SUPPLEMENTARY MATERIAL Journal: Clinical Drug Investigation Title: Safety profile of biologic drugs in the treatment of inflammatory bowel diseases: a systematic review and network meta-analysis of randomized controlled trials Paweł Moćko (P.M.) 1, Paweł Kawalec (P.K.) 1, Andrzej Pilc (A.P.) 1,2 1 Drug Management Department, Institute of Public Health, Faculty of Health Sciences, Jagiellonian University, Kraków, Poland 2 Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland Corresponding author: Paweł Kawalec MD, PhD Address: Drug Management Department, Institute of Public Health, Faculty of Health Sciences, Jagiellonian University, ul. Grzegórzecka 20, 31-531 Kraków, Poland. Phone: +48 12 424 13 90; fax: +48 12 421 74 47; e-mail: pawel.kawalec@uj.edu.pl
Supplementary material Table 1. MeSH subject headings and EMTREE keywords used in constructed search strategy for the primary studies Keywords (Combined with Boolean operator(s), OR/AND) Medical condition Intervention I (UC, CD) Intervention II (UC) Intervention III (UC, CD) Intervention IV (UC, CD) Intervention V (CD) Methodological limits Language limits Ulcerative Colitis OR Colitis Ulcerosa OR Colitis Ulcerativa OR Ulcerous Colitis OR Ulcerative Colorectitis OR Colitis Ulcerosa Chronica OR Chronic Ulcerative Colitis OR Chronic Ulceration OR Idiopathic Proctocolitis OR Ulcerative Procto Colitis OR Ulcerative Proctocolitis OR Histiocytic Ulcerative Colitis OR Mucosal Colitis OR Colitis Gravis Crohn's Disease OR Crohn Disease OR Crohns Disease OR Colon Crohn Disease OR Colonic Crohn Disease OR Crohn's Enteritis OR Regional Enterocolitis OR Regional Enteritis OR Enteritis Regionalis OR Colon Regional Enteritis OR Regional Colitis OR Granulomatous Enteritis OR Ileocolitis OR Granulomatous Colitis OR Terminal Ileitis OR Regional Ileitides OR Regional Ileitis OR Morbus Crohn Infliximab OR Monoclonal Antibody ca2 OR MAb ca2 OR Remsima OR Remicade OR Avakine OR Inflectra OR Revellex Golimumab OR cnto 148 OR cnto148 OR Simponi Adalimumab OR D2E7 Antibody OR Monoclonal Antibody D2E7 OR LU200134 OR Humira OR Trudexa Vedolizumab OR mln0002 OR mln 0002 OR mln 02 OR mln02 OR Monoclonal Antibody mln 02 OR Monoclonal Antibody ldp 02 OR ldp 02, ldp02 OR Entyvio Certolizumab OR Certolizumab Pegol OR Cimzia OR CDP870 OR CDP 870 OR Pha 738144 OR Pha738144 OR Pegylated Tumor Necrosis Factor Alpha Antibody Fab Fragment OR Pegylated Tumour necrosis Factor Alpha Antibody Fab Fragment PubMed: humans, Randomized Controlled Trial; Embase: humans, Embase only, Randomized Controlled Trial; Cochrane: Cochrane Central Register of Controlled Trials, word variations have been searched Only English publications
Supplementary material Table 2. Summary of the safety profile of biologic drugs Outcome Number of events/number of participants (%) Long-term follow-up ADA ADA GLM GLM VDZ VDZ IFX IFX Biological Placebo Biological Placebo Biological Placebo Biological Placebo Any AEs 713/836 478/564 225/308 103/156 1203/1434 466/576 106/121 103/121 (85) (85) (73) (66) (84) (81) (88) (85) SAEs 112/1013 94/660 35/308 12/156 276/1434 83/576 99/452 119/453 (11) (14) (11) (8) (19) (14) (22) (26) AEs leading to 81/1013 83/660 22/308 (7) 10/156 n/d n/d 46/463 29/466 discontinuation (8) (13) (6) (10) (6) of study drug Injection site 54/496 17/399 46/308 18/156 33/814 (4) 14/301 79/463 55/466 reaction (11) (4) (15) (12) (5) (17) (12) Infections 519/1013 293/660 120/308 44/156 730/1434 276/576 53/121 47/121 (51) (44) (39) (28) (51) (48) (44) (39) Serious infections 15/542 (3) 11/286 (4) n/d n/d 45/814 (6) 9/301 (3) 12/331 (4) 17/332 (5) Infections n/d n/d 83/308 24/156 n/d n/d 150/452 134/453 requiring (27) (15) (33) (30) antimicrobial treatment Abdominal pain 39/517 (8) 17/261 22/308 (7) 4/156 114/1434 49/576 11/121 16/121 (7) (3) (8) (9) (11) (13) Middle-term follow-up IFX IFX CZP CZP Biological Placebo Biological Placebo 116/162 106/164 409/547 403/541 (72) (65) (75) (74) 16/162 28/164 46/547 (8) 37/541 (10) (17) (7) n/d n/d n/d n/d 17/162 12 (164 15/547 (3) 78/541 (10) (7) (14) n/d n/d n/d n/d n/d n/d n/d n/d n/d n/d n/d n/d 10/121 (8) 14/123 37/331 37/329 (11) (11) (11)
