Table 1 Overview of trial designs

Exclusion criteria

Abatacept studies

AIM trial [14, 18]

PBO + MTX;

ABA 10 mg/kg every four weeks + MTX

Phase 3 RCT; Active RA despite MTX

Met ACR criteria, > = 18 years, RA for > = 1 year, > = 10 SJC, > = 12 TJC, CRP > = 10.0 mg/L, MTX (≥ 15 mg/week) for ≥ 3 months with stable dose for 28 days prior to enrolment

ACR20 at six months; HAQ-DI (≥ 0.3); CFB in joint erosion score at one year

Nov '02 to Oct' 04; 52 weeks

Positive tuberculin skin test

Kremer et al. 2005, Kremer et al. 2003 [16, 17]

PBO + MTX;

ABA 2 mg/kg every four weeks + MTX;

ABA 10 mg/kg every four weeks + MTX

Phase 3 RCT; Active RA despite MTX.

Met ACR criteria, > = 10 SJC, > = 12 TJC, CRP > 1 mg/dl, MTX (10 to 30 mg/week) for > = 6 months with stable dose for 28 days prior to enrolment

ACR20 at six months

Date n/s; 52 weeks + 6 months

n/s

ATTEST trial [15]

PBO + MTX;

ABA 10 mg/kg every four weeks + MTX;

INF 3 mg/kg every eight weeks + MTX

RCT, double-dummy, PBO and active (INF)-controlled; RA and MTX-IR

Met ACR criteria, > = 18 years, RA for > = 1 year, > 10 SJC, > 12 TJC, CRP > 1 mg/dl, MTX > 15 mg/week for > 3 months prior to randomisation, other DMARDs washed out

Reduction in DAS28 with abatacept vs placebo at six months

Feb '05 to June '06; 52 weeks

PBO arm = PBO for six months followed by ABA

Prior experience with abatacept or an other approved biologic RA therapy, failed on > 4 conventional DMARDs

Adalimumab studies

ARMADA [25]

PBO + MTX;

ADA 20 mg every other week + MTX;

ADA 40 mg every other week + MTX;

ADA 80 mg every other week + MTX

RCT; Active RA despite MTX

Met ACR criteria; > = 18 years, > 9 TJC, > 6 SJC, MTX for > = 6 months and stable weekly dose for > = 4 weeks before enrolment, failed treatment with > = 1 DMARD besides MTX, but not > 4 DMARDs

ACR20

Date n/s; 24 weeks

Prior anti-CD4 therapy or TNF-α antagonists, history of active listeriosis or mycobacterial infection, any major infection

DE019 [24]

PBO + MTX;

ADA 20 mg weekly + MTX;

ADA 40 mg every other week + MTX

RCT; Active RA treated with MTX.

Met ACR criteria; > = 18 years, > = 9 TJC, > = 6 SJC, CRP > 1 mg/dl, either rheumatoid factor positivity or > = 1 joint erosion on radiographs of hands + feet, MTX for > = 3 months at stable dose of 12.5 to 25 mg/week for > = 4 weeks

ACR20 at week 24

Date n/s; 52 weeks

Prior anti-CD4 therapy or TNF antagonists;

history of: other active inflammatory arthritide, active listeriosis/mycobacterial infection, lymphoma/leukemia within five years; any major infection

Certolizumab Pegol studies

RAPID I [26, 27, 29]

PBO + MTX;

CZP 200 mg every other week + MTX;

CZP 400 mg every other week + MTX

Phase 3 RCT; Active RA with MTX-IR

> = 18 years, active RA for > = 6 months + < 15 years, > = 9 TJC + SJC with either ESR > = 30 m/hour or CRP > 15 mg/l, MTX for > = 6 months with a stable dosage of > = 10 mg/week for > = 2 months.

ACR20 at week 24; mean CFB in modified total Sharp score at week 52

Feb '05 to Oct' 06; 52 weeks.

