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Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial

BMJ 2013; 346 doi: https://doi.org/10.1136/bmj.f3039 (Published 30 May 2013) Cite this as: BMJ 2013;346:f3039
  1. South East Asia Infectious Disease Clinical Research Network
  1. Correspondence to: J Farrar, SEAICRN Hospital for Tropical Diseases, 764 Vo Van Kiet, District 5, Ho Chi Minh City 5, Vietnam jfarrar{at}oucru.org
  • Accepted 7 May 2013

Abstract

Objective 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

Footnotes

  • We thank the patients for enrolling themselves and their guardians for granting permission to enrol their children into the study. We dedicate this work to the memory of Endang Rahayu Sedyaningsih, Minister of Health of the Republic of Indonesia 22 October 2009 to 30 April 2012, and Niklas Lindegardh Mahidol, Oxford Research Unit.

  • We thank the following for their support: Nguyen Thi Dung, Pham Thi Ngoc Dung, Dao Tuyet Trinh, Van Dinh Trang, Nguyen Nhu Ha, Nguyen Thi Dai Phong, Nguyen Thi Kim Yen, Khuat Thi Oanh, Nguyen Thi Hang, Pham Thi Thanh Hoa, Vu Thi Nham, Nguyen Thi Oanh, Nguyen Hai Van, Nguyen Bang Giang, Duong Thi Hoa, Nguyen Hong Vu, Mai Thi Hong Hanh, Dang Thi Thu Hang, Tran Thi Sinh, Ngo Thi Hoa, Phung Thi Bich Thuy, Pham Thi Thanh Hoa, Nghiem Thi Tuyet, Do Quang Vi, Nguyen Trung Hang, Nguyen Thi Hong Ha, Sorasak Lohchindarat, Chalermthai Aksilp, Naris Waranawat, Kaewta Intalapaporn, Ruamboon Arjwong, Nantaka Kongstan, Chariya Utenpitak, Ms. Hatairat Lerdsamran, Ms. Phisanu Pooruk, Supaloek Komolsiri, Kantima Sangsiriwut, Supeda Thongyen, Masfi’ah Rivai, Fitriany Darwis, Edha Barapadang, Winarni Arimanunggal, Inggraeni A Soeratman, Ns Emil, Dewi Lesthiowati, Budhi Antariksa, Marsaulina, Dewi Kartika Turbawati, Pudjiastuti Kartidjo, Rima Fajarwati, Nur Izzatun Nafsi, Juva Manurung, Neneng Kurniati, Isman Muhammad Toha, Evan Susandi, Eli Nurhayati, Nita Lestari, Ondri Dwi Sampurno, Hana Apsari Pawestri, Naning Agustiningsih, Christian Yoder, Joseph Chu, Celine Loke, Selina Chee, Rongfang Wang.

  • Investigators in the South East Asia Infectious Diseases Clinical Research Network