Outcome Number of events/number of participants (%) Long-term follow-up Middle-term follow-up ADA Biological ADA Placebo GLM Biological GLM Placebo VDZ Biological VDZ Placebo IFX Biological IFX Placebo IFX Biological IFX Placebo CZP Biological CZP Placebo Arthralgia 61/517 (12) 23/261 (9) 19/308 (6) 12/156 (8) 166/1434 (12) 65/576 (11) 21/121 (17) 18/121 (15) 16/121 (13) 6/123 (5) 22/331 (7) 16/329 (5) Headache 55/517 (11) 15/261 (6) 24/308 (8) 14/156 (9) 177/1434 (12) 75/576 (13) 22/121 (18) 27/121 (22) 19/121 (16) 18/123 (15) 75/547 (14) 68/541 (13) Nausea 41/517 (8) 16/261 (6) n/d n/d 128/1434 (9) 49/576 (9) 14/121 (12) 14/121 (12) 6/121 (5) 9/123 (7) 26/331 (8) 27/329 (8) Cough n/d n/d 14/308 (5) 5/156 36/620 (6) 13/275 n/d n/d n/d n/d n/d n/d (3) (5) Nasopharyngitis 67/554 25/279 35/308 11/156 80/620 26/275 1/11 (9) 2/13 n/d n/d n/d n/d (12) (9) (11) (7) (13) (9) (15) Pyrexia 31/517 (6) 14/261 n/d n/d 103/814 40/301 n/d n/d n/d n/d n/d n/d (5) (13) (13) Pharyngitis n/d n/d 13/308 (4) 4/156 n/d n/d 12/121 10/121 n/d n/d n/d n/d (3) (10) (8) URTI 28/517 (5) 16/261 (6) 17/308 (6) 4/156 (3) 236/1434 (16) 77/576 (13) 20/121 (17) 28/121 (23) n/d n/d n/d n/d The table includes only data for the endpoints for which it was possible to conduct a network meta-analysis; ADA adalimumab; AE adverse event; CZP certolizumab pegol; GLM golimumab; IFX infliximab; n/d no data; SAE serious adverse event; URTI upper respiratory tract infection; VDZ vedolizumab
Supplementary material Table 3. Summary of the safety profile of biologic drugs in the extended phases Biologic drugs Infliximab Adalimumab Certolizumab pegol Extension phase of study ACT-1 and ACT-2 ULTRA CHARM Watanabe et al. 2012 RECISE 1 and RECISE 2 Duration Up to 3 years Up to 4 years Up to 2 years Up to 4 years Up to 148 weeks Up to 7 years Outcome E/100-PY E (E/100-PY)* n/n=854 E (E/100- E (E/100- n/n=79 E (E/100- n/n=595 (%) (N=230) (N=1010) (%) PY)** (N=854) PY)^ (N=854) (%) PY)^^ (N=79) Any AEs 506 8.057 (344.6) 804 (94.1) 7644 (713.0) 9736 (583.1) 7 (100.0) 1154 (743.1) 525 (88.2) SAEs 21 414 (17.7) 219 (25.6) 357 (33.3) 517 (31.0) 49 (62.0) 88 (56.7) 240 (40.3) AEs leading to 4.63 249 (10.7) 174 (20.4) 212 (19.8) 252 (15.1) 28 (35.4) 29 (18. 204 (34.3) discontinuation of study drug 7) AE leading to death 0.20 2 (0.1) n/d n/d 2 (0.1) n/d n/d 4 (0.7) AE related to study drug 4.63 n/d 475 (55.6) 1637 (152.7) 1933 (115.8) 47 (59.5) 127 (81.8) 252 (42.4) Infection 99 n/d 510 (59.7) 1424 (132.8) 1966 (117.7) 68 (86.1) 337 (217.0) n/d Serious infection 3.4 79 (3.4) 56 (6.6) 69 (6.4) 102 (6.1) 9 (11.4) 11 (7.1) n/d Infections requiring 41 n/d n/d n/d n/d n/d n/d n/d antimicrobial treatment Malignancy 1.01 23 (1.0) 11 (1.3) 12 (1.1) 26 (1.6) 0 0 n/d Injection site pain n/d n/d 54 (6.3) 59 (5.5) 125 (7.5) n/d n/d n/d Injection site reaction 7.25 246 (10.5) n/d n/d n/d 6 (7.6) 6 (3.9) n/d Opportunistic infection n/d 6 (0.3) 19 (2.2) 22 (2.1) 22 (1.3) 1 (1.3) 1 (0.6) 114 (19.2) Tuberculosis n/d 1 (<1) 3 (0.4) 3 (0.3) 3 (0.2) 0 0 n/d Congestive heart failure n/d 4 (0.2) 0 0 0 0 0 n/d
Biologic drugs Infliximab Adalimumab Certolizumab pegol Extension phase of study ACT-1 and ACT-2 ULTRA CHARM Watanabe et al. 2012 RECISE 1 and RECISE 2 Duration Up to 3 years Up to 4 years Up to 2 years Up to 4 years Up to 148 weeks Up to 7 years Outcome E/100-PY E (E/100-PY)* n/n=854 E (E/100- E (E/100- n/n=79 E (E/100- n/n=595 (%) (N=230) (N=1010) (%) PY)** (N=854) PY)^ (N=854) (%) PY)^^ (N=79) Demyelinating disorder 0 3 (0.1) 2 (0.2) 3 (0.3) 3 (0.2) 0 0 n/d Hepatic event n/d 12 (0.5) n/d n/d 53 (3.2) 21 (26.6) 36 (23.2) n/d Allergic reaction n/d n/d n/d n/d n/d 1 (1.3) 1 (0.6) n/d Lupus-like syndrome n/d n/d n/d n/d n/d 0 0 n/d Blood disorder n/d n/d n/d n/d n/d 2 (2.5) 2 (1.3) n/d Lymphoma n/d 3 (0.1) n/d n/d n/d n/d n/d n/d AE adverse event; E events; E/100-PY events/100 patient-years; PY patient-year.*py=2338.0; **PY=1072.1; ^PY=1669.7; ^^PY=155.3
Supplementary material Figure 1. Forest plot for results from pair-wise meta-analyses (blank squares) and from network meta-analysis (solid squares) for outcomes: A) any adverse events (AEs); B) serious AEs; C) AEs leading to discontinuation of study drug; D) injection site reaction; E) infections; F) serious infections; G) infections requiring antimicrobial treatment long-term follow-up. Squares represent pooled estimates of OR. Lines for 95% confidence intervals (CIs) represent 95% CIs in pair-wise meta-analyses and 95% credible intervals (CrIs) in network meta-analysis. The result of a single study was provided as OR with 95% CI.
Supplementary material Figure 2. Forest plot for results from pair-wise meta-analyses (blank squares) and from network meta-analysis (solid squares) for outcomes: A) abdominal pain; B) arthralgia; C) cough; D) headache; E) nausea; F) nasopharyngitis; G) pharyngitis; H) pyrexia; I) upper respiratory tract infection long-term follow-up. Squares represent pooled estimates of OR. Lines for 95% confidence intervals (CIs) represent 95% CIs in pair-wise meta-analyses and 95% credible intervals (CrIs) in network meta-analysis. The result of a single study was provided as OR with 95% CI.
Supplementary material Figure 3. Forest plot for results from pair-wise meta-analyses (blank squares) and from network meta-analysis (solid squares) for outcomes: A) any adverse events; B) serious adverse events; C) injection site reaction; D) abdominal pain; E) arthralgia; F) headache; G) nausea middle-term followup. Squares represent pooled estimates of OR. Lines for 95% confidence intervals (CIs) represent 95% CIs in pair-wise meta-analyses and 95% credible intervals (CrIs) in network meta-analysis. The result of a single study was provided as OR with 95% CI.
Any AE 8 6 4 Rank 1 CZP Rank 2 IFX Rank 3 PLC Injection site reaction 10 8 6 4 CZP IFX PLC Arthralgia 8 6 4 SAEs 10 8 6 4 Abdominal pain 8 6 4 Headache 6 4 CZP IFX PLC CZP IFX PLC CZP IFX PLC CZP IFX PLC Nausea 8 6 4 CZP IFX PLC Supplementary material Figure 4. Ranking of treatment strategies based on the probability of their protective effects on analyzed outcomes middle-term follow-up
Any AE 6 4 Rank 4 Rank 5 AEs leading to discontinuation of study drug 8 6 4 Rank 4 ADA GLM IFX PLC Infections 8 6 4 SAEs 8 6 4 Rank 4 Rank 5 Injection site reaction 6 4 Rank 4 Rank 5 Serious infections 8 6 4 Rank 4 Rank 5 Infections requiring antimicrobial treatment 10 8 6 4 GLM IFX PLC Rank 4 ADA IFX PLC VDZ Supplementary material Figure 5. Ranking of treatment strategies based on the probability of their protective effects on analyzed outcomes long-term follow-up
Abdominal pain 8 6 4 Rank 4 Rank 5 Headache 8 Arthralgia 6 4 Rank 4 Rank 5 Cough 6 6 4 Rank 4 Rank 5 Pyrexia 6 4 4 Nausea 8 6 4 GLM PLC VDZ ADA PLC VDZ Pharyngitis 8 6 4 GLM IFX PLC Upper respiratory tract infection 8 Rank 4 ADA IFX PLC VDZ Nasopharyngitis 6 4 Rank 4 Rank 5 6 4 Rank 4 Rank 5 Supplementary material Figure 6. Ranking of treatment strategies based on the probability of their protective effects on analyzed outcomes (individual adverse events) long-term follow-up