A Study of Oseltamivir (Tamiflu) for Treatment of Influenza in Immunocompromised Participants.

Study Overview
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Brief Summary
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This 2-arm study will investigate the safety and tolerability of oseltamivir for the treatment of influenza in immunocompromised participants and characterize the effects of oseltamivir in immunocompromised participants on the development of resistant influenza virus. Eligible immunocompromised participants with laboratory-confirmed influenza will be randomized to receive either conventional dose (30 milligrams [mg] to 75 mg twice daily orally [po], depending on age and weight) or double dose (60 mg-150 mg twice daily po depending on age and weight) olseltamivir for 10 days. Nasal and throat swabs will be taken, and safety evaluations made, at intervals during the study. The anticipated time on study medication is 10 days and the anticipated time on study is 40 days.

Official Title
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A Double-Blind, Randomized, Stratified Multi-Center Trial Evaluating Conventional and Double Dose Oseltamivir in the Treatment of Immunocompromised Patients With Influenza

Conditions
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Influenza, Human

Intervention / Treatment
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* Drug: oseltamivir
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Rapid diagnostic test, PCR, or viral culture positive for influenza in the 96 hours prior to first dose Immunocompromised participants with primary or secondary immunodeficiency Symptoms suggestive of influenza-like illness Use of an effective contraceptive, as specified by protocol; women of childbearing potential cannot be pregnant or breastfeeding Exclusion Criteria: Influenza vaccination with live attenuated vaccine in the 2 weeks prior to randomization Antiviral treatment for influenza in 2 weeks prior to randomization Severe hepatic impairment Any current renal replacement therapy Any gastrointestinal disorders which may interfere with the absorption of oseltamivir Participation in a study with an investigational drug from 4 weeks prior to study start until study end

Ages Eligible for Study
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Minimum Age: 1 Year

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Conventional dose<br>Immunocompromised participants will receive oseltamivir syrup at a dose ranging from 30 to 75 mg based on body weight, twice daily for children (1 to 12 years old) and oseltamivir capsules 75 mg twice daily for adults/adolescents greater than or equal to (>/=) 13 years old or placebo-matched to oseltamivir twice daily over 10 days. | Drug: oseltamivir<br>* Dose ranging between 30 to 150 mg orally administered as syrup or capsules (depending on participant's age and weight) po twice daily for 10 days<br>* Other names: Tamiflu;Other: placebo<br>* Placebo matched to oseltamivir po twice daily for 10 days<br>|
| Experimental: Double dose<br>Immunocompromised participants will receive oseltamivir syrup at a dose ranging from 60 to 150 mg based on body weight, twice daily for children (1 to 12 years old) and oseltamivir capsules 150 mg twice daily for adults/adolescents (>/=13 years old) or placebo matched to oseltamivir twice daily over 10 days. | Drug: oseltamivir<br>* Dose ranging between 30 to 150 mg orally administered as syrup or capsules (depending on participant's age and weight) po twice daily for 10 days<br>* Other names: Tamiflu;Other: placebo<br>* Placebo matched to oseltamivir po twice daily for 10 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events | An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. | Baseline up to Day 40 | 
| Percentage of Participants Who Developed Viral Resistance to Oseltamivir | Resistance was defined as the presence of oseltamivir resistance mutations in viruses isolated from nasopharyngeal swab samples, identified by sequencing of the neuraminidase (NA) and hemagglutinin (HA) genes (genotypic resistance) and/or determination of the oseltamivir concentration at which the response is reduced by half (IC50) in an NA inhibition assay (phenotypic resistance). Reported are post-baseline phenotypic and genotypic resistance in adults >/= 18 years and children and adolescents <18 years in the modified Intent-to-Treat infected (mITTi) population. | Baseline up to Day 40 | 
| Percentage of Participants With Tissue Rejection or Graft Versus Host Disease (GVHD) | The percentage of transplant patients in the safety population who experienced tissue rejection and/or GvHD is reported. | Baseline up to Day 40 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Resolution (TTR) of All Clinical Influenza Symptoms | TTR of all clinical influenza symptoms was defined as the time from treatment initiation to the start of the 24-hour period in which all 7 influenza symptoms had scores </= 1 (mild) and remained </=1 for at least 21.5 hours. . Reported are TTRs in adults >/= 18 years, adults and adolescents >/= 13 years and children <13 years in the mITTi population. | Baseline up to Day 40 | 
