Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Dobson J, Whitley RJ, Pocock S, Monto AS. Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials. Lancet 2015; published online Jan 30. http://dx.doi.org/10.1016/S0140-6736(14)62449-1. Appendix 1: Search strategy Inclusion criteria: randomised double-blind placebo-controlled trials of oseltamivir in treatment of naturally occurring influenza-like illness in adults, reporting at least one of the following outcomes: time to symptom alleviation, complications, hospitalisations and adverse events. Trials reporting before 1 st January 2014 were eligible for inclusion. Search results: MEDLINE (176 records) EMBASE (343 records) CENTRAL (107 records) PubMed (35 records; year 2013 only) Clinical Trials.gov (85 records) Roche database (9 records) 741 excluded after reviewing titles/abstracts as duplicates or did not meet search criteria 14 records full text reviewed 3 excluded as secondary publications of published trials 11 eligible for meta-analysis 2 excluded as individual patient data not available 9 included in individual patient data meta-analysis Details of search strategy: 1. Medline (OVID) – 176 records The Cochrane highly sensitive search strategy for identifying RCTs in MEDLINE (sensitivity and precision maximising version) [2008 revision] was used. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 randomized controlled trial.pt. controlled clinical trial.pt. randomized.ab. placebo.ab. clinical trials as topic.sh. randomly.ab. trial.ti. 1 or 2 or 3 or 4 or 5 or 6 or 7 exp animals/ not humans.sh. 8 not 9 oseltamivir.sh. oseltamivir.nm. oseltamivir.tw. tamiflu.tw. 64-0796.tw. 11 or 12 or 13 or 14 or 15 exp Influenza, Human/ exp Influenzavirus B/ or exp Influenzavirus A/ influenza*.tw. flu.tw. 17 or 18 or 19 or 20 1 22 10 and 16 and 21 23 limit 22 to yr="1902 - 2013" 2. EMBASE (Ovid) – 343 records 1 (random$ or placebo$ or factorial$ or crossover$ or cross-over$ or volunteer$ or assign$ or allocate$ or ((singl$ or doubl$) adj3 blind$)).ab,ti. 2 exp randomized controlled trial/ or exp single blind procedure/ or exp double blind procedure/ or exp crossover procedure/ 3 1 or 2 4 (oseltamivir or tamiflu or 64-0796).ab,ti. 5 exp oseltamivir/ 6 4 or 5 7 (influenza$ or flu).ab,ti. 8 exp influenza/ or exp influenza virus a/ or exp influenza virus b/ 9 7 or 8 10 3 and 6 and 9 11 limit 10 to yr="1900 - 2013" 3. Cochrane Central Register of Controlled Trials (CENTRAL) – 107 records Adapted from MEDLINE search (excluding trial search terms) #1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11 #12 MeSH descriptor: [Influenza, Human] explode all trees MeSH descriptor: [Influenzavirus A] explode all trees MeSH descriptor: [Influenzavirus B] explode all trees influenza*:ti,ab,kw "flu":ti,ab,kw #1 or #2 or #3 or #4 or #5 MeSH descriptor: [Oseltamivir] explode all trees tamiflu:ti,ab,kw 64-0796:ti,ab,kw #7 or #8 or #9 #6 and #10 #11 Publication Year from 1900 to 2013 4. Additional sources PubMed – 35 records Text terms (search all fields) used to identify un-indexed recent trial publications (limited to year 2013). Clinical trials.gov – 107 records Text terms used to identify registered trials of oseltamivir. Roche database – 9 records Roche (manufacturer of oseltamivir) provided individual patient data for all their trials of oseltamivir in adults, both published and unpublished. 