Evaluating the Use of Oseltamivir for the Treatment of Influenza in Adults

Seasonal influenza is responsible for excess hospitalizations and, despite effective
antivirals, causes significant morbidity and mortality (about 24,000 deaths each year in the
United States alone). The influenza virus that emerged in 2009 (A/California/07/2009 H1N1)
caused fewer deaths (12,000 flu-related deaths in the U.S.) but in contrast to seasonal flu,
nearly 90% of the deaths with the 2009 H1N1 occurred among people younger than 65 years of
age. Although there are four currently licensed anti-influenza medications (amantadine and
rimantadine, oseltamivir, and zanamivir), previous studies have not demonstrated conclusively
to what extent these medications affect influenza viral shedding. This study will evaluate
whether oseltamivir modifies the viral shedding during the treatment of uncomplicated
influenza in an adult population and also assess methods to detect viral replication in the
upper respiratory tract.

Subjects who presented with an influenza-like illness without any risk factors for severe
disease were screened for the study. Those with a confirmatory test for influenza (rapid
antigen or polymerase chain reaction [PCR]) were randomized in a 1:1 manner to receive a
blinded study treatment consisting of either the oseltamivir or placebo for 5 days. Clinical,
virologic, and laboratory assessments on Days 1, 3, 7, and 28 were used for both safety and
efficacy analysis.

Inclusion Criteria:

- Written informed consent prior to initiation of any study procedures

- History of an influenza-like illness defined as:

1) One or more respiratory symptom (cough, sore throat, or nasal symptoms)

- Onset of illness no more than 48 hours before screening, defined as when the
participant experienced at least one respiratory symptom

- Willing to have samples stored

- Positive test for influenza (either rapid antigen or polymerase chain reaction [PCR]);
randomization could proceed in cases of discrepant results (one positive and one
negative)

Exclusion Criteria:

- Hospitalization at the time of screening

- Presence of a medical condition(s) that had been associated with increased risk of
complications from influenza

1. Aged 65 years of age or older

2. Asthma

3. Neurological and neuro-developmental conditions (including disorders of the
brain, spinal cord, peripheral nerve, and muscle, such as cerebral palsy,
epilepsy [seizure disorders], stroke, moderate to severe developmental delay,
muscular dystrophy, or spinal cord injury)

4. Chronic lung disease (such as chronic obstructive pulmonary disease [COPD] or
cystic fibrosis)

5. Heart disease (such as congenital heart disease, congestive heart failure, or
coronary artery disease)

6. Blood disorders

7. Endocrine disorders (such as diabetes mellitus)

8. Kidney disorders

9. Liver disorders

10. Metabolic disorders (such as inherited metabolic disorders or mitochondrial
disorders)

11. Weakened immune system due to disease or medication (such as people with HIV/AIDS
or cancer, or use of chronic steroids or other medications causing immune
suppression)

12. Pregnant or 4 weeks postpartum

13. Body mass index (BMI) greater than or equal to 40

- Breastfeeding

- Inability to take oral medication or a history of gastrointestinal malabsorption that
would preclude the use of oral medication

- Received more than one dose of any antiviral influenza medication since onset of
influenza symptoms

- Known end stage kidney dysfunction (e.g., creatinine clearance less than 30 mL/min)

- Known hypersensitivity to oseltamivir, peramivir, or zanamivir

- Received live attenuated influenza virus vaccine within 3 weeks prior to study entry

- Use of any investigational drug within 30 days or 5 half-lives (whichever was longer)
prior to study entry

- Participated in other research protocols that required more than 100mL of blood to be
drawn in a 4-week period that overlapped with this study.