| Total Symptom Score Area Under the Efficacy Curve (AUE) | The overall extent and severity of illness was quantified by the AUE of the total symptom scores over the duration of illness, i.e., from the start of treatment to the time symptoms first alleviated. Total symptom scores were calculated from the sum of seven individual symptom scores with each individual symptom scored from 0 (healthy) to 3 (worst sickness) and a maximum total symptom score of 21. The AUE of these average scores was then calculated for each participant using the trapezoidal rule (the trapezoidal rule calculates the area under any curve by adding up all trapezoids under such a curve). A larger area indicates more severe disease. In this study participants were treated for 10 days. If a participant had scored 21 on every visit then AUE would have been 21 score x 10 days x 24 hours/day =5040 score x hours units, which is the highest possible score. The lowest possible score is 0. Reported are results for adults >/= 18 years in the mITTi population. | Baseline up to Day 40 | 
| Time to Resolution of Fever | Fever was defined as temperature >/= 37.8 degrees Celsius at any time point during the study. TTR of fever was determined in Adults >/= 18 years, Adults and adolescents >/= 13 years and Children < 13 years of the mITTi population. | Baseline up to Day 40 | 
| Change From Baseline in Viral Load Assessed by Culture | Nasopharyngeal swab samples were cultured in Madin-Darby Canine Kidney cells. Culture supernatants were harvested after 2 weeks, or after a full-blown cytopathic effect was observed. Presence of infectious viruses in the cell culture supernatants (viral titer), expressed as log10 50% Tissue Culture Infectious Dose/milliliter (TCID50/mL), was determined by hemagglutination assay using turkey erythrocytes for H1 and B viruses or by detection of the virus nucleoprotein (NP) using ELISA for H3 viruses. A value of < 0.5 log10 TCID50/mL was interpreted as negative. Data are reported for adults >/= 18 years and adolescents and children < 18 years. | Baseline (Day 1), Day 2/3, Day 6, Day 8, Day 11 end of treatment (EOT), follow-up (FU) Day 15 and FU Day 40. | 
| Percentage of Participants With Viral Shedding Assessed by Culture Over Time | Viral shedding was determined through measurement of the viral titer after viral culture in Madin-Darby Canine Kidney cells by hemagglutination assay (for Flu A/H1N1 and Flu B) and NP-ELISA (for Flu A/H3N2) and expressed in log10 TCID50/mL. Reported is the percentage of participants with viral shedding over time in adults >/= 18 years and adolescents and children < 18 years. | Baseline (Day 1), Day 2/3, Day 6, Day 8, Day 11 end of treatment (EOT), follow-up (FU) Day 15 and FU Day 40. | 
| Time to Cessation of Viral Shedding by Cell Culture | Viral shedding was determined through measurement of the viral titer after viral culture in Madin-Darby Canine Kidney cells by hemagglutination assay (for Flu A/H1N1 and Flu B) and NP-ELISA (for Flu A/H3N2) and expressed in log10 TCID50/mL. Reported is the time to cessation of viral shedding over time in adults >/= 18 years and adolescents and children < 18 years. | Baseline up to Day 40 | 
| Change From Baseline in Viral Load Assessed by Reverse Transcription Polymerase Chain Reaction (RT-PCR) | Nasopharyngeal swab samples were tested for influenza A and B RNA using semi-quantitative RT-PCR specific for influenza A and B matrix gene, respectively, after viral RNA isolation. Cycle threshold (Ct) value was determined for each sample. Conversion of Ct values into viral load, expressed as log10 virus particles/mL (vp/mL), was obtained using external standard curves ran in parallel in all RT-PCR experiments. A value of < 2.6 log10 vp/mL for Flu A strains and < 3.0 log10 vp/mL for Flu B strains was interpreted as a negative result. Data are reported for adults >/= 18 years and adolescents and children < 18 years. | Baseline (Day 1), Day 2/3, Day 6, Day 8, Day 11 end of treatment (EOT), follow-up (FU) Day 15 and FU Day 40. | 
| Percentage of Participants With Viral Shedding Assessed by RT-PCR Over Time | Viral shedding was determined by direct viral load measurement from nasopharyngeal swabs by RT-PCR assay and expressed in log10 vp/mL. Reported is the percentage of subjects with viral shedding over time in adults >/= 18 years and adolescents and children < 18 years. | Baseline (Day 1), Day 2/3, Day 6, Day 8, Day 11 end of treatment (EOT), follow-up (FU) Day 15 and FU Day 40. | 