2 Appendix Table 2: Characteristics of oseltamivir treatment trials (bid = twice daily; ITT = intention-to-treat; ITTI = intention-to-treat infected) Trial number, timing and location M760018 1998-1999 USA WV15819/WV15876/W V159789 1999-2000 Europe, Israel, USA, Canada, South Africa, New Zealand, Australia WV1567010 1997-1998 Europe, Canada, China WV15812/WV158729 1999 Australia, New Zealand, South Africa, Europe, USA, Canada JV1582311 1999-2000 Japan WV1567112 1997-1998 USA WV16277 2001 Europe WV1573013 1998 Australia, South Africa WV15707 1998 Australia, South Africa, South America Key inclusion criteria Interventions Length of followup 21 days (+/- 4) Primary endpoint of trial Total (planned) number subjects 1) Aged ≥13 to 80 yrs 2) Fever ≥100°F, ≥ 1 respiratory symptom and ≥1 constitutional symptom of influenza, and within 36 hours of onset of influenza symptoms. 1) Aged ≥65 years. 2) Fever ≥37·5°C, ≥ 1 respiratory symptom and ≥1 constitutional symptom of influenza, and within 36 hours of onset of influenza symptoms. 75mg bid Oseltamivir vs placebo (2:1 randomisation). 5 days at approx 12 hour intervals. Time to alleviation of all symptoms ITT: 1447 (1425) ITTI: 1063 (783) 73% infected 75mg bid Oseltamivir vs placebo (1:1 randomisation). 5 days at approx 12 hour intervals. 21 days (+/- 4) Time to alleviation of all symptoms ITT: 736 (500) ITTI: 477 (250) 65% infected 360 223 (62) 376 254 (68) 1) Aged ≥18 and ≤ 65 yrs. 2) Fever ≥38·0°C, ≥ 1 respiratory symptom and ≥1 constitutional symptom of influenza, and within 36 hours of onset of influenza symptoms. 1) Aged ≥13 years. 2) Fever ≥38°C (100° F) if <65yrs / fever ≥37·5°C (99·5°F) if ≥65yrs, ≥ 1 respiratory symptom and ≥1 constitutional symptom of influenza, and within 36 hours of onset of influenza symptoms. 3) Chronic cardiac and/or respiratory disease. 1) Aged >16 yrs. 2) Fever >38·0°C, >2 clinical symptoms of influenza, and within 36 hours of onset of influenza symptoms. 1) Aged ≥18 and ≤65 years. 2) Fever ≥38·0°C, ≥ 1 respiratory symptom and ≥1 constitutional symptom of influenza, and within 36 hours of onset of influenza symptoms. 1) Aged ≥13 yrs 2) Fever ≥37·8°C, ≥ 1 respiratory symptom and ≥1 constitutional symptom of influenza, and within 36 hours of onset of influenza symptoms. 75mg bid Oseltamivir vs 150mg bid Oseltamivir vs placebo (1:1:1 randomisation). 5 days at approx 12 hour intervals. 75mg bid Oseltamivir vs placebo (1:1 randomisation). 5 days at approx 12 hour intervals. 21 days (+/- 4) Time to alleviation of all symptoms 235 161 (69) Time to alleviation of all symptoms 75mg 241 150mg 243 199 158 (66) 21 days (+/- 4) ITT: 476 (500) ITTI: 319 (75mg + plac) 67% infected ITT: 402 (500) ITTI: 251 (250) 62 % infected 118 (59) 203 133 (66) 75mg bid Oseltamivir vs placebo (1:1 randomisation). 5 days after morning and evening meals. 75mg bid Oseltamivir vs 150mg bid Oseltamivir vs placebo (1:1:1 randomisation). 5 days at approx 12 hour intervals. 75mg bid Oseltamivir vs placebo (1:1 randomisation). 