Table III.

Summary of biologic efficacy in randomized, double-blind, phase 3 trials.

Study	Study design	Relevant inclusion/exclu-sion criteria	Treatment groups	Relevant demographics	Efficacy summary – primary end point(s)	Efficacy summary –selected secondary end points
Anti-TNFs:
Weinblatt et al. (2003); ARMADA³⁹	r, db, pc, 24 wk	Active RA MTX-IR, and IR to 1–4 other DMARDs	Pbo Q2wks + MTX n=62 ADA 20 mg Q2wks + MTX n=69 ADA 40 mg Q2wks + MTX n=67 ADA 80 mg Q2wks + MTX n=73	Mean age 55.5 yrs Mean disease duration 12.3 yrs Mean number previous DMARDs ≈ 3 74.6–82.3% female	ACR20: 47.8%, 67.2%, and 65.8% of pts in the ADA 20mg, 40mg, and 80mg gps (P<0.001 for all vs pbo)	ACR50: 31.9%, 55.2%, and 42.5% of pts in the ADA 20mg, 40mg, and 80mg gps (P=0.003, 20mg; P<0.001, 40mg and 80mg vs pbo) ACR70: 10.1%, 26.9%, and 19.2% of pts in the ADA 20mg, 40mg, and 80mg gps (P=NS, 20mg; P<0.001 40mg; P=0.02 80mg vs pbo)
Keystone et al. (2004)⁴⁴	r, db, pc, 52 wk (24-wk data shown)	Active RA Stable MTX 12.5–25 mg/wk No previous anti-CD4 antibody or TNFi therapy	Pbo Q1wk + MTX n=200 ADA 20 mg Q1wk + MTX n=212 ADA 40mg Q2wks + pbo alternate wks + MTX n=207	Mean age 56–57 yrs Mean disease duration 10.9 yrs Mean number previous DMARDs 2.4 73–76% female	ACR20 at 24 weeks: ADA 20 mg, 60.8%; ADA 40 mg, 63.3% (P≤0.001 for both vs pbo)	ACR50 at 24 weeks: ADA 20 mg, 41.0%; ADA 40 mg, 39.1% (P≤0.001 for both vs pbo) ACR70 at 24 weeks: ADA 20 mg, 17.5%; ADA 40 mg, 20.8% (P≤0.001 for both vs pbo)
Van de Putte et al. (2004)⁴⁵	r, db, pc, 26 wk	Active RA DMARD-IR	Pbo Q1wk n=110 ADA 20 mg Q2wks + pbo on alternate weeks n=106 ADA 20 mg Q1wk n=112 ADA 40 mg Q2wks + pbo on alternate weeks n=113 ADA 40 mg Q1wk n=103	Mean age 53 yrs Mean disease duration 11 yrs Mean number previous DMARDs 3.7 77% female	ACR20: 35.8%, 39.3%, 46.0%, and 53.4% for ADA 20 mg Q2wks, ADA 20 mg Q1wk, ADA 40 mg Q2wks, and ADA 40 mg Q1wk (P≤ 0.01 vs pbo)	ACR50: 18.9%, 20.5%, 22.1%, and 35.0% for ADA 20 mg Q2wks, ADA 20 mg Q1wk, ADA 40 mg Q2wks, and ADA 40 mg Q1wk (P≤ 0.05 vs pbo) ACR70: 8.5%, 9.8%, 12.4%, and 18.4% for ADA 20 mg Q2wks, ADA 20 mg Q1wk, ADA 40 mg Q2wks, and ADA 40 mg Q1wk (P≤ 0.05 vs pbo)
Breedveld et al. (2006); PREMIER⁴⁷	r, db, 2 yr (1-yrs data shown)	RA <3 yrs Not received MTX, cyclophosphamide, cyclosporine, azathioprine or >2 other DMARDs	Pbo Q2wks + MTX (MTX gp) n=257 ADA 40 mg Q2wks + MTX (combo gp) n=268 ADA 40 mg Q2wks + pbo (ADA gp) n=274	Mean age 52 yrs Mean disease duration 0.7–0.8 yrs 32–33% of pts had received previous DMARDs 72–77% female	ACR50 at 1 yr: 62% (combo gp) vs 41% (ADA gp) vs 46% (MTX gp) [P<0.001 for combo vs both] Mean change in mTSS at 1 yr: +1.3 (combo gp) vs +3.0 (ADA gp) vs +5.7 (MTX gp) [P≤0.002 for combo vs both]	ACR20: 73% (combo gp) vs 54% (ADA gp) vs 63% (MTX gp) [P≤0.022 for both vs combo; P=0.043 MTX vs ADA] ACR70: 46% (combo gp) vs 26% (ADA gp) vs 28% (MTX gp) [P<0.001 for both vs combo] DAS28 remission: 43% (combo gp) vs 23% (ADA gp) vs 21% (MTX gp) [P<0.001 for both vs combo]