ACR20 non-responders at weeks 12 + 14 were withdrawn

History of: tuberculosis, malignancy;

PPD positive skin test; biologic therapy within 6 months, prior failure to respond to anti-TNF agent

RAPID II [28, 29]

PBO + MTX;

CZP 200 mg every other week + MTX;

CZP 400 mg every other week + MTX

Phase 3 RCT; Active RA despite > = 6 months of MTX

Met ACR criteria, > 18 years, RA > 6 months duration but < 15 years, MTX for > 6 months (stable dose > 10 mg/week for > 2 months at baseline)

ACR20 at week 24

June '05 to Sept' 06; 24 weeks

ACR20 non-responders at weeks 12 + 14 were withdrawn

Biologic agent in previous six months, severe reaction to biologic agents, no response to previous anti-TNF therapy, history of tuberculosis, PPD positive skin test

Etanercept studies

Weinblatt et al. 1999 [32]

PBO + MTX;

ETN 25 mg 2x week + MTX

Double-blind, randomised; Active RA despite > = 6 months of MTX

Met ACR criteria, > = 18 years, > = 6 SJC + TJC, MTX for > = 6 months at stable dose of 15 to 25 mg/week for last 4 weeks, discontinued sulfasalazine + hydroxychloroquine > = 2 weeks + DMARDs other than MTX > = 4 weeks prior to study

ACR 20 at 24 weeks

Date n/s; 24 weeks

n/s

TEMPO [30, 31]

PBO + MTX;

ETN 25 mg 2x week;

ETN 25 mg 2x week + MTX

Randomised, double-blind, parallel group study; RA patients with DMARD-IR

Met ACR criteria, > = 18 years, active disease for 6 months-20 years, > 10 SJC, > 12 painful joints, IR to > = 1 DMARD other than MTX, previous MTX (without toxic effects/lack of response), no MTX within 6 months of enrolment

ACR response (ACR-N) AUC for the first 24 weeks

Oct '00 to July' 01; 52 weeks

Prior therapy with ETN or other TNF antagonists, immunosuppressive drugs within 6 months; investigational drug or biologic agent within 3 months, any other DMARDs or corticosteroid within 4 weeks, presence of relevant co morbidity

Golimumab studies

GO-FORWARD [33, 34]

PBO + MTX;

GOL 100 mg every four weeks;

GOL 50 mg every four weeks + MTX;

GOL 100 mg every four weeks + MTX

Phase 3 RCT; active RA despite MTX

Met ACR criteria, > 18 years, RA > = 3 months, tolerated stable MTX dose of 15-25 mg/week for > = 3 months prior to screening, > = 4 SJC & TJC, met the tuberculosis screening criteria

ACR20 at week 14 and improvement from baseline in HAQ-DI score at week 24.

Dec '05 to Sept' 07; 52 weeks. At week 16, patients < 20% CFB in TJC and SJC had medication adjusted

Hypersensitivity to GOL, previous anti-TNF agent, RTX, natalizumab, cytotoxic agents, anakinra, DMARDs other than MTX, corticosteroids within four weeks, alefacept or efalizumab within three months.

Infliximab studies

ATTRACT [35, 36]

PBO + MTX;

INF 3 mg/kg every eight weeks + MTX;

INF 3 mg/kg every four weeks + MTX;

INF 10 mg/kg every eight weeks + MTX;

INF 10 mg/kg every four weeks + MTX

International Phase 3 RCT; Active RA despite MTX

Met ACR criteria, > = 6 SJC + TJC, MTX for > = 3 months not stopped for > 2 weeks, MTX at stable dose > 12.5 mg/week for > = 4 weeks, oral corticosteroids or NSAIDs on stable dose for > = 4 weeks

ACR20 at week 30

Date n/s; 54 weeks

DMARD (not MTX) or non-oral corticosteroids in four weeks before screening, alkylating agents, any other agent to reduce TNF, allergic to murine proteins, serious infections in previous three months, chronic infectious disease

Rituximab studies

DANCER [39, 40]

PBO + MTX;

RTX 500 mg x2 injections + MTX;

RTX 1,000 mg x2 injections + MTX

Phase 2b international RCT, double-dummy; Active RA with DMARD-IR and MTX-IR.

