Oseltamivir clinical studies

# Clinical Studies

## Treatment of Influenza

### Adult and Adolescents Subjects (13 years of age and older)
Two placebo-controlled double-blind clinical trials were conducted: one in the U.S. and one outside the U.S. Subjects were eligible for these trials if they had fever >100F, accompanied by at least one respiratory symptom (cough, nasal symptoms, or sore throat) and at least one systemic symptom (myalgia, chills/sweats, malaise, fatigue, or headache) and influenza virus was known to be circulating in the community. In addition, all subjects enrolled in the trials were allowed to take fever-reducing medications.
Of 1355 subjects enrolled in these two trials, 849 (63%) subjects were influenza-infected (age range 18 to 65 years; median age 34 years; 52% male; 90% Caucasian; 31% smokers). Of the 849 influenza-infected subjects, 95% were infected with influenza A, 3% with influenza B, and 2% with influenza of unknown type.
TAMIFLU was started within 40 hours of onset of symptoms. Subjects participating in the trials were required to self-assess the influenza-associated symptoms as "none," "mild," "moderate," or "severe." Time to improvement was calculated from the time of treatment initiation to the time when all symptoms (nasal congestion, sore throat, cough, aches, fatigue, headaches, and chills/sweats) were assessed as "none" or "mild." In both studies, at the recommended dose of TAMIFLU 75 mg twice daily for 5 days, there was a 1.3 day reduction in the median time to improvement in influenza-infected subjects receiving TAMIFLU compared to subjects receiving placebo. Subgroup analyses of these studies by gender showed no differences in the treatment effect of TAMIFLU in men and women.
In the treatment of influenza, no increased efficacy was demonstrated in subjects receiving treatment of 150 mg TAMIFLU twice daily for 5 days.

### Geriatric Subjects
Three double-blind placebo-controlled treatment trials were conducted in subjects 65 years of age in three consecutive seasons. The enrollment criteria were similar to that of adult trials with the exception of fever being defined as >97.5F. Of 741 subjects enrolled, 476 (65%) subjects were influenza-infected. Of the 476 influenza-infected subjects, 95% were infected with influenza type A and 5% with influenza type B.
In the pooled analysis, at the recommended dose of TAMIFLU 75 mg twice daily for 5 days, there was a 1-day reduction in the median time to improvement in influenza-infected subjects receiving TAMIFLU compared to those receiving placebo (p=NS). However, the magnitude of treatment effect varied between studies.

### Pediatric Subjects (1 to 12 years of age)
One double-blind placebo-controlled treatment trial was conducted in pediatric subjects aged 1 to 12 years (median age 5 years), who had fever (>100F) plus one respiratory symptom (cough or coryza) when influenza virus was known to be circulating in the community. Of 698 subjects enrolled in this trial, 452 (65%) were influenza-infected (50% male; 68% Caucasian). Of the 452 influenza-infected subjects, 67% were infected with influenza A and 33% with influenza B.
The primary endpoint in this study was the time to freedom from illness, a composite endpoint that required 4 individual conditions to be met. These were: alleviation of cough, alleviation of coryza, resolution of fever, and parental opinion of a return to normal health and activity. TAMIFLU treatment of 2 mg/kg twice daily, started within 48 hours of onset of symptoms, significantly reduced the total composite time to freedom from illness by 1.5 days compared to placebo. Subgroup analyses of this study by gender showed no differences in the treatment effect of TAMIFLU in male and female pediatric subjects.

### Pediatric Subjects (2 weeks to less than 1 year of age)
Two open label trials evaluated the safety and pharmacokinetics of oseltamivir and oseltamivir carboxylate in influenza infected pediatric subjects 2 weeks to less than 1 year of age (including premature infants at least 36 weeks post conceptional age). Subjects received TAMIFLU at doses ranging from 2 to 3.5 mg/kg twice daily for 5 days depending on subject age. These clinical trials were not designed to evaluate clinical efficacy or virologic response.
Of the 136 subjects under the age of 1 year enrolled and dosed in the trials, the majority of the subjects were male (55%), white (79%), non-Hispanic (74%), full term (76%) and infected with influenza A (80%). Pharmacokinetic data indicated that a dose of 3 mg/kg twice daily in pediatric subjects 2 weeks to less than 1 year of age provided TAMIFLU concentrations similar to or higher than those observed in older pediatric subjects and adults receiving the approved dose and, by extrapolation, is expected to provide similar efficacy. The trials provided adequate safety data to support this dose selection .