5 days at approx 12 hour intervals. 21 days Time to alleviation of all symptoms ITT: 313 ITTI: 252 (250) 81% infected 153 122 (80) 160 130 (81) 21 days (+/- 4) Time to alleviation of all symptoms ITT: 419 (500) ITTI: 253 (250) (75mg + plac) 60% infected ITT: 451 (1250) ITTI: 228 (750) 51% infected 75mg 210 150mg 208 226 124 (59) 209 129 (62) 119 (53) 225 109 (48) 1) Aged ≥18 and ≤65 years. 2) Fever ≥38·0°C, ≥ 1 respiratory symptom and ≥1 constitutional symptom of influenza, and within 36 hours of onset of influenza symptoms. 1) Aged >65 years. 2) Fever ≥37·5 deg C, ≥ 1 respiratory symptom and ≥1 constitutional symptom of influenza, and within 36 hours of onset of influenza symptoms. 75mg bid Oseltamivir vs placebo (1:1 randomisation). 5 days at approx 12 hour intervals. 21 days (+/- 4) ITT: 58 (500) ITTI: 38 (250) 66% infected 31 19 (61) 27 19 (70) 75mg bid Oseltamivir vs placebo (1:1 randomisation). 5 days at approx 12 hour intervals. 21 days (+/- 4) ITT: 26 (400) ITTI: 12 (200) 46% infected 17 6 (35) 9 6 (67) 21 days (+/- 4) Prop alleviated of cough and without fever at 36 hours Time to alleviation of all symptoms Time to alleviation of all symptoms Oseltamivir Number Number of ITT ITTI (% subjects infected) 965 702 (73) Placebo Number Number of ITT ITTI (% subjects infected) 482 361 (75) 156 (64) 121 (58) 3 Appendix Table 3: Number of subjects by influenza virus type, both overall and for each trial (n=2893) Virus type A Virus type B Unknown type ALL A: Nonspecific A A-H3N2 M76001 866 760 102 4 197 0 WV15819_876_978 450 148 302 0 26 1 WV15670 308 0 295 13 11 0 WV15812_872 205 134 71 0 46 0 JV15823 240 2 184 54 11 1 WV15671 236 1 235 0 4 13 WV16277 205 40 6 159 21 2 WV15730 36 0 33 3 0 2 WV15707 12 1 11 0 0 0 A-H1N1 Overall 2558 (88%) 1086 1239 233 316 (11%) 19 (1%) Note: culture type taken in preference to antibody type, unless antibody type more specific (e.g. non-specific A on culture). 4 Appendix Table 4: Baseline characteristics of subjects in the intention-to-treat population of trials, by treatment group (number [%] unless otherwise stated) M76001 WV15819_876_ 978 Oselt Plac 34 (24, 46) 80 (8) 856 (89) 29 (3) 32·5 (23, 46) 38 (8) 431 (89) 13 (3) 424 (44) WV15730 WV15707 Oselt Plac Oselt Plac Oselt Plac Oselt Plac Oselt Plac 376 241 235 199 203 153 160 210 209 226 225 31 27 17 9 72 (68, 77) - 71 (67, 77) - 56 (40, 68) 3 (2) 127 (64) 69 (35) 51 (38, 62) 3 (1) 158 (78) 41 (20) 30 (23, 44) 146 (95) 7 (5) 30 (23, 37) 2 (1) 149 (93) 9 (6) 29.5 (23, 40) 210 (100) 31 (24, 40) 209 (100) - 32 (24, 43) 17 (8) 200 (89) 8 (4) 32 (26, 41) 31 (100) - 33 (25, 43) 15 (7) 203 (90) 8 (4) - 34 (27, 45) 26 (96) 1 (4) 70 (66, 73) - 376 (100) 36 (28, 47) 234 (100) 1 (0) 71 (69, 74) - 360 (100) 37 (30, 46) 240 (100) 1 (0) 17 (100) 9 (100) 215 (45) 150 (42) 166 (44) 120 (50) 117 (50) 86 (43) 91 (45) 66 (43) 85 (53) 98 (47) 97 (46) 112 (50) 112 (50) 16 (52) 14 (52) 10 (59) 4 (44) 24·0 (17·3, 29·7) 475 (49) 24·3 (16·5, 30·3) 235 (49) 25·2 (18·5, 30·3) 158 (44) 25·3 (19·2, 30·1) 154 (41) 23·7 (16·5, 28·7) 122 (51) 23·0 (16·5, 28·5) 125 (53) 26·3 (19·0, 30·7) 79 (40) 25·8 (19·5, 30·4) 75 (37) 24·0 (17·5, 29·8) 76 (50) 24·2 (17·6, 27·5) 77 (48) 24·5 (18·8, 30·8) 