Met ACR criteria, 19 to 79 years, RA > 6 months, MTX at 10 to 25 mg/week for > = 12 weeks before randomization, stable dose for last 4 weeks, > 8 SJC + TJC, either ECR > = 28 mm/hour or CRP > = 1.5 mg/dl, IR to 1 to 5 DMARDs (other than MTX) and/or biologic agents discontinued > = 4 weeks before randomization and INF, ADA, leflunomide > = 8 weeks before randomization

ACR20 for RF-positive patients at week 24

Date n/s; 24 weeks

Significant systemic involvement secondary to RA, other illnesses or laboratory abnormalities, severe allergic or anaphylactic reactions to monoclonal antibodies, previous treatment with RTX or any lymphocyte-depleting therapies,

recurrent significant infection

N/S

Strand et al. 2006 [41]

PBO + MTX;

RTX 1,000 mg x2 injections;

RTX 1,000 mg x2 injections + cyclophosphamide;

RTX 1,000 mg x2 injections + MTX

RCT; Active RA despite MTX

Met ACR criteria, > 21 years, MTX > = 10 mg/week, > = 8 SJC + TJC, CRP > = 15 mg/l and/or ESR > = 28 mm/h, and/or morning stiffness > 45 minutes, plasma rheumatoid factor level > 20 IU/ml

ACR 50 at week 24

Date n/s; 48 weeks

Other autoimmune disease, ARA functional class IV disease, active rheumatoid vasculitis, history of systemic diseases associated with arthritis, chronic fatigue syndrome, serious and uncontrolled coexisting diseases

SERENE [37, 38]

PBO + MTX;

RTX 500 mg x2 injections + MTX;

RTX 1,000 mg x2 injections + MTX

Phase 3 RCT; Active RA with MTX-IR and naïve to prior biologic therapy

≥ 8 SJC + TJC, elevated CRP (≥ 0.6 mg/dL) and/or ESR (≥ 28 mm/h) despite MTX for ≥ 12 wks

ACR20 at week 24

Date n/s; 48 weeks

N/S

Tocilizumab studies

OPTION [43, 44]

PBO + MTX;

TCZ 4 mg/kg every four weeks + MTX;

TCZ 8 mg/kg every four weeks + MTX

Phase 3 RCT, parallel group; RA with MTX-IR

Met ACR criteria, adults, RA > 6 months, MTX-IR, > = 6 SJC, > = 8 TJC, CRP > 10 mg/L or ESR > = 28 mm/h, MTX for > = 12 weeks before start of study (stable dose of 10 to 25 mg/week for > = 8 weeks), discontinuation of other DMARDs: leflunomide > = 12 weeks, anakinra > = 1 week, etanercept > = 2 weeks, infliximab or adalimumab > = 8 weeks prior to start of study

ACR20 at 24 weeks

Date n/s; 24 weeks. At week 16, patients < 20% CFB in TJC and SJC were eligible for rescue therapy

with TCZ 8 mg/kg

other autoimmune diseases, significant systemic involvement secondary to RA, functional class IV RA, inflammatory joint disease other than RA, recurrent infections,

active liver disease, anti-TNF agent failure

Not stated

LITHE [42]

PBO + MTX;

TCZ 4 mg/kg every four weeks + MTX;

TCZ 8 mg/kg every four weeks + MTX

Phase 3 RCT, double-blind; RA with MTX-IR

N/S

CFB in Genant-modified Sharp score and AUC in the HAQ-DI at Week 52

two years

A switch to blinded rescue treatment was available at weeks 16 and 28, if required.