Maini et al. (1999); ATTRACT⁴²	r, db, pc, 30 wk	Active RA MTX-IR	Pbo + MTX n=88 IFX 3mg/kg Q8wk + MTX n=86 IFX 3mg/kg Q4wk + MTX n=86 IFX 10mg/kg Q8wk + MTX n=87 IFX 10mg/kg Q4wk + MTX n=81	Median age 51–56 yrs Median disease duration 7.2–9.0 yrs Mean number previous DMARDs (excluding MTX) = 2.5–2.8 73–81% female	ACR20: 50–60% of IFX+MTX-treated pts (P<0.001 vs pbo+MTX)	ACR50: 26–31% of IFX+MTX-treated pts (P<0.001 vs pbo+MTX) ACR70: 8–18% of IFX+MTX-treated pts (P≤0.007 vs pbo+MTX)
St Clair et al. (2004)⁴⁸	r, db, pc, 54 wk	RA ≤3 yrs MTX and TNFi-naïve (or ≤3 previous MTX doses) No other DMARDs within 4 wks of baseline	MTX Q1wk + pbo at wks 0, 2, 6 and Q8wks thereafter n=282 MTX Q1wk + IFX 3mg/kg at wks 0, 2, 6 and Q8wks thereafter n=359 MTX Q1wk + IFX 6mg/kg at wks 0, 2, 6 and Q8wks thereafter n=363	Mean age 50–51 yrs Mean disease duration 0.8–0.9 yrs 65–71% of pts were DMARD-naïve 68–75% female	ACR-N improvement: 38.9% (IFX 3 mg/kg + MTX gp), and 46.7% (IFX 6 mg/kg + MTX gp) [both P<0.001 vs pbo+MTX]	ACR20: 62.4% (IFX 3mg/kg + MTX; P=0.024 vs pbo), and 66.2% (IFX 6mg/kg + MTX; P=0.001 vs pbo) ACR50: 45.6% (IFX 3mg/kg + MTX), and 50.4% (IFX 6mg/kg + MTX) [both P<0.001 vs pbo]
Schiff et al. (2006); ATTEST⁶¹	r, db, pc, 1 yr (6-mo data shown)	RA ≥1 yr MTX-IR No previous ABA or anti-TNFs	Pbo+MTX n=110 IFX 3 mg/kg on days 1, 15, 43, 85 and Q8wks thereafter + MTX n=165 ABA ~10 mg/kg on days 1, 15, 29 and Q4wks thereafter + MTX n=156	Mean age 49 yrs Mean disease duration 7.3–8.4 yrs 82–87% female	Reduction in DAS28 at 6 mos: −2.53 (ABA+ MTX), and −2.25 (IFX+MTX) [both P<0.001 vs pbo+MTX]	ACR20 at 6 mos: 66.7% (ABA+MTX; P<0.001 vs pbo+MTX), and 59.4% (IFX+MTX; P=0.006 vs pbo+MTX) ACR50 at 6 mos: 40.4% (ABA+MTX; P<0.001 vs pbo+MTX), and 37.0% (IFX+MTX; P=0.004 vs pbo+MTX) ACR70 at 6 mos: 20.5% (ABA+MTX; P=0.019 vs pbo+MTX), and 24.2% (IFX+MTX; P=0.002 vs pbo+MTX)
Moreland et al. (1999)³⁸	r, db, pc, 6 mos	Active RA DMARD-IR	Pbo bw n=80 ETN 10 mg bw n=76 ETN 25 mg bw n=78	Mean age 52 yrs Mean disease duration 12 yrs Mean number previous DMARDs 3.0–3.4 78% female	ACR20: 51% (ETN 10 mg), and 59% (ETN 25 mg) [both P<0.001 vs pbo] ACR50: 24% (ETN 10 mg), and 40% (ETN 25 mg) [both P<0.001 vs pbo]	ACR70: 9% (ETN 10 mg), and 15% (ETN 25 mg) [P=0.031 for 10 mg vs pbo; P=0.001 for 25 mg vs pbo]
Bathon et al. (2000)⁵⁰	r, pc, 12 mos	RA <3 yrs MTX-naive	MTX 7.5–20 mg Q1wk n=217 ETN 10 mg bw n=208 ETN 25 mg bw n=207	Mean age 49–51 yrs Mean disease duration 11–12 mos Mean number previous DMARDs 0.5–0.6 74–75% female	AUC for ACR-N: Significantly greater in the ETN 25 mg gp vs MTX at 3, 6, 9, and 12 mos (P<0.05)	ACR20, ACR50 and ACR70: Significantly higher % pts treated with ETN 25 mg vs MTX achieved responses in the first 4–6 mos (P<0.05), with NS difference thereafter. At 12 mos, ACR20 was 72% vs 65% (NS)