96 (46) 25·6 (19·8, 30·3) 76 (36) 23·5 (18·0, 28·5) 119 (53) 22·5 (14·8, 28·5) 124 (55) 26·3 (15·6, 30·8) 11 (35) 26·8 (20·8, 30·2) 10 (37) 25·7 (21·8, 29·7) 5 (29) 26·0 (19·5, 33·6) 4 (44) 15 (12, 17) 15 (12, 17) 12 (10, 15) 12 (10, 15) 14 (11, 16) 15 (11·5, 17) 14 (11, 16) 13 (11, 16) 12 (10, 14) 12 (10·5, 14) 14 (12, 16) 14 (12, 17) 13 (11, 16) 13 (11, 16) 13 (11, 15) 14 (13, 15) 12 (8, 15) 13 (9, 14) COAD 5 (1) 2 (0) 24 (7) 38 (10) 0 0 155 (78) 150 (74) 0 0 0 0 6 (3) 7 (3) 0 0 4 (24) 0 Smoker 206 (21) 80 (17) N/A N/A 82 (34) 85 (36) 40 (20) 48 (24) 44 (29) 65 (41) 58 (28) 57 (27) N/A N/A 7 (23) 5 (19) N/A N/A 0 8 (4) 3 (1) 0 0 0 1 (4) 0 0 Total symptom score Median (IQR) 360 WV16277 Plac Time from onset to treatment in hrs Median (IQR) <24hrs 482 WV15671 Oselt Male 965 JV15823 Plac 65+ yrs Plac WV15812_872 Oselt N subjects Age in yrs Median (IQR) 13-16 yrs 17-64 yrs Oselt WV15670 Antibiotic s at baseline 39 (4) 26 (5) 7 (2) 12 (3) 12 (5) 4 (2) 6 (3) 8 (4) 0 IQR = interquartile range; COAD = chronic obstructive airways disease; N/A = not available 5 Appendix Table 5: Meta-analyses of all on treatment adverse events in the safety population, by treatment received Number of events Oseltamivir Placebo n=2401 n=1917 1033 819 21 22 574 370 247 118 201 63 147 147 16 12 13 20 45 29 20 18 103 93 14 9 231 217 15 4 26 29 26 29 38 25 Overall risk ratio (95% CI) 0·97 (0·91, 1·04) 0·79 (0·43, 1·47) 1·21 (1·07, 1·36) 1·60 (1·29, 1·99) 2·43 (1·83, 3·23) 0·75 (0·60, 0·95) 1·01 (0·47, 2·18) 0·49 (0·25, 0·98) 1·10 (0·68, 1·77) 0·86 (0·45, 1·65) 0·85 (0·64, 1·12) 1·01 (0·45, 2·23) 0·84 (0·70, 1·00) 3·37 (1·08, 10·47) 0·84 (0·51, 1·37) 0·73 (0·43, 1·25) 1·19 (0·73, 1·95) Placebo group risk (%)* 42·7 1·1 19·3 6·2 3·3 7·7 0·6 1·0 1·5 0·9 4·9 0·5 11·3 0·2 1·5 1·5 1·3 Outcomes P-value All AE 0·41 Serious AE 0·46 Gastrointestinal disorders 0·0019 Nausea <0·0001 Vomiting <0·0001 Diarrhoea 0·016 Blood & lymphatic system disorders 0·97 Cardiac disorders 0·043 Ear & labyrinth disorders 0·70 Eye disorders 0·65 General disorders 0·24 Hepato-biliary disorders 0·99 Infections & infestations 0·049 Injury & poisoning 0·036 Investigations 0·48 Metabolism & nutrition disorders 0·25 Musculoskeletal, connective tissue & bone 0·48 disorders Neurological disorders 124 93 1·00 (0·76, 1·30) 0·97 4·9 Psychiatric disorders 11 13 0·62 (0·26, 1·45) 0·27 0·7 Renal & Urinary disorders 22 9 1·81 (0·84, 3·88) 0·13 0·5 Reproductive system & breast disorders 6 2 2·19 (0·35, 13·71) 0·40 0·1 Respiratory, thoracic & mediastinal 158 143 0·74 (0·60, 0·93) 0·0081 7·5 disorders Skin & subcutaneous tissue disorders 45 31 1·14 (0·72, 1·80) 0·58 1·6 Vascular disorders 17 10 1·42 (0·63, 3·21) 0·40 0·5 Additional analyses in influenza-infected subjects: n=1590 n=1299 Neurological disorders 91 73 0·95 (0·70, 1·29) 0·76 5·6 Psychiatric disorders 10 9 0·81 (0·31, 2·08) 0·65 0·7 Nausea 172 85 1·60 (1·24, 2·07) 0·0003 6·5 Vomiting 155 41 3·00 (2·11, 4·26) <0·0001 3·2 Additional analyses in subjects without influenza: n=811 n=618 Nausea 75 33 1·67 (1·12, 2·49) 0·011 5·3 Vomiting 46 22 1·49 (0·90, 2·46) 0·12 3·6 n=number of subjects. Events = number of subjects having ≥1 event. * Placebo group risk is calculated