## Prophylaxis of Influenza

### Adult and Adolescent Subjects (13 years of age and older)
The efficacy of TAMIFLU in preventing naturally occurring influenza illness has been demonstrated in three seasonal prophylaxis studies and a postexposure prophylaxis study in households. The primary efficacy parameter for all these studies was the incidence of laboratory-confirmed clinical influenza. Laboratory-confirmed clinical influenza was defined as oral temperature 99.0F/37.2C plus at least one respiratory symptom (cough, sore throat, nasal congestion) and at least one constitutional symptom (aches and pain, fatigue, headache, chills/sweats), all recorded within 24 hours, plus either a positive virus isolation or a four-fold increase in virus antibody titers from baseline.
In a pooled analysis of two seasonal prophylaxis studies in healthy unvaccinated adults (aged 13 to 65 years), TAMIFLU 75 mg once daily taken for 42 days during a community outbreak reduced the incidence of laboratory-confirmed clinical influenza from 5% (25/519) for the placebo group to 1% (6/520) for the TAMIFLU group.
In a seasonal prophylaxis study in elderly residents of skilled nursing homes, TAMIFLU 75 mg once daily taken for 42 days reduced the incidence of laboratory-confirmed clinical influenza from 4% (12/272) for the placebo group to <1% (1/276) for the TAMIFLU group. About 80% of this elderly population were vaccinated, 14% of subjects had chronic airway obstructive disorders, and 43% had cardiac disorders.
In a study of postexposure prophylaxis in household contacts (aged 13 years) of an index case, TAMIFLU 75 mg once daily administered within 2 days of onset of symptoms in the index case and continued for 7 days reduced the incidence of laboratory-confirmed clinical influenza from 12% (24/200) in the placebo group to 1% (2/205) for the TAMIFLU group. Index cases did not receive TAMIFLU in the study.

### Pediatric Subjects (1 to 12 years of age)
The efficacy of TAMIFLU in preventing naturally occurring influenza illness has been demonstrated in a randomized, open-label, postexposure prophylaxis study in households that included pediatric subjects aged 1 to 12 years, both as index cases and as family contacts. All index cases in this study received treatment. The primary efficacy parameter for this study was the incidence of laboratory-confirmed clinical influenza in the household. Laboratory-confirmed clinical influenza was defined as oral temperature 100F/37.8C plus cough and/or coryza recorded within 48 hours, plus either a positive virus isolation or a four-fold or greater increase in virus antibody titers from baseline or at illness visits. Among household contacts 1 to 12 years of age not already shedding virus at baseline, TAMIFLU for oral suspension 30 mg to 60 mg taken once daily for 10 days reduced the incidence of laboratory-confirmed clinical influenza from 17% (18/106) in the group not receiving prophylaxis to 3% (3/95) in the group receiving prophylaxis.

### Immunocompromised Subjects
A double-blind, placebo-controlled study was conducted for seasonal prophylaxis of influenza in 475 immunocompromised subjects (including 18 pediatric subjects 1 to 12 years of age) who had received solid organ (n=388; liver, kidney, liver and kidney) or hematopoietic stem cell transplants (n=87). Median time since transplant for solid organ transplant recipients was 1105 days for the placebo group and 1379 days for the oseltamivir group. Median time since transplant for hematopoietic stem cell transplant recipients was 424 days for the placebo group and 367 days for the oseltamivir group. Approximately 40% of subjects received influenza vaccine prior to entering the study. The primary efficacy endpoint for this study was the incidence of confirmed, clinical influenza, defined as oral temperature >99.0F/37.2C plus cough and/or coryza, all recorded within 24 hours, plus either a positive virus culture or a four-fold increase in virus antibody titers from baseline. The incidence of confirmed clinical influenza was 3% (7/238) in the group not receiving TAMIFLU compared with 2% (5/237) in the group receiving TAMIFLU; this difference was not statistically significant. A secondary analysis was performed using the same clinical symptoms and RT-PCR for laboratory confirmation of influenza. Among subjects who were not already shedding virus at baseline, the incidence of RT-PCR-confirmed clinical influenza was 3% (7/231) in the group not receiving TAMIFLU and <1% (1/232) in the group receiving TAMIFLU.