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. Author manuscript; available in PMC: 2013 Jul 10.
Published in final edited form as: Clin Ther. 2011 Jun;33(6):679–707. doi: 10.1016/j.clinthera.2011.05.044

Table IV.

Summary of major adverse events in randomized, controlled, phase 3 trials of biologics.

Study Length of study Summary of treatment Injection-site reactionsa Serious infectionsa Malignanciesa
Anti-TNFs:
Weinblatt et al. (2003); ARMADA39 24 wks ADA 20, 40, or 80 mg, or pbo, Q2wks 15.3 (all ADA gps combined)
ADA 80 mg: 11.0 (P≤0.05 vs pbo)		 1.0 (all ADA gps combined) 0.5 (all ADA gps combined)
Keystone et al. (2004)44 52 wks ADA 20 mg Q1wk, or 40 mg Q2wks, or pbo, + MTX 24.1 3.8 (P≤0.02 vs pbo) 0.1
Van de Putte et al. (2004)45 26 wks ADA 20 or 40 mg Q2wks or Q1wk, or pbo 10.6 (P≤0.05 vs pbo) 2.3 (NS vs pbo) 0.9 (NS vs pbo)
Breedveld et al. (2006); PREMIER47 2 yrs ADA 40 mg Q2wks, ADA 40mg Q2wks + MTX, or MTX NR ADA: 0.7b
MTX: 1.6b
ADA+MTX: 2.9b (P<0.05 vs ADA)		 ADA: 0.9b
MTX: 0.9b
ADA+MTX: 0.4b
Maini et al. (1999);42 ATTRACT 30 wks IFX 3mg/kg or 10 mg/kg Q4wks or Q8wks, or pbo, + MTX IFX + MTX: 16–20c
Pbo + MTX:10c 		4.1 (all IFX + MTX gps combined; NS vs pbo) 0.9 (all IFX + MTX gps combined; however, all 3 cases in IFX 10 mg/kg Q4wks gp)
St Clair et al. (2004)48 54 wks IFX 3 or 6 mg/kg, or pbo (at 0, 2, and 6 wks, then Q8wks), + MTX IFX 3 mg/kg: 21c
IFX 6 mg/kg: 15c
Pbo: 7c 		IFX 3 mg/kg: 5.6 (P=0.02 vs pbo)
IFX 6 mg/kg: 5.0 (P=0.04 vs pbo)		 1.1 (4 pts in IFX 6 mg/kg)
Schiff et al. (2008); ATTEST61 1 yr IFX 3 mg/kg Q8wks, or ABA ~10 mg/kg Q4wks, or pbo Q4wks, + MTX NA (IV) IFX: 8.5
ABA: 1.9		 IFX: 1.2
ABA: 0.6
Moreland et al. (1999)38 6 mos ETN 10 or 25 mg bw, or pbo ETN 10 mg: 43 (P<0.001 vs pbo)
ETN 25 mg: 49 (P<0.001 vs pbo)		 NR NR
Bathon et al. (2000)50 12 mos ETN 10 or 25 mg bw, or MTX Q1wk ETN 10 mg: 30 (P<0.05 vs MTX)
ETN 25 mg: 37 (P<0.001 vs MTX)		 <3 (in each gp) ETN 10 mg: 1.0
ETN 25 mg: 1.4
Klareskog et al. (2004); TEMPO43 52 wks ETN 25 mg bw, MTX alone, or ETN 25 mg bw + MTX ETN: 21 (P<0.0001 vs MTX)
ETN + MTX: 10 (P=0.0002 vs MTX)
MTX: 2		 4 (for each gp) ETN: 1.8
ETN + MTX: 0.4
MTX: 0.4
Weinblatt et al. (2007)51 1 yr ETN 25 mg bw + ABA 2mg/kg Q4wks, or ETN 25 mg bw + pbo NR ETN + ABA: 3.5
ETN + pbo: 0.0		 NR
Emery et al. (2008); COMET49 52 wks ETN 50 mg Q1wk, or pbo, + MTX NR ETN + MTX: 1.8
MTX: 3.0		 ETN+MTX: 1
MTX: 1
Fleischmann et al. (2008); FAST4WARD57 24 wks CTZ 400 mg, or pbo, Q4wks CTZ: 4.5