Klareskog et al. (2004); TEMPO⁴³	r, db, 52 wk	Active RA IR to ≥1 DMARD (except MTX) No MTX 6 mo before baseline	MTX Q1wk n=228 ETN 25 mg bw n=223 ETN+MTX (combo) n=231	Mean age 53 yrs Mean disease duration 6.3–6.8 yrs Mean number previous DMARDs 2.3 Mean DAS 5.5–5.7 74–79% female	Mean difference in ACR-N AUC at 24 wks: 6.1 for combo vs MTX (P<0.0001); 2.5 for ETN vs MTX (P=0.0034)	ACR20: 85% for combo vs 75% for MTX (P=0.0091) and vs 76% for ETN (P=0.0151) ACR50: 69% for combo vs 43% for MTX (P<0.0001), and vs 48% for ETN (P<0.0001) ACR70: 43% for combo vs 19% for MTX (P<0.0001), and vs 24% for ETN (P<0.0001) DAS28 remission: 35% for combo vs 13% for MTX (P<0.0001), and 16% for ETN (P<0.0001)
Weinblatt et al. (2007)⁵¹	r, db, pc, 1 yr	Active RA Received ETN ≥3 mos	ETN 25 mg bw + pbo n=36 ETN 25 mg bw + ABA 2 mg/kg on days 1, 15, 30, and Q4wk thereafter n=85	Mean age 50–54 yrs Mean disease duration 13 yrs 76% female	ACR20 at 6 mos: 48.2% (ETN+ABA gp) vs 30.6% (ETN+pbo gp) [NS]	ACR20 at 1 yr: 48.2% (ETN+ABA gp) vs 30.6% (ETN+pbo gp) [NS] ACR50 at 1 yr: 28.2% (ETN+ABA gp) vs 16.7% (ETN+pbo gp) [NS] ACR70 at 1 yr: 9.4% (ETN+ABA gp) vs 5.6% (ETN+pbo gp) [NS]
Emery et al. (2008); COMET⁴⁹	r, db, 52 wks	RA <2 yrs MTX and TNFi-naïve (no other DMARDs within 4 wks of baseline)	Pbo + MTX Q1wk n=263 ETN 50 mg + MTX Q1wk n=265	Mean age 51.4 yrs Mean disease duration 9 mos 21% of pts received previous DMARDs 73% female	DAS28 remission: 50% of pts in ETN+MTX gp vs 28% in MTX gp (P<0.0001) No radiographic progression (change in mTSS ≤0.5): 80% of pts in ETN+MTX gp vs 59% in MTX gp (P<0.0001)	ACR20/50/70: 86%/71%/48% for ETN+MTX vs 67%/49%/28% for Pbo+MTX (P<0.0001)
Fleischmann et al. (2008); FAST4WARD⁵⁷	r, db, pc, 24 wks	Active RA IR to ≥1 DMARD No biologic within 6 mos No previous anti-TNFs	Pbo Q4wks n=109 CTZ 400 mg Q4wks n=111	Mean age 53–55 yrs Mean disease duration 8.7–10.4 yrs Mean number previous DMARDs 2 78–89% female	ACR20: 45.5% for CTZ gp (P<0.001 vs pbo)	ACR50: 22.7% for CTZ gp (P<0.001 vs pbo) ACR70: 5.5% for CTZ gp (P<0.05 vs pbo)
Keystone et al. (2008); RAPID-1⁵⁵	r, db, pc, 52 wks (24-wk data shown)	Active RA MTX-IR Not anti-TNF-IR No biologic within 6 mos of baseline	Pbo Q2wks + MTX n=199 CTZ 200 mg Q2wks + MTX n=393 CTZ 400 mg Q2wks + MTX n=390	Mean age 51–52 yrs Mean disease duration 6.1–6.2 yrs Mean number previous DMARDs 1.3–1.4 82–84% female	ACR20 at wk 24: 58.8% for the CTZ 200mg + MTX gp, and 60.8% for the CTZ 400mg + MTX gp (both P<0.001 vs pbo+MTX) Mean change in mTSS at wk 52: +0.4 for the CTZ 200 mg + MTX gp, and +0.2 for the CTZ 400 mg + MTX gp (both P<0.001 vs pbo+MTX)	ACR50 at wk 24: 37.1% for the CTZ 200 mg + MTX gp, and 39.9% for the CTZ 400mg + MTX gp (both P<0.001 vs pbo+MTX) ACR70 at wk 24: 21.4% for the CTZ 200 mg + MTX gp, and 20.6% for the CTZ 400 mg + MTX gp (both P<0.001 vs pbo+MTX)