| Time to Cessation of Viral Shedding by RT-PCR | Viral shedding was determined by direct viral load measurement from nasopharyngeal swabs by RT-PCR assay and expressed in log10 vp/mL. Reported is the time to cessation of viral shedding over time in adults >/= 18 years and adolescents and children < 18 years. | Baseline up to Day 40 | 
| Percentage of Participants With Persistent Viral Shedding | Persistent shedding was defined as a viral load reduction <1 log10 vp/mL at end of treatment compared with baseline. Reported is the percentage of participants with persistent viral shedding at end of treatment in adults >/= 18 years and adolescents and children < 18 years. | Baseline to Day 11 (EOT) | 
| Percentage of Participants Who Developed Secondary Illness | Secondary illness included bronchitis, pneumonia, acute sinusitis, sinusitis, lower respiratory infection or otitis media. Reported is the percentage of participants with at least one event in adults >/= 18 years and adolescents and children < 18 years. | Baseline up to Day 40 | 
| Percentage of Participants Who Initiated Antibiotic Treatment | Secondary illness included bronchitis, pneumonia, acute sinusitis, sinusitis, lower respiratory infection or otitis media. Reported is the percentage of participants with secondary illness, who initiated antibiotic treatment, in adults >/= 18 years and adolescents and children < 18 years. | Baseline up to Day 40 | 
| Percentage of Participants Hospitalized | Reported is the percentage of participants, who required hospitalization at any time between treatment initiation and the end of the study period, in adults >/= 18 years and adolescents and children < 18 years. | Baseline up to Day 40 | 
| Duration of Hospitalization | Reported is the duration of hospitalization at any time between treatment initiation and the end of the study period, in adults >/= 18 years and adolescents and children < 18 years. | Baseline up to Day 40 | 
| Pharmacokinetics: Maximum Plasma Concentration (Cmax) of Oseltamivir in Adults | Reported here are oseltamivir Cmax data for adults >/= 18 years. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Trough Plasma Concentration (Ctrough) of Oseltamivir in Adults | Reported here are oseltamivir Ctrough data for adults >/= 18 years. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics : Area Under the Concentration-Time Curve From 0 to 12 Hours (AUC0-12) at Steady State of Oseltamivir in Adults | AUC0-12 was reported at steady state as nanograms per hour per milliliter. (ng*hr/mL). Reported here are oseltamivir AUC0-12 data for adults >/= 18 years. | Pre-dose (30 minutes), 1.5, 4, 8 hours on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Time to Maximum Concentration (Tmax) of Oseltamivir in Adults | Reported here are oseltamivir tmax data for adults >/= 18 years. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Elimination Constant (ke) of Oseltamivir in Adults | Reported here are oseltamivir ke data for adults >/= 18 years. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Apparent Clearance (CL/F) of Oseltamivir in Adults | Reported here are oseltamivir CL/F data for adults >/= 18 years. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Apparent Volume of Distribution (Vc/F) of Oseltamivir in Adults | Reported here are oseltamivir Vc/F data for adults >/= 18 years. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Cmax of Oseltamivir Carboxylate in Adults | Reported here are oseltamivir carboxylate Cmax data for adults >/= 18 years. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Ctrough of Oseltamivir Carboxylate in Adults | Reported here are oseltamivir carboxylate Ctrough data for adults >/= 18 years. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics : AUC0-12 at Steady State of Oseltamivir Carboxylate in Adults | Reported here are oseltamivir carboxylate AUC0-12 data for adults >/= 18 years. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Tmax of Oseltamivir Carboxylate in Adults | Reported here are oseltamivir carboxylate tmax data for adults >/= 18 years. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Elimination Constant (ke) of Oseltamivir Carboxylate in Adults | Reported here are oxeltamivir carboxylate ke data for adults >/= 18 years. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Apparent Clearance (CL/F) of Oseltamivir Carboxylate in Adults | Reported here are oseltamivir carboxylate CL/F data for adults >/= 18 years. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Apparent Volume of Distribution (Vc/F) of Oseltamivir Carboxylate in Adults | Reported here are oseltamivir carboxylate Vc/F data for adults >/= 18 years. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Cmax of Oseltamivir in Adolescents and Children | Reported here are oseltamivir Cmax data for adolescents and children < 18 years. Individual data are provided as participants received different drug doses. Drug dose is indicated in the row title for each participant. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Ctrough of Oseltamivir in Adolescents and Children | Reported here are oseltamivir Ctrough data for adolescents and children < 18 years. Individual data are provided as participants received different drug doses. Drug dose is indicated in the row title for each participant. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: AUC0-12 at Steady State of Oseltamivir in Adolescents and Children | AUC0-12 will be reported at steady state as ng*hr/mL. Reported here are oseltamivir AUC0-12 data for adolescents and children < 18 years. Individual data are provided as participants received different drug doses. Drug dose is indicated in the row title for each participant. | Pre-dose (30 minutes), 1.5, 4, 8 hours on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Tmax of Oseltamivir in Adolescents and Children | Reported here are oseltamivir data for adolescents and children < 18 years. Individual data are provided as participants received different drug doses. Drug dose is indicated in the row title for each participant. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Cmax of Oseltamivir Carboxylate in Adolescents and Children | Reported here are oseltamivir carboxylate Cmax data for adolescents and children < 18 years. Individual data are provided as participants received different drug doses. Drug dose is indicated in the row title for each participant. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Ctrough of Oseltamivir Carboxylate in Adolescents and Children | Reported here are oseltamivir carboxylate Ctrough data for adolescents and children < 18 years. Individual data are provided as participants received different drug doses. Drug dose is indicated in the row title for each participant. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: AUC0-12 at Steady State of Oseltamivir Carboxylate in Adolescents and Children | AUC0-12 will be reported at steady state as ng*hr/mL. Reported here are oseltamivir carboxylate AUC0-12 data for adolescents and children < 18 years. Individual data are provided as participants received different drug doses. Drug dose is indicated in the row title for each participant. | Pre-dose (30 minutes), 1.5, 4, 8 hours on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Tmax of Oseltamivir Carboxylate in Adolescents and Children | Reported here are oseltamivir carboxylate tmax data for adolescents and children < 18 years. Individual data are provided as participants received different drug doses. Drug dose is indicated in the row title for each participant. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Elimination Constant (ke) of Oseltamivir in Adolescents and Children | Reported here are oseltamivir ke data for adolescents and children < 18 years. Individual data are provided as participants received different drug doses. Drug dose is indicated in the row title for each participant. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Apparent Clearance (CL/F) of Oseltamivir in Adolescents and Children | Reported here are oseltamivir CL/F data for adolescents and children < 18 years. Individual data are provided as participants received different drug doses. Drug dose is indicated in the row title for each participant. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Apparent Volume of Distribution (Vc/F) of Oseltamivir in Adolescents and Children | Reported here are oseltamivir Vc/F data for adolescents and children < 18 years. Individual data are provided as participants received different drug doses. Drug dose is indicated in the row title for each participant. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Elimination Constant (ke) of Oseltamivir Carboxylate in Adolescents and Children | Reported here are oseltamivir carboxylate ke data for adolescents and children < 18 years. Individual data are provided as participants received different drug doses. Drug dose is indicated in the row title for each participant. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Apparent Clearance (CL/F), of Oseltamivir Carboxylate in Adolescents and Children | Reported here are oseltamivir carboxylate CL/F data for adolescents and children < 18 years. Individual data are provided as participants received different drug doses. Drug dose is indicated in the row title for each participant. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose | 
| Pharmacokinetics: Apparent Volume of Distribution (Vc/F) of Oseltamivir Carboxylate in Adolescents and Children | Reported here are oseltamivir carboxylate Vc/F data for adolescents and children < 18 years. Individual data are provided as participants received different drug doses. Drug dose is indicated in the row title for each participant. | Pre-dose (30 minutes), 1.5, 4, 8 hours postdose on Day 6 or any day after the 11th dose |