using all trials (including trials with 0 outcomes in each arm). ** Oseltamivir group risk and risk difference (95% CI) obtained by applying overall risk ratio and 95% CI to pooled placebo group risk Oseltamivir group risk (%)** 41·5 0·9 23·3 9·9 8·0 5·8 0·6 0·5 1·7 0·8 4·1 0·5 9·5 0·7 1·3 1·1 1·6 Risk difference (95% CI) (%) -1·2 (-4·0, 1·8) -0·2 (-0·7, 0·5) 4·0 (1·4, 6·9) 3·7 (1·8, 6·1) 4·7 (2·7, 7·3) -1·9 (-3·1, -0·4) 0·0 (-0·3, 0·7) -0·5 (-0·8, -0·0) 0·2 (-0·5, 1·2) -0·1 (-0·5, 0·6) -0·7 (-1·7, 0·6) 0·0 (-0·3, 0·6) -1·8 (-3·4, -0·0) 0·5 (0·0, 2·0) -0·2 (-0·7, 0·6) -0·4 (-0·9, 0·4) 0·2 (-0·4, 1·2) 4·8 0·4 0·8 0·2 5·5 -0·0 -0·3 0·4 0·1 -1·9 (-1·2, 1·5) (-0·5, 0·3) (-0·1, 1·4) (-0·1, 1·3) (-3·0, -0·6) 1·8 0·7 0·2 0·2 (-0·5, 1·3) (-0·2, 1·2) 5·4 0·6 10·5 9·5 -0·3 -0·1 3·9 6·3 (-1·7, 1·6) (-0·5, 0·7) (1·6, 7·0) (3·5, 10·3) 8·9 5·3 3·6 1·7 (0·7, 7·9) (-0·4, 5·2) 6 Appendix Table 6a: Number of subjects with on treatment serious adverse events in the safety population, by body system class and treatment received. Number of events Oseltamivir Placebo Outcomes n=2401 n=1917 Gastrointestinal disorders 2 2 Benign & malignant neoplasms 0 1 Blood & lymphatic system disorders 1 1 Cardiac disorders 1 2 General disorders 2 3 Infections & infestations 11 10 Injury & poisoning 1 0 Metabolism & nutrition disorders 1 1 Neurological disorders 0 1 Psychiatric disorders 0 1 Respiratory, thoracic & mediastinal disorders 4 2 Surgical & medical procedures 1 0 Vascular disorders 1 0 n=number of subjects. Events=number of subjects having ≥1 serious adverse event within each body system class. Note: a subject may experience a serious adverse event in more than one body system class. Appendix Table 6b: Number of subjects with off treatment serious adverse events in the safety population, by body system class and treatment received. Number of events Oseltamivir Placebo Outcomes n=2401 n=1917 Gastrointestinal disorders 1 4 Benign & malignant neoplasms 1 0 Cardiac disorders 1 3 Eye disorders 0 1 Infections & infestations 1 4 Investigations 0 1 Neurological disorders 0 1 Pregnancy, puerperium & perinatal condiations 1 4 Psychiatric disorders 0 1 Reproductive system & breast disorders 1 0 Respiratory, thoracic & mediastinal disorders 0 1 Vascular disorders 1 2 n=number of subjects. Events=number of subjects having ≥1 serious adverse event within each body system class. Note: a subject may experience a serious adverse event in more than one body system class. Appendix Table 6c: Number of subjects with on treatment cardiac disorder adverse events in the safety population, by preferred term and treatment received. Number of events Oseltamivir Placebo Outcomes n=2401 n=1917 Angina pectoris 0 1 Angina unstable 1 1 Atrial fibrillation 1 1 Atrial tachycardia 1 0 Cardiac failure aggravated 0 1 Cardiac failure nos 1 0 Chest pain – cardiac 0 1 Cyanosis nos 0 1 Heart rate increased 2 1 Left ventricular failure 0 2 Oedema lower limb 1 0 Oedema upper limb 1 0 Palpitations 2 5 Pericarditis nos 0 1 Pulse irregular 1 2 Tachycardia nos 1 3 Valvular heart disease nos 1 0 n=number of subjects. Events=number of subjects having ≥1 cardiac disorder adverse event within each preferred term. 7