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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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00988325
First received: September 30, 2009
Last updated: January 30, 2017
Last verified: January 2017
  Purpose
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.

Condition Intervention Phase
Influenza
Drug: Tamiflu
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • 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


Secondary Outcome Measures:
  • 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.


Enrollment: 65
Study Start Date: January 2011
Study Completion Date: April 2012
Primary Completion Date: April 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Oseltamivir 3 mg
infants 3 to <12 months
Drug: Tamiflu
oral repeating dose
Experimental: Oseltamivir 2.5 mg
infants 1 to <3 months of age
Drug: Tamiflu
oral repeating dose
Experimental: Oseltamivir 2 mg
infants 0 to 30 days (post natal) of age
Drug: Tamiflu
oral repeating dose

  Eligibility

Ages Eligible for Study:   up to 12 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00988325

Locations
Belgium
Cliniques Universitaires St-Luc
Bruxelles, Belgium, 1200
France
Hôpital Femme Mère Enfant; Service de rhumatologie pédiatrique
Bron, France, 69677
Germany
CAMPUS VIRCHOW-KLINIKUM CharitéCentrum 17 Klinik f.Pädiatrie Abt.Pneumologie u.Immunologie
Berlin, Germany, 13353
LWL-Klinik-Bochum
Bochum, Germany, 44792
Onkologische Schwerpunktpraxis Dr. Med. O. Burkhard & B. Reimann
Worms, Germany, 67547
Italy
Fondazione Ospedale Maggiore Policlinico
Milan, Lombardia, Italy, 20122
Poland
Vitamed
Bydgoszcz, Poland, 85-021
Samodzielny Publiczny Zakład Opieki; Wcześniaków I Intensywnej Terapii
Bydgoszcz, Poland, 85-168
Zespol Opieki Zdrowotnej Debica; Oddzial Dzieciecy
Debica, Poland, 39-200
St Hedwig Hospital In Trzebnica
Trzebnica, Poland, 55-100
Spain
Complejo Hospitalario Universitario de Santiago (CHUS) ; Intermedios y Urgencias Pediatricas
Santiago de Compostela, La Coruña, Spain, 15706
Hospital Universitario de Getafe; Servicio de Pediatria
Madrid, Spain, 28905
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT00988325     History of Changes
Other Study ID Numbers: WP22849
2009-014365-12
Study First Received: September 30, 2009
Results First Received: February 18, 2016
Last Updated: January 30, 2017

Additional relevant MeSH terms:
Influenza, Human
Orthomyxoviridae Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Respiratory Tract Diseases
Oseltamivir
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on March 29, 2017