WV15730.

Methods	Randomised, double‐blind, placebo‐controlled, parallel‐group study. Participants were stratified by current smoking behaviour (smoker/non‐smoker). Centres activated to recruit participants during an influenza outbreak in the locality, detected using standardised surveillance techniques Location, number of centres: Australia and South Africa, 12 centres Duration of study: 21 +/‐ 4 days
Participants	Number screened: not described Number randomised: 58 (oseltamivir: 31; placebo: 27) Number completed: 56 M = 52% F = 48% Mean age: 35 years Baseline details: 93% Caucasian; 21% smoking history Inclusion criteria: Fever ≥ 38 °C 1 or more respiratory symptom (cough, sore throat, nasal symptoms) 1 or more constitutional symptom (headache, myalgia, (aches and pains), sweat/chills (feeling feverish), prostration (fatigue)) ≤ 36 hours post onset of feeling unwell Between 18 and 65 years of age Willing and able to comprehend and give written informed consent Participants were to utilise an effective method of contraception throughout the study period and for 1 reproductive cycle following cessation of study drug Females of childbearing potential had to have negative urine pregnancy test prior to drug dosing Exclusion criteria: Active clinically significant renal, cardiac, pulmonary, vascular, neurologic, metabolic (diabetes, thyroid disorder, adrenal disease) disease, immunodeficiency disorders, cancer, hepatitis or cirrhosis Receipt of transplant Steroids or immuno‐suppressant therapy Pregnant or breast‐feeding females Known HIV infection Allergy to any excipients in capsule or paracetamol Chronic therapy for asthma Previous episode of acute upper respiratory tract infection (URTI): otitis, bronchitis or sinusitis; or received antibiotics for URTI, otitis, sinusitis or bronchitis, or antiviral therapy for influenza within 2 weeks prior to study entry Participation in a clinical study with an investigational drug within 4 weeks prior to study entry Administrations of influenza vaccine less than 12 months prior to study entry The use of the antiviral drugs for influenza such as rimantadine, ribavirin, zanamivir and amantadine was not permitted during this study A clinically relevant history of abuse of alcohol or other drugs Presentation > 36 hours post the onset of feeling unwell Definition of patient populations for analysis  ITTI population (N = 38) Participants analysed according to groups to which they were randomised providing they had received at least 1 dose of study treatment and had laboratory‐confirmed influenza virus infection  ITT population (N = 58) The ITT population consisted of the same participants as the ITTI population; also included participants who did not have laboratory‐confirmed influenza but took at least 1 dose of study medication. Participants analysed by groups to which they were randomised  Safety population (N = 58) All participants randomised, who received at least 1 dose of study medication and at least 1 safety follow‐up, whether or not they had withdrawn prematurely. Participants who received therapy other than intended were analysed according to therapy received  Standard population (N = 38) All randomised participants without major protocol violations or deviations, with laboratory‐confirmed influenza and who received at least the first 6 scheduled doses within 72 hours or who received the first 5 doses within 72 hours and went on to take 9 or 10 doses. Participants analysed according to treatment received
Interventions	Intervention: oseltamivir 75 mg bid (total daily dose: 150 mg), given as size 2 capsule Control: placebo, given as size 2 capsule Treatment period: 5 days Follow‐up period: between 12 and 20 days post‐treatment Co‐interventions: rescue medication pack
Outcomes	Primary outcome: time to alleviation of symptoms. Assessed as alleviation of nasal congestion, sore throat, cough, aches and pains, fatigue, headache and feeling feverish. Time to alleviation of symptoms calculated from study drug initiation to time at which all symptoms were alleviated. Participants withdrawing prior to alleviation of all symptoms were censored at the time of withdrawal Secondary outcomes: Extent and severity of illness Duration of viral shedding Serology Symptoms Rescue medication consumption Household contacts developing ILI Viral resistance Quality of life Pharmacokinetics Adverse events
Notes	Study period not specified
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Original randomisation list not provided
Allocation concealment (selection bias)	Low risk	Central randomisation service
Incomplete outcome data (attrition bias) Symptoms	High risk	Missing data imputed; number missing not reported
Incomplete outcome data (attrition bias) Complications of influenza	High risk	Diagnosis of complication not standardised and based on objective criteria. Method of diagnosis was based on local centre definitions. Unknown what effect this could have on classification of outcome
Incomplete outcome data (attrition bias) Safety data	High risk	Adverse events could be classified as either symptoms of influenza, complications of influenza or adverse events. Reporting is inconsistent and some trials reported the same outcome in the same patient in different categories
Selective reporting (reporting bias)	High risk	70% under‐recruitment
Other bias	High risk	Placebo capsule contained dehydrocholic acid. Unknown what effect this could have had on AEs Mentioned in protocol amendment that South American (SA) sites could not diagnose influenza by culture due to delays in processing, however there is no mention in M1 or rest of M2 that SA sites were included
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Certificates of analysis show identical colour and size
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"No open key to the code was available at the study centre, to the monitors, statistician or at Roche Headquarters. In the event of a medical emergency the blinding was to be broken if considered absolutely mandatory to properly manage the patient by contacting the randomisations centre. The blinding was not broken for any participant during the study."