Endang Rahayu SedyaningsihMoh Suhud MalikVivi SetiawatyTrihono TrihonoErlina BurhanTjandra Yoga AditamaPrijanti Z. SoepandiLia G. PartakusumaAgung P. SutiyosoIka PriatniHadi JusufEmmy Hermiyanti PranggonoArto Yuwono SoerotoDjatnika SetiabudiDadang Hudaya SomasetiaSri SudarwatiTini T. MaskoenYovita HartantriIda ParwatiSardikin GiriputroDewi MurniatiSondang Maryutka SiraitTony SoetantoSri SulastriRismali AgusAdria RusliSila WiwekaSteve WignallKevin BairdIko SafikaChariya SangsajjaWeerawat ManosuthiPatama SuthaChareon ChuchottawornPiamlarp SansayunhKittima BangpattanasiriWalter R.J. TaylorKasia StepniewskaCaroline FukudaNiklas LindegardhNicholas WhiteNick DayTawee ChotpitayasunondhPiyarat SuntarattiwongUmaporn ChantbuddhiwetSupichaya NetsawangKulkanya ChokephaibulkitNirun VanpraparWasana PrasitsuebsaiOrasri WittawatmongkolThanomsak AnekthananonWinai RatanasuwanYong RongrungruangPilaipan PuthavathanaPaul A. TambyahYee Sin LeoDale FisherLouis ChaiLawrence LeeRaymond LinNgo Ngoc Quang MinhTruong Huu KhanhLe Phan Kim ThoaLe Anh TuanTran Thi My DungLam Thi Thuy HaLe Minh QuiLe Quoc ThinhNguyen Ngoc Tu AnhTran Anh TuanTrinh Hong NhienBui Pham PhuongPhan Tu QuiTieu Chau ThyBui Xuan VuLe Binh Bao TinhDang Thi ThanhVo Phuong KhanhDo Chau VietTran Thi ThuyVo Quoc BaoLe Nguyen Nhat TrungHo Thi Kim ThoaTran Thi Ngoc AnhTran Thi Thu LoanTran Quynh HuongNguyen Thi Hanh LeHo Lu VietHa Manh TuanNguyen Thi Thanh HaNguyen Van Vinh ChauNguyen Thanh TruongLe Thi Thu ThaoNguyen Thanh PhongPham Tran Dieu HienPham Thi Hai MenCao Thi TamTran Vinh DietNguyen Van HaoBadan Penelitian Dan Pengembangan Kesehatan, Kementerian Kesehatan Republik IndonesiaPersahabatan HospitalRumah Sakit Hasan Sadikan BandungSulianto Saroso Hospital JakartaEijkman Oxford Clinical Research UnitBamrasnaradura Infectious Disease InstituteChest Disease Institute NonthaburiMahidol Oxford Research Unit BangkokQueen Sirikit National Institute of Child HealthMahidol UniversityNational University Hospital, SingaporeChildren's Hospital 1Children's Hospital 2UCLNational Hospital for Tropical Diseases2018-10-192018-10-192013-06-08BMJ (Online). Vol.346, No.7911 (2013)175618332-s2.0-84878821350https://repository.li.mahidol.ac.th/handle/20.500.14594/32300Objective: To investigate the validity of recommendations in treatment guidelines to use higher than approved doses of oseltamivir in patients with severe influenza. Design: Double blind randomised trial. Setting: Thirteen hospitals in Indonesia, Singapore, Thailand, and Vietnam. Participants: Patients aged ≥1 year admitted to hospital with confirmed severe influenza. Interventions: Oral oseltamivir at double dose (150 mg twice a day/paediatric equivalent) versus standard dose (75 mg twice a day/paediatric equivalent). Main outcome measure: Viral status according to reverse transcriptase polymerase chain reaction (RT-PCR) for influenza RNA in nasal and throat swabs on day five. Results: Of 326 patients (including 246 (75.5%) children aged <15), 165 and 161 were randomised to double or standard dose oseltamivir, respectively. Of these, 260 (79.8%) were infected with influenza virus A (133 (40.8%) with A/H3N2, 72 (22.1%) with A/H1N1-pdm09, 38 (11.7%) with seasonal A/H1N1, 17 (5.2%) with A/H5N1) and 53 (16.2%) with influenza virus B. A further 3.9% (13) were false positive by rapid antigen test (negative by RT-PCR and no rise in convalescent haemagglutination inhibition titers). Similar proportions of patients were negative for RT-PCR on day five of treatment: 115/159 (72.3%, 95% confidence interval 64.9% to 78.7%) double dose recipients versus 105/154 (68.2%, 60.5% to 75.0%) standard dose recipients; difference 4.2% (-5.9 to 14.2); P=0.42. No differences were found in clearance of virus in subgroup analyses by virus type/subtype, age, and duration of illness before randomisation. Mortality was similar: 12/165 (7.3%, 4.2% to 12.3%) in double dose recipients versus 9/161 (5.6%, 3.0% to 10.3%) in standard dose recipients. No differences were found between double and standard dose arms in median days on supplemental oxygen (3 (interquartile range 2-5) v 3.5 (2-7)), in intensive care (4.5 (3-6) v 5 (2-11), and on mechanical ventilation (2.5 (1-16) v 8 (1-16)), respectively. No important differences in tolerability were found. Conclusions: There were no virological or clinical advantages with double dose oseltamivir compared with standard dose in patients with severe influenza admitted to hospital. Registration: Clinical Trials NCT00298233.Mahidol UniversityMedicineArticleSCOPUS10.1136/bmj.f3039