  • National Institute for Health Research and Development, Jakarta, Indonesia: Endang Rahayu Sedyaningsih, Moh Suhud Malik, Vivi Setiawaty, Trihono Trihono. Persahabatan Hospital Jakarta, Indonesia: Erlina Burhan, Tjandra Yoga Aditama, Prijanti Z. Soepandi, Lia G Partakusuma, Agung P Sutiyoso, Ika Priatni. Rumah Sakit Hasan Sadikan Bandung, Indonesia: Hadi Jusuf, Emmy Hermiyanti Pranggono, Arto Yuwono Soeroto, Djatnika Setiabudi, Dadang Hudaya Somasetia, Sri Sudarwati, Tini T Maskoen, Yovita Hartantri, Ida Parwati. Sulianto Saroso Hospital Jakarta, Indonesia: Sardikin Giriputro, Dewi Murniati, Sondang Maryutka Sirait, Tony Soetanto, Sri Sulastri, Rismali Agus, Adria Rusli, Sila Wiweka. Eijkman Oxford Clinical Research Unit Indonesia: Steve Wignall, Kevin Baird, Iko Safika. Bamrasnaradura Infectious Disease Institute Nonthaburi, Thailand: Chariya Sangsajja, Weerawat Manosuthi, Patama Sutha. Chest Disease Institute Nonthaburi, Thailand: Chareon Chuchottaworn, Piamlarp Sansayunh, Kittima Bangpattanasiri. Mahidol Oxford Research Unit Bangkok, Thailand: Walter R J Taylor , Kasia Stepniewska, Caroline Fukuda, Niklas Lindegardh, Nicholas White, Nick Day. Queen Sirikit National Institute of Child Health Bangkok, Thailand: Tawee Chotpitayasunondh, Piyarat Suntarattiwong, Umaporn Chantbuddhiwet, Supichaya Netsawang. Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand: Kulkanya Chokephaibulkit, Nirun Vanprapar, Wasana Prasitsuebsai, Orasri Wittawatmongkol, Thanomsak Anekthananon, Winai Ratanasuwan, Yong Rongrungruang, Pilaipan Puthavathana. National University Hospital Singapore: Paul A Tambyah, Yee-Sin Leo, Dale Fisher, Louis Chai, Lawrence Lee, Raymond Lin. Children’s Hospital 1 Ho Chi Minh City, Vietnam: Ngo Ngoc Quang Minh, Truong Huu Khanh, Le Phan Kim Thoa, Le Anh Tuan, Tran Thi My Dung, Lam Thi Thuy Ha, Le Minh Qui, Le Quoc Thinh, Nguyen Ngoc Tu Anh, Tran Anh Tuan, Trinh Hong Nhien, Bui Pham Phuong, Phan Tu Qui, Tieu Chau Thy, Bui Xuan Vu, Le Binh Bao Tinh, Dang Thi Thanh. Children’s Hospital 2 Ho Chi Minh City, Vietnam: Vo Phuong Khanh, Do Chau Viet, Tran Thi Thuy, Vo Quoc Bao, Le Nguyen Nhat Trung, Ho Thi Kim Thoa, Tran Thi Ngoc Anh, Tran Thi Thu Loan, Tran Quynh Huong, Nguyen Thi Hanh Le, Ho Lu Viet, Ha Manh Tuan, Nguyen Thi Thanh Ha. Hospital for Tropical Diseases Ho Chi Minh City, Vietnam: Nguyen Van Vinh Chau, Nguyen Thanh Truong, Le Thi Thu Thao, Nguyen Thanh Phong, Pham Tran Dieu Hien, Pham Thi Hai Men, Cao Thi Tam, Tran Vinh Diet, Phan Tu Qui, Nguyen Van Hao. National Hospital for Tropical Diseases Hanoi, Vietnam: Nguyen Van Kinh, Nguyen Duc Hien, Nguyen Hong Ha, Hoang Van Tuyet, Nguyen Ngoc Phuc, Nguyen Quoc Thai, Luong Quoc Chinh, Nguyen Trung Cap, Vu Dinh Phu, Tran Thi Hai Ninh, Nguyen Vu Trung. National Hospital of Pediatrics Hanoi, Vietnam: Nguyen Thanh Liem, Bui Vu Huy, Luong Thi San, Phan Huu Phuc, Ho Anh Tuan, Cao Viet Tung, Doan Thi Mai Thanh, Le Xuan Ngoc, Pham Viet Hung, Dau Viet Hung, Pham Thu Hien. National Institute of Allergy and Infectious Diseases: John Beigel, Michael Polis, Elizabeth Higgs. Oxford University Clinical Research Unit Vietnam: Nghiem My Ngoc, Tran Thuy Ngan, Nguyen thi Tham, Duong Thi Tam, Nguyen Thi Thuy Chinh BKrong, Le Thi Tam Uyen, Vu thi Ty Hang, Tran Tan Thanh, Juliet E Bryant, Do Quang Ha, Vo Minh Hien, Lam An Nguyet, Le Nguyen Truc Nhu, Huynh Duy Khuong, Elaine Stockwell, Laura Merson, Jeremy J Farrar, Frederick Hayden, Tran Tinh Hien, Annette Fox, Menno D de Jong, Peter Horby, Heiman L Wertheim, H Rogier van Doorn.

  • Contributors: The investigators were involved in all aspects including protocol design, study execution and oversight, and the writing of the paper. All authors have seen and approved the final version. JF is guarantor.

  • Funding and sponsorship: The study was conducted by the South East Asia Infectious Diseases Clinical Research Network (www.seaicrn.org/) and supported by the National Institute of Allergy and Infectious Diseases and the Wellcome Trust of Great Britain. The Singapore site was supported by the Singapore National Medical Research Council.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: Paul Anantharajah Tambyah has received financial support from Inviragen, Fabentech, Sanofi-Pasteur, GSK, MSD, AstraZeneca, and 3M; M d De Jong has received financial support from AIMM therapeutics, Crucell BV, and AviBiopharma. F Hayden received grants from National Institute of Allergy and Infectious Disease/SAIC during the conduct of the study; personal fees from law firms, Practice Point Communications, and the American Society for Microbiology; since 2008 he has provided non-compensated advice to multiple companies involved in the development and/or marketing of antiviral agents or biologics for influenza including Roche, GSK, Biocryst, Medivector, Romark, Nexbio, Theraclone, and others.

  • Ethical approval: The protocol was approved by the ethics committees of all hospitals, the National Institute of Allergy and Infectious Diseases, and the Oxford University tropical ethics committee, and informed consent was given by all patients (or proxies).

  • Data sharing: Technical appendix, statistical code, and dataset available from the corresponding author. Consent from participants for data sharing was not obtained but the presented data are anonymised and risk of identification is low.

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