Smolen et al. (2009); RAPID-2⁵⁶	r, db, pc, 24 wks	Active RA MTX-IR Not anti-TNF-IR No biologic within 3–6 mos before baseline	Pbo Q2wks + MTX n=127 CTZ 200 mg Q2wks + MTX n=246 CTZ 400 mg Q2wks + MTX n=246	Mean age 52 yrs Mean disease duration 5.6–6.5 yrs Mean number previous DMARDs (excluding MTX) = 1.2–1.3 78–84% female	ACR20: 57.3% in the CTZ 200 mg + MTX gp, and 57.6% in the CTZ 400 mg + MTX gp (both P<0.001 vs pbo+MTX)	ACR50: 32.5% in the CTZ 200 mg + MTX gp, and 33.1% in the CTZ 400 mg + MTX gp (both P<0.001 vs pbo+MTX) ACR70: 15.9% in the CTZ 200 mg + MTX gp, and 10.6% in the CTZ 400 mg + MTX gp (both P≤0.01 vs pbo+MTX)
Keystone et al. (2009); GO-FORWARD⁶⁰	r, db, pc, 52 wks	Active RA MTX-IR (stable 15–25 mg/wk) Anti-TNF naïve No biologic or DMARDs (except MTX) within 4 wks of baseline	Pbo Q4wks + MTX n=133 GOL 100 mg Q4wks + PBO n= 133 GOL 50 mg Q4wks + MTX n=89 GOL 100 mg Q4wks + MTX n=89	Mean age 50–52 yrs Mean disease duration 4.5–6.7 yrs 71–79% of pts had previous DMARDs (excluding MTX) 79–82% female	ACR20 at wk 14: 44.4%, 55.1%, and 56.2% for the GOL 100 mg + pbo, GOL 50 mg + MTX, and GOL 100 mg + MTX gps, respectively (NS, P=0.001, and P<0.001 vs pbo+MTX) HAQ-DI change from baseline to wk 24: –0.13, –0.38, and –0.50 for the GOL 100 mg + pbo, GOL 50 mg + MTX, and GOL 100 mg + MTX gps, respectively (NS, P<0.001, and P<0.001 vs pbo+MTX)	ACR20 at wk 24: 35.3%, 59.6%, and 59.6% for the GOL 100 mg + pbo, GOL 50 mg + MTX, and GOL 100 mg + MTX gps, respectively (NS, P<0.001, and P<0.001 vs pbo+MTX) ACR50 at wk 24: 19.5%, 37.1%, and 32.6% for the GOL 100mg + pbo, GOL 50 mg + MTX, and GOL 100 mg + MTX gps, respectively (NS, P<0.001, and P<0.001 vs pbo+MTX) ACR70 at wk 24: 11.3%, 20.2%, and 14.6% for the GOL 100 mg + pbo, GOL 50 mg + MTX, and GOL 100 mg + MTX gps, respectively (NS, P<0.001, and P=0.017 vs pbo+MTX) DAS28 remission at wk 24: 12.0%, 20.2%, and 22.5% for the GOL 100 mg + pbo, GOL 50 mg + MTX, and GOL 100 mg + MTX gps, respectively (NS, P=0.001, and P<0.001 vs pbo+MTX)
Smolen et al. (2009); GO-AFTER⁵⁹	r, db, 24 wk	Active RA Previously received ≥1 anti-TNF Concomitant, stable DMARDs permitted but not required	GOL 50 mg Q4wks GOL 100 mg Q4wks Pbo Q4wks	Median age 54–55 yrs Median disease duration 8.7–9.8 yrs 66–67% received MTX 74–85% female	ACR20 at wk 14: 35% and 38% for the GOL 50 mg, and GOL 100 mg gps (P=0.0006, and P=0.0001 vs pbo)	ACR20 at wk 24: 34% and 44% for the GOL 50 mg and GOL 100 mg gps (P=0.0005, and P<0.0001 vs pbo) ACR50 at wk 24: 18% and 20% for the GOL 50 mg and GOL 100 mg gps (P=0.0003, and P=0.0001 vs pbo) ACR 70 at wk 24: 12% and 10% for the GOL 50 mg and GOL 100 mg gps (P=0.0041, and P=0.0107 vs pbo)
IL-1 receptor inhibitor:
Bresnihan et al. (1998)⁵⁴	r, db, pc, 24 wks	Active RA >6 months and <8 yrs DMARDs discontinued ≥6 wks previously	Pbo n=121 ANA 30 mg od n=119 ANA 75 mg od n=116 ANA 150 mg od n=116	Mean age 52–54 yrs Mean disease duration 3.7–4.3 yrs Previous DMARDs 66–81% of pts 70–79% female	ACR composite criteria (% pts improved): 39%, 34%, and 43% for the ANA 30 mg, 75 mg, and 150 mg gps, respectively (P=0.054, P= 0.258, P=0.014 vs pbo)	ACR20/50/70 responses not reported
Cohen et al. (2002)⁵³	r, db, pc, 24 wks	Active RA >6 mos and <12 yrs MTX-IR	Pbo+MTX n=74 ANA 2 mg/kg (only highest dose of dose-ranging study shown) + MTX n=72	Mean age 53–54 yrs Mean disease duration 8 yrs Mean number previous DMARDs (excluding MTX) 2 63–85% female	ACR20 at wk 12: 38% with ANA 2mg/kg (P=0.007 vs pbo)	ACR20 at wk 24: 35% with ANA 2mg/kg (P=0.143 vs pbo) ACR50 at wk 24: 17% with ANA 2mg/kg (P not shown) ACR70 at wk 24: 7% with ANA 2mg/kg (P not shown)
T-cell co-stimulation inhibitor:
Genovese et al. (2005)³⁷	r, db, pc, 6 mo	RA ≥1 yr TNFi-IR	Pbo on days 1, 15, 29, and Q4wks thereafter n=133 ABA ~10mg/kg on days 1, 15, 29, and Q4wks thereafter n=258	Mean age 53 yrs Mean disease duration 11.4–12.2 yrs Current TNFi 38–41% Former TNFi 59–62% 77–80% female	ACR20: 50.4% in ABA gp vs 19.5% in pbo gp (P<0.001) HAQ-DI improvement ≥0.3: 47.3% in ABA gp vs 23.3% in pbo gp (P<0.001)	ACR50: 20.3% in ABA gp vs 3.8% in pbo gp (P<0.001) ACR70: 10.2% in ABA gp vs 1.5% in pbo gp (P=0.003) DAS28 remission: 10.0% in ABA gp vs 0.8% in pbo gp (P<0.001)
B-cell CD20 antigen:
Cohen et al. (2006); REFLEX³⁶	r, db, pc, 24 wks	RA ≥6 mos Stable MTX 10–25 mg/wk TNFi-IR	Pbo wk 1 and 15 + MTX Q1wk n=209 RTX wk 1 and 15 + MTX Q1wk n=308	Mean age 52–53 yrs Mean disease duration 12 yrs Mean number previous DMARDs (excluding MTX) 2.4–2.6 81% female	ACR20: 51% (RTX+MTX) vs 18% (pbo+MTX) [P<0.0001]	ACR50: 27% (RTX+MTX; P<0.0001 vs pbo+MTX) ACR70: 12% (RTX+MTX; P<0.0001 vs pbo+MTX) SF-36: Mean increase from baseline in mental and physical summary scores 4.7 and 5.8 for RTX+MTX (P=0.0002 vs pbo+MTX) Joint space narrowing (JSN) score: change +0.2 (RTX+MTX; P=0.016 vs pbo+MTX)

ABA = abatacept; ADA = adalimumab; ANA = anakinra; anti-TNF = tumor necrosis factor inhibitor; AUC = area under the curve; bw = twice weekly; CTX = certolizumab pegol; db = double-blind; DMARD = disease-modifying antirheumatic drug; ETN = etanercept; GOL = golimumab; gp = group; HAQ-DI = Health Assessment Questionnaire-Disability Index; IFX = infliximab; IR = inadequate response; mTSS = modified total Sharp score; MTX = methotrexate; mo = month; NS = not significant; od = once daily; pbo = placebo; pc = placebo-controlled; pts = patients; Q1wk = every week; Q2wks = every 2 weeks, etc.; r = randomized; RTX = rituximab; SF-36 = Short Form-36; TNFi = tumor necrosis factor inhibitor; wk = week; yrs = years.