Pbo: 13.8		 CTZ: 1.8
Pbo: 0		 CTZ: 0
Pbo: 0
Keystone et al. (2008);55 RAPID-1 52 wks CTZ 200 or 400 mg Q2wks, or pbo, + MTX CTZ 200 mg + MTX: 2.3
CTZ 400 mg + MTX: 0.8
Pbo + MTX: 0		 CTZ 200 mg + MTX: 5.3b
CTZ 400 mg + MTX: 7.3b
Pbo + MTX: 2.2b 		CTZ 200 mg + MTX: 1.8
CTZ 400 mg + MTX: 1.0
Pbo + MTX: 0.5
Smolen et al. (2008); RAPID-256 24 wks CTZ 200 or 400 mg Q2wks, or pbo, + MTX CTZ 200 mg + MTX: 1.2
CTZ 400 mg + MTX: 2.0		 CTZ 200 mg + MTX: 3.2
CTZ 400 mg + MTX: 2.4
Pbo + MTX: 0.8		 CTZ 200 mg + MTX: 0.4
CTZ 400 mg + MTX: 0.4
Pbo + MTX: 0.8
Keystone et al. (2009); GO-FORWARD60 52 wks (24-wk data presented) GOL 100 mg Q4wks; GOL 50 or 100 mg Q4wks + MTX; or pbo + MTX GOL 50 mg + MTX: 2.4
GOL 100 mg + MTX: 4.8
GOL 100 mg: 7.5
Pbo + MTX: 3.0		 GOL 50 mg + MTX: 0.9
GOL 100 mg + MTX: 4.8
GOL 100 mg: 3.0
Pbo + MTX: 0.7		 GOL 50 mg + MTX: 0.0
GOL 100 mg + MTX: 1.0
GOL 100 mg: 1.5
Pbo + MTX: 0.7
Smolen et al. (2009); GO-AFTER59 24 wks GOL 50 or 100mg, or pbo, Q4wks GOL 50 mg: 4.0
GOL 100 mg: 11.0
Pbo: 3.0		 GOL 50 mg: 2.0
GOL 100 mg: 1.0
Pbo: 2.0		 GOL 50 mg: 1.0
GOL 100 mg: 1.0
Pbo: 0.0
IL-1 inhibitor:
Bresnihan et al. (1998)54 24 wks ANA 30, 75, or 150 mg od, or pbo ANA 30 mg: 50
ANA 75 mg: 73
ANA 150 mg: 81
Pbo: 25		 ANA 75 mg: 0.9
ANA 150 mg: 3.4
Pbo: 0.8		 NR
Cohen et al. (2002)53 24 wks ANA 0.04–2 mg/kg od (2 mg/kg data shown), or pbo ANA 2 mg/kg: 63
Pbo: 28		 ANA 2 mg/kg: 0.0
Pbo: 0.0		 ANA 2 mg/kg: 1.4
Pbo: 1.4
T-cell co-stimulation inhibitor:
Genovese et al. (2005)37 6 mos ABA ~10mg/kg, or pbo, + DMARDs ABA: 5.0c
Pbo: 3.0c 		2.3 (in each gp) NR
B-cell CD20 antigen:
Cohen et al. (2006); REFLEX36 24 wks RTX (2 × 1000 mg), or pbo, + MTX RTX: 23c,d
Pbo: 18c,d 		RTX + MTX: 1.4
Pbo + MTX: 2.3		 NR
a

Data shown as percent of pts unless stated otherwise. Statistical significance is shown where available.

b

Number of events per 100 pt-yrs.

c

% pts with infusion reactions.

d

Occurring within 24 hours of first infusion.

ABA = abatacept; ADA = adalimumab; ANA = anakinra; bw = twice weekly; CTZ = certolizumab pegol; DMARD = disease-modifying antirheumatic drug; ETN = etanercept; GOL = golimumab; gp = group; IFX = infliximab; mos = months; MTX = methotrexate; NA = not applicable; NR = not reported; NS = not significant; od = once daily; pbo = placebo; pts = patients; Q1wk = every week; Q2wks = every 2 weeks; r = randomized; RTX = rituximab; wks = weeks; yrs = years.