2 days, Day 30+/-2 days ]
    This was performed for all participants who had fever at baseline Fever is defined as body temperature >37.0ºC. Rectal temperature is converted by subtracting 1 ºC. The rate of decline of body temperature was calculated as the slope of body temperature between the baseline temperature and the 1st temperature below 37°C. Participants with decline in body temperature were considered to have no fever; however, participants who did not show any decline in body temperature were considered to have persisting fever.
  • Number of Participants With Adverse Events, Serious Adverse Events and Secondary Illness [ Time Frame: Up to 3 days after the last dose of oseltamivir (Approximately 14 days) ]
    An Adverse Event (AEs) is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product. An Serious Adverse Event (SAE) is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or results in a congenital anomaly/birth defect. Secondary illnesses were influenza disease-related events, namely bronchitis, pneumonia, otitis media, and sinusitis that resolved without sequelae. Adverse events, serious adverse events, and secondary illness are reported for on-treatment period (from the first dose of oseltamivir upto 3 days after the last dose of oseltamivir [Approximately 14 days].
  • Number of Participants Showing Within-patient Variability in Vital Signs [ Time Frame: Post baseline, Day 3, 4, 6, 11, 18+/- 2 days, 30+/-2 days ]
    Systolic blood pressure, diastolic blood pressure, pulse rate, respiratory rate, and heart rate were examined for any consistent within-patient post-baseline changes.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 30, 2009)
  • Other pharmacokinetic parameters, including t½, Tmax, ke, CL/F, V/F, CLm, Clast, and Tlast [ Time Frame: Until study discontinuation ]
  • Tolerability and safety parameters, including vital signs and neurological assessments [ Time Frame: Until study discontinuation ]
  • Pharmacodynamic parameters, including results of viral culture and PCR testing and time to resolution of fever [ Time Frame: Until study discontinuation ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Pharmacokinetic/Pharmacodynamic (PK/PD) and Safety Evaluation of Oseltamivir [Tamiflu] in the Treatment of Infants 0 to <12 Months of Age With Confirmed Flu Infection
Official Title  ICMJE An Open Label, Prospective, Pharmacokinetic/Pharmacodynamic and Safety Evaluation of Oseltamivir (Tamiflu®) in the Treatment of Infants 0 to <12 Months of Age With Confirmed Influenza Infection
Brief Summary This study will assess the pharmacokinetics/pharmacodynamics and safety of oseltamivir [Tamiflu] therapy in infants less than 1 year of age with influenza diagnosed in the 96 hours prior to the first dose. Patients age 3-12 months will receive 3 mg/kg, 1-3 months will receive 2.5 mg/kg, and birth to 1 month will receive 2 mg/kg twice a day for a total of 10 doses. Patients positive for influenza virus on Day 6 will be eligible to receive continued study treatment for an additional 10 doses (5 days). The anticipated time on study treatment is 4 weeks, and the target sample size is 65-85 male and female infants.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Influenza
Intervention  ICMJE Drug: Tamiflu
oral repeating dose
Study Arms  ICMJE
  • Experimental: Oseltamivir 3 mg
    infants 3 to <12 months
    Intervention: Drug: Tamiflu
  • Experimental: Oseltamivir 2.5 mg
    infants 1 to <3 months of age
    Intervention: Drug: Tamiflu
  • Experimental: Oseltamivir 2 mg
    infants 0 to 30 days (post natal) of age
    Intervention: Drug: Tamiflu
Publications * Rath BA, Brzostek J, Guillén S, Niranjan V, Chappey C, Rayner CR, Clinch B. Safety, virology and pharmacokinetics of oseltamivir in infants with laboratory-confirmed influenza: a Phase I/II, prospective, open-label, multicentre clinical trial. Antivir Ther. 2015;20(8):815-25. doi: 10.3851/IMP2967. Epub 2015 May 27.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 30, 2017)
65
Original Estimated Enrollment  ICMJE
 (submitted: September 30, 2009)
0
Actual Study Completion Date  ICMJE April 2012
Actual Primary Completion Date April 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • infants </=12 months of age
  • laboratory confirmed diagnosis of influenza within 96 hours prior to first dose
  • influenza symptoms for </=96 hours prior to first dose

Exclusion Criteria:

  • preterm infants less than 40 weeks (corrected for gestational age)
  • weight less than 5th percentile for age (corrected for gestational age)
  • concurrent gastrointestinal conditions that preclude enteric absorption of the drug
  • bronchopulmonary dysplasia/chronic lung disease on assisted ventilation at time of enrollment
  • active or uncontrolled respiratory, cardiac, hepatic, CNS or renal disease at baseline
  • symptomatic inborn errors of metabolism
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 12 Months   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   France,   Germany,   Italy,   Poland,   Spain
Removed Location Countries Israel,   Lebanon,   Netherlands,   United Kingdom
 
Administrative Information
NCT Number  ICMJE NCT00988325
Other Study ID Numbers  ICMJE WP22849
2009-014365-12
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date January 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP