1081 Full

Clinical and epidemiological research
Ann Rheum Dis: first published as 10.1136/annrheumdis-2015-207628 on 28 October 2015. Downloaded from http://ard.bmj.com/ on October 16, 2024 by guest. Protected by copyright.
EXTENDED REPORT
Tocilizumab in early progressive rheumatoid

arthritis: FUNCTION, a randomised controlled trial
Gerd R Burmester,1 William F Rigby,2 Ronald F van Vollenhoven,3 Jonathan Kay,4
Andrea Rubbert-Roth,5 Ariella Kelman,6 Sophie Dimonaco,7 Nina Mitchell7
Handling editor Tore K Kvien ABSTRACT antirheumatic drugs (DMARDs) in combination or

▸ Additional material is Objectives The efficacy of tocilizumab (TCZ), an anti- early initiation of a biological DMARD.
published online only. To view, interleukin-6 receptor antibody, has not previously been Interleukin-6 (IL-6) plays a pivotal role in RA
please visit the journal online evaluated in a population consisting exclusively of pathogenesis, and has been implicated in the
(http://dx.doi.org/10.1136/
annrheumdis-2015-207628).
patients with early rheumatoid arthritis (RA). development of systemic symptoms and local
Methods In a double-blind randomised controlled trial inflammation, pannus formation and bone resorp-
For numbered affiliations see (FUNCTION), 1162 methotrexate (MTX)-naive patients tion leading to joint damage.6 7 RA disease activity
end of article.
with early progressive RA were randomly assigned correlates with elevated IL-6 level and activity.7 8
Correspondence to (1:1:1:1) to one of four treatment groups: 4 mg/kg TCZ Tocilizumab (TCZ), a humanised monoclonal
Dr Gerd R Burmester, +MTX, 8 mg/kg TCZ+MTX, 8 mg/kg TCZ+placebo and antibody that binds to IL-6 receptor-α and inhibits
Department of Rheumatology placebo+MTX (comparator group). The primary outcome IL-6–mediated pro-inflammatory signalling,9 has
and Clinical Immunology,
Charité-Universitätsmedizin was remission according to Disease Activity Score using demonstrated efficacy and safety in the treatment of
Berlin, Free University and 28 joints (DAS28–erythrocyte sedimentation rate (ESR) patients with RA.10–14 Four phase III trials have
Humboldt University of Berlin, <2.6) at week 24. Radiographic and physical function demonstrated the clinical benefit of combining TCZ
Charitéplatz 1, Berlin 10117, outcomes were also evaluated. We report results through with DMARDs in patients with RA with inadequate
Germany;
week 52. responses to DMARDs (including antitumour
[email protected]
Results The intent-to-treat population included 1157 necrosis factor (anti-TNF) agents).10 12–14 Three
Received 20 March 2015 patients. Significantly more patients receiving 8 mg/kg trials have demonstrated the efficacy and safety of
Revised 1 October 2015 TCZ+MTX and 8 mg/kg TCZ+placebo than receiving TCZ monotherapy in patients with RA.11 15 16
Accepted 3 October 2015 placebo+MTX achieved DAS28-ESR remission at week The efficacy of inhibiting IL-6 signalling has not
Published Online First
28 October 2015 24 (45% and 39% vs 15%; p<0.0001). The 8 mg/kg been evaluated previously in a population consisting
TCZ+MTX group also achieved significantly greater exclusively of methotrexate (MTX)-naive patients
improvement in radiographic disease progression and with early RA. We present results from the primary
physical function at week 52 than did patients treated analysis of the first 52 weeks of FUNCTION, a
with placebo+MTX (mean change from baseline in van 2-year phase III trial evaluating clinical and radio-
der Heijde–modified total Sharp score, 0.08 vs 1.14 graphic efficacy and safety of TCZ, in combination
( p=0.0001); mean reduction in Health Assessment with MTX and as monotherapy, in early RA.
Disability Index, −0.81 vs −0.64 ( p=0.0024)). In
addition, the 8 mg/kg TCZ+placebo and 4 mg/kg TCZ METHODS
+MTX groups demonstrated clinical efficacy that was at Trial design
least as effective as MTX for these key secondary FUNCTION was a multicentre, double-blind,
endpoints. Serious adverse events were similar among double-dummy, parallel-group, phase III trial in
treatment groups. Adverse events resulting in premature which patients were randomly assigned (1:1:1:1) to
withdrawal occurred in 20% of patients in the 8 mg/kg 4 mg/kg TCZ+MTX, 8 mg/kg TCZ+MTX, 8 mg/
TCZ+MTX group. kg TCZ+placebo or placebo+MTX. The random-
Conclusions TCZ is effective in combination with MTX isation sequence was stratified by serological status
and as monotherapy for the treatment of patients with (presence of rheumatoid factor (RF) and/or anticyc-
early RA. lic citrullinated peptide (anti-CCP) antibodies) and
Trial registration number ClinicalTrials.gov, number by geographical region. TCZ or placebo was admi-
NCT01007435 nistered intravenously every 4 weeks. MTX/placebo
Open Access
Scan to access more was initiated at 7.5 mg/week (to accommodate local
free content
recommendations of some countries at the time of
study design), and was increased to a maximum of
INTRODUCTION 20 mg/week by week 8 in patients with ongoing
Patients with rheumatoid arthritis (RA) can achieve swollen or tender joints.
long-term beneficial clinical and radiographic out- The trial was conducted in accordance with the
comes with early, effective treatment.1–3 For those Declaration of Helsinki and Good Clinical Practice
with severe RA and poor prognostic features (sero- guidelines. All patients provided written informed
positivity, erosive disease, high disease activity), consent.
To cite: Burmester GR,
Rigby WF, van recommendations support early intensive treatment
Vollenhoven RF, et al. Ann to achieve remission or low disease activity,4 5 Patients
Rheum Dis 2016;75: thus maximising long-term benefits. This may Adults (≥18 years) with moderate to severe active
1081–1091. include use of conventional disease-modifying RA, classified according to revised 1987 American
Burmester GR, et al. Ann Rheum Dis 2016;75:1081–1091. doi:10.1136/annrheumdis-2015-207628 1081
College of Rheumatology (ACR) criteria,17 of ≤2 years’ dur- adjusted for stratification factors (serological status and region)
ation who had not previously received MTX or biological within the model. Patients who withdrew or for whom a
agents were included. Patients with features of poor prognosis DAS28-ESR score or an ACR20/50/70 response could not be
were enrolled: inclusion criteria included Disease Activity Score determined were considered non-responders.
using 28 joints and erythrocyte sedimentation rate (DAS28-ESR) Changes from baseline in radiographic scores at week 52
>3.2, swollen joint count ≥4 (66 joint count), tender joint were compared between the TCZ and placebo+MTX groups
count ≥6 (68 joint count), ESR ≥28 mm/h or C reactive protein using non-parametric Van Elteren analysis stratified by region
≥1 mg/dl, positive RF or anti-CCP antibodies or one or more and serological status using linear extrapolation for missing
erosion of hands, wrists or feet attributable to RA based on a data. Other continuous variables (eg, HAQ-DI score) were
central radiographic reading. Before baseline, DMARDs were analysed using analysis of covariance that included treatment
withdrawn for appropriate washout periods (see online group, baseline score and baseline stratification factors.
supplementary appendix). Patients could continue treatment Non-radiographic continuous endpoints used a combination
with oral non-steroidal anti-inflammatory drugs and/or oral cor- of last-observation-carried-forward and no imputation for
ticosteroids (≤10 mg/day prednisone or equivalent), provided missing data.
the doses had been stable for at least 2 or 4 weeks before base-
line, respectively, and remained stable throughout the study. RESULTS
Patients could withdraw from the study at any time for any Patient population
reason. In addition, withdrawal was recommended for patients In total, 1162 patients were randomly assigned, and 920 (79%)
who had alanine aminotransferase (ALT) or aspartate amino- completed 52 weeks of treatment; 96.1% of patients assigned to
transferase (AST) elevations ≥3× the upper limit of normal 4 mg/kg TCZ+MTX, 8 mg/kg TCZ+MTX or placebo+MTX
(ULN) that was accompanied by total bilirubin >2× ULN; achieved MTX doses of 15 mg/week or higher (see online
withdrawal was required for patients with ALT or AST elevations supplementary appendix, results and tables S2–S4). Although
>5× ULN. overall withdrawal rates were similar among groups (figure 1),
withdrawals in the placebo+MTX group were driven primarily
Endpoints by non-safety–related reasons (most notably insufficient thera-
The proportion of patients achieving remission (DAS28-ESR peutic response and treatment refusal); withdrawals in the TCZ
<2.6) at week 24 was the primary endpoint. Key secondary groups were driven primarily by safety (AEs, most notably
endpoints included assessment of ACR response criteria, radio- laboratory abnormalities), with the highest incidence in the
graphic efficacy by the van der Heijde–modified total Sharp 8 mg/kg TCZ+MTX group, in which 47 of 291 patients
score (mTSS), quality of life using the Short Form-36 (SF-36) (16.2%) experienced an AE that led to withdrawal (see Safety).
physical and mental component scores (PCS and MCS) and Baseline demographics and disease characteristics were
physical function assessment by the Health Assessment balanced among treatment groups (table 1). Overall, patients
Questionnaire–Disability Index (HAQ-DI) score. Exploratory/ had very early RA (mean duration, 0.4–0.5 years) with little
post hoc analyses included evaluation of Clinical Disease radiographic damage at baseline (mean mTSS score, 5.66–7.72).
Activity Index (CDAI <2.8) remission and ACR/European Most patients were also RF or anti-CCP antibody positive
League Against Rheumatism (EULAR) preliminary criteria for (89%–91% and 86%–87%, respectively).
remission. Serum levels of TCZ were measured. Safety was
evaluated by the frequency and severity of adverse events (AEs). Efficacy
Signs and symptoms
Statistical analysis The primary endpoint was met: statistically significantly more
Analysis of efficacy was performed on the intent-to-treat popula- patients achieved DAS28-ESR remission at weeks 24 and 52
tion (all randomly assigned patients who received at least one with 8 mg/kg TCZ+MTX than with placebo+MTX (45% vs
TCZ/placebo infusion). The safety population included all 15% and 49% vs 20%, respectively; p<0.0001; table 2; OR,
patients who received at least one TCZ/placebo infusion and 24-week analysis, 4.77; p<0.0001). Significantly more 8 mg/kg
had at least one post-dose safety assessment. TCZ+placebo than placebo+MTX patients achieved
Overall, the study required 1128 patients (282 per arm) to DAS28-ESR remission at week 24 (39% vs 15%; p<0.0001).
provide 80% power to detect an absolute difference of 10% in Results from sensitivity analyses were consistent with those of
DAS28-ESR remission (DAS28-ESR <2.6) rate in the primary the primary analysis (see online supplementary appendix, results
comparison between 8 mg/kg TCZ+MTX and placebo+MTX and table S5). Mean DAS28-ESR scores decreased over time to
(assumed DAS28 remission rates were 26% and 16%, respect- week 52 in all groups; the 8 mg/kg TCZ+MTX group consist-
ively, under the null hypothesis of no treatment difference) in a ently showed the greatest decrease from baseline (figure 2A) and
two-sided test with a 5% significance level. The study was not the lowest mean scores.
powered to detect differences between TCZ groups. The sample Significantly greater response rates were also observed for
size was not inflated to account for withdrawals as the primary 8 mg/kg TCZ+MTX versus placebo+MTX for ACR20/50/70
analysis implemented a non-responder imputation approach that responses at weeks 24 and 52 ( p≤0.0142; figure 2B,C).
accounted for withdrawals. DAS28-ESR remission and ACR response rates indicated
Primary and all secondary efficacy endpoints were evaluated improvement in RA signs and symptoms in the 8 mg/kg TCZ
sequentially in a fixed hierarchy of statistical testing (with priori- +placebo and 4 mg/kg TCZ+MTX groups at weeks 24 and 52
tisation of the primary comparator group, 8 mg/kg TCZ (table 2, figure 2B, C). A non-significant result in the statistical
+MTX) to reduce the occurrence of false-positive conclusions testing hierarchy (see online supplementary appendix table S1)
resulting from multiple testing (see online supplementary occurred at the comparison of week 24 ACR50 response
appendix table S1). For the primary endpoint and dichotomous between 8 mg/kg TCZ+placebo and placebo+MTX
response variables (eg, ACR responses), TCZ groups were com- (p=0.2743). Therefore, all endpoints subsequently tested in the
pared with the placebo+MTX group using logistic regression, hierarchical chain were considered non-significant.
1082 Burmester GR, et al. Ann Rheum Dis 2016;75:1081–1091. doi:10.1136/annrheumdis-2015-207628
Figure 1 Patient disposition. *Five patients (two in the placebo+MTX group, two in the 4 mg/kg TCZ+MTX group and one in the 8 mg/kg TCZ
+MTX group) did not receive study treatment and were excluded from analysis populations. Withdrawals in the placebo+MTX group were mainly
driven by insufficient therapeutic response and refused treatment; withdrawals in the TCZ combination therapy groups were mainly related to safety
( primarily hepatic transaminase elevations). Two patients randomly assigned to the placebo+MTX group received TCZ at the baseline visit and were
allocated to the 4 mg/kg TCZ+MTX group for safety analysis. The ITT population comprised 1157 patients, and the safety population comprised
1153 patients. ITT, intent-to-treat; MTX, methotrexate; TCZ, tocilizumab.
Improvements in SF-36 PCS and MCS were observed in all Physical function
arms at weeks 24 and 52; the numerically greatest changes were Significantly greater improvements in mean HAQ-DI scores
with 8 mg/kg TCZ+MTX (see online supplementary appendix from baseline to week 52 were observed for 8 mg/kg TCZ
figure S1). Analysis of ACR/EULAR Boolean and Index remis- +MTX than for placebo+MTX (mean, −0.81 vs −0.64; differ-
sion and CDAI remission demonstrated numerically higher ence (95% CI) from placebo+MTX, −0.17 (−0.28 to −0.06),
remission rates with 8 mg/kg TCZ+MTX than with placebo p=0.0024; figure 2D). Both 8 mg/kg TCZ+placebo and 4 mg/
+MTX at week 24; however, as exploratory endpoints, these kg TCZ+MTX showed improvements in HAQ-DI scores from
were not adjusted for multiplicity (figure 2B). baseline to week 52 (mean (difference from placebo+MTX;
95% CI), −0.67 (−0.03 to −0.15; 0.08) and −0.75 (−0.11 to
Radiographic −0.22; 0.00), respectively) at least equal to those of placebo
Compared with placebo+MTX, inhibition of joint damage was +MTX (−0.64).
significantly greater with 8 mg/kg TCZ+MTX (mean (SD)
change in mTSS=0.08 (2.09) vs 1.14 (4.30); p=0.0001; figure Serum levels
3A). Mean changes from baseline to week 52 in mTSS were In patients for whom data were available, after the administra-
smaller with 8 mg/kg TCZ+placebo and 4 mg/kg TCZ+MTX tion of study drug, serum concentration profiles of TCZ were
(mean (SD), 0.26 (1.88) and 0.42 (2.93), respectively) than with similar with 8 mg/kg TCZ+placebo and 8 mg/kg TCZ+MTX
placebo+MTX (1.14 (4.30); figure 3A). Up to 83% of patients and lower with 4 mg/kg TCZ+MTX (figure 4).
in all TCZ-treated groups showed no radiographic progression
from baseline (change in mTSS ≤0) at weeks 24 and 52, whereas Safety
73% in the placebo+MTX group showed no change (see online AEs/serious AEs (SAEs) were reported in 88.3%/10.7% of 8 mg/
supplementary appendix figure S2). Mean change from baseline kg TCZ+MTX patients, 85.6%/8.6% of 8 mg/kg TCZ+placebo
to week 52 in erosion and joint space narrowing scores followed patients, 88.6%/10.0% of 4 mg/kg TCZ+MTX patients and
a trend similar to that of the overall mTSS (figure 3A). 83.3%/8.5% of placebo+MTX patients (table 3). AEs resulting
Sensitivity analyses confirmed these findings (see online in premature withdrawal occurred in 20.3% of 8 mg/kg TCZ
supplementary appendix figure S3). The cumulative distribution +MTX patients, 11.6% of 8 mg/kg TCZ+placebo patients,
plot of change from baseline in mTSS at week 52 shows a shift 12.1% of 4 mg/kg TCZ+MTX patients and 7.4% of placebo
to the right, indicating less progression of joint damage for the +MTX patients. In all TCZ treatment groups, the most
TCZ groups than for the placebo+MTX group (figure 3B). common reasons for treatment discontinuation were attributed
Table 1 Baseline demographics and disease characteristics (ITT population)
Placebo+MTX 4 mg/kg TCZ+MTX 8 mg/kg TCZ+MTX 8 mg/kg TCZ +placebo Missing values
n=287 n=288 n=290 n=292 (all groups), n
Female, n (%) 229 (80) 228 (79) 228 (79) 219 (75) 0
Age, years 49.6±13.10 (50.0) 51.2±13.84 (53.0) 49.5±13.70 (50.5) 49.9±13.22 (51.0) 0
Duration of RA, years 0.4±0.48 (0.2) 0.4±0.49 (0.2) 0.5±0.53 (0.3) 0.5±0.48 (0.2) 0
DMARD naive, n (%)* 228/282 (80.9) 236/289 (81.7) 230/290 (79.3) 223/292 (76.4) 4
Number of previous DMARDs† 0.2±0.41 (0.0) 0.2±0.41 (0.0) 0.2±0.49 (0.0) 0.3±0.52 (0.0) 0
0, n (%) 228 (80.9) 236 (81.7) 230 (79.3) 223 (76.4) –
1, n (%) 53 (18.8) 51 (17.6) 53 (18.3) 60 (20.5) –
2, n (%) 1 (0.4) 2 (0.7) 6 (2.1) 8 (2.7) –
3, n (%) 0 (0.0) 0 (0.0) 1 (0.3) 1 (0.3) –
Receiving corticosteroids, n (%) 109 (38) 107 (37) 95 (33) 118 (40) 0
RF positive, n (%) 254 (89) 255 (89) 264 (91) 262‡ (90) 1
Anti-CCP antibody positive, n (%) 246 (86) 245§ (86) 252 (87) 247 (86) 6
DAS28-ESR 6.6±0.99 (6.5) 6.7±1.05 (6.7) 6.7±1.11 (6.8) 6.7±0.99 (6.7) 0
CRP, mg/dL 2.31±2.667 (1.28) 2.59±3.053 (1.58) 2.58±2.978 (1.69) 2.48±3.186 (1.26) 0
ESR, mm/h 50.4±26.81 (44.0) 55.7±30.62 (48.0) 52.8±30.15 (46.0) 51.3±28.39 (41.5) 0
Tender joint count 27.4±16.54 (23.0) 28.1±15.63 (25.0) 28.7±16.74 (24.5) 28.7±16.33 (25.0) 0
(68 joints)
Swollen joint count 16.2±10.44 (13.0) 16.1±10.16 (13.0) 17.6±12.38 (14.0) 16.5±10.10 (13.0) 0
(66 joints)
HAQ-DI score 1.48±0.665 (1.50) 1.62±0.662 (1.75) 1.50±0.625 (1.50) 1.58±0.672 (1.63) 11
Patient pain VAS 59.8±22.02 (62.0) 59.5±22.62 (61.0) 61.6±22.10 (65.0) 62.5±21.82 (65.0) 4
Physician VAS 62.7±17.27 (65.0) 62.4±17.03 (63.0) 63.6±18.12 (65.0) 63.9±18.09 (65.0) 0
Patient global VAS 63.8±21.51 (66.0) 65.3±22.50 (66.0) 66.5±21.46 (70.0) 67.5±22.39 (71.0) 0
mTSS 5.66±14.581 (1.50) 7.72±17.155 (2.00) 6.17±11.078 (2.00) 6.85±16.100 (1.50) 4
JSN score 2.34±7.452 (0.00) 3.60±9.600 (0.00) 2.67±6.488 (0.00) 3.00±8.598 (0.00) 4
Erosion score 3.32±7.642 (1.00) 4.13±8.510 (1.50) 3.49±5.722 (1.50) 3.85±8.299 (1.00) 4
Data are presented as mean±SD (median) unless stated otherwise.

*Reported for the safety population. Note: all patients were MTX naive per protocol.
†Rates of previous DMARD use included for placebo+MTX, 4 mg/kg TCZ+MTX, 8 mg/kg TCZ+MTX and 8 mg/kg TCZ+placebo, respectively, are as follows: hydroxychloroquine, 7%, 4%,
8% and 10%; chloroquine, 4%, 3%, 3% and 4%; sulfasalazine, 6%, 9%, 10% and 9%; leflunomide, 2%, 1%, 1% and 3%; azathioprine, 0%, 0%, 1% and 1%; gold, 0%, <1%, 0% and
<1%; and penicillamine, 0%, 0%, <1% and 0%.
‡Based on 291 patients.
§Based on 286 patients.
CCP, cyclic citrullinated peptide; CRP, C reactive protein; DAS28, Disease Activity Score using 28 joints; DMARD, disease-modifying antirheumatic drug; ESR, erythrocyte sedimentation
rate; HAQ-DI, Health Assessment Questionnaire–Disability Index; ITT, intent-to-treat; JSN, joint space narrowing; mTSS, modified total Sharp score; MTX, methotrexate; RA, rheumatoid
arthritis; RF, rheumatoid factor; TCZ, tocilizumab; VAS, Visual Analogue Scale.
to the investigations system organ class, particularly events The most frequently reported AEs and SAEs were infections;
related to liver enzyme elevations (the most common preferred the percentage of infections was similar overall in the two 8
terms in TCZ groups were ALT increased (27 patients), trans- mg/kg TCZ groups and the placebo+MTX group and a numer-
aminase increased (22 patients) and AST increased (4 patients)). ically higher percentage of infections in the 4 mg/kg TCZ
Table 2 Proportions of patients achieving DAS28-ESR remission at week 24 and week 52

Placebo+MTX 4 mg/kg TCZ+MTX 8 mg/kg TCZ+MTX 8 mg/kg TCZ+placebo
n=287 n=288 n=290 n=292
Week 24
Responders, n (%) 43 (15.0) 92 (31.9) 130 (44.8) 113 (38.7)
(95% CI) (10.9 to 19.1) (26.6 to 37.3) (39.1 to 50.6) (33.1 to 44.3)
p Value vs placebo+MTX <0.0001* <0.0001 <0.0001
OR (95%) relative to placebo+MTX 2.72 (1.80 to 4.11) 4.77 (3.19 to 7.14) 3.70 (2.47 to 5.55)
p<0.0001* p<0.0001 p<0.0001
Week 52
Responders, n (%) 56 (19.5) 98 (34.0) 142 (49.0) 115 (39.4)
(95% CI) (14.9 to 24.1) (28.6 to 39.5) (43.2 to 54.7) (33.8 to 45.0)
p Value vs placebo+MTX <0.0001* <0.0001 <0.0001*
ORs were determined by logistic regression analysis.
*The comparison occurred after a break in the hierarchically ordered testing sequence.
DAS28, Disease Activity Score using 28 joints; ESR, erythrocyte sedimentation rate; MTX, methotrexate; TCZ, tocilizumab.

Figure 2 Efficacy endpoints (A) DAS28-ESR over 52 weeks. Mean DAS28-ESR scores by visit. Error bars show SEM (ITT population). (B) Secondary
and exploratory endpoints at week 24. (C) Secondary and exploratory endpoints at week 52. (D) Change from baseline in HAQ-DI. All
post-withdrawal efficacy data were excluded from analyses. Boolean criteria for ACR/EULAR remission require that the following be satisfied at the
same visit: tender joint count (68) ≤1, swollen joint count (66) ≤1, Patient Global Assessment of Disease Activity (cm) ≤1, C-reactive protein
≤1 mg/dL. The index-based definition of ACR/EULAR remission is an SDAI score ≤3.3. SDAI is defined as the sum of tender joint count (28), swollen
joint count (28), Patient Global Assessment of Disease Activity (cm), Physician Global Assessment of Disease Activity (cm) and C-reactive protein
(mg/dL). ACR endpoints used non-responder imputation; CDAI used LOCF for missing data; ACR/EULAR and HAQ-DI used no imputation for missing
data. ACR, American College of Rheumatology; CDAI, Clinical Disease Activity Index; DAS28, Disease Activity Score using 28 joints; ESR, erythrocyte
sedimentation rate; EULAR, European League Against Rheumatism; HAQ-DI, Health Assessment Questionnaire–Disability Index; ITT, intent-to-treat;
LOCF, last-observation-carried-forward; MTX, methotrexate; SDAI, Simplified Disease Activity Index; TCZ, tocilizumab.

Burmester GR, et al. Ann Rheum Dis 2016;75:1081–1091. doi:10.1136/annrheumdis-2015-207628

Figure 2 Continued
1086
Figure 3 Inhibition of joint damage over 52 weeks. (A) Mean change in radiographic scores from baseline to week 52 (ITT population). Missing Ann Rheum Dis: first published as 10.1136/annrheumdis-2015-207628 on 28 October 2015. Downloaded from http://ard.bmj.com/ on October 16, 2024 by guest. Protected by copyright.
data were imputed using linear extrapolation. (B) Cumulative probability plot of change in mTSS from baseline based on radiographs taken at
baseline, week 24, week 52 and withdrawal. Radiographic endpoints were analysed using a non-parametric Van Elteren analysis method. Because of
the primary imputation method of linear extrapolation for patients with one baseline and one or more post-baseline radiographs, 93%, 93%, 94%
and 94% of patients in the placebo+MTX group, the 4 mg/kg TCZ+MTX group, the 8 mg/kg TCZ+MTX group and the 8 mg/kg TCZ+placebo
group, respectively, contributed to the week 52 analysis. Linear extrapolation was used for 15% to 17% of patients across all treatment arms at
week 52 ( placebo+MTX group, 44/287; 4 mg/kg TCZ+MTX group, 44/288; 8 mg/kg TCZ+MTX group, 50/290; 8 mg/kg TCZ+placebo group, 45/292).
ITT, intent-to-treat; JSN, joint space narrowing; mTSS, van der Heijde–modified total Sharp score; MTX, methotrexate; TCZ, tocilizumab.
+MTX group (table 3). The most frequently reported serious TCZ+MTX groups, and were dose dependent: grade ≥2 eleva-
infection was pneumonia, accounting for 12 of 35 serious infections were seen in 15.6%, 23.8%, 8.2% and 8.5% of patients in
tions. No opportunistic infections were reported. One newly the 4 mg/kg TCZ+MTX, 8 mg/kg TCZ+MTX, 8 mg/kg TCZ
diagnosed case of tuberculosis occurred in a patient in the 8 mg/ +placebo and placebo+MTX groups, respectively. No instances
kg TCZ+MTX group through close exposure to a relative with of grade 4 elevations were reported. Most elevations >3× the
active tuberculosis. ULN in all treatment groups occurred at a single time point
Elevations in ALT concentrations according to the Common during the 52-week treatment period (8.3%, 8.3%, 4.5% and
Toxicity Criteria (V.3.0; table 3) occurred most frequently in the 4.6% with 4 mg/kg TCZ+MTX, 8 mg/kg TCZ+MTX, 8 mg/
Figure 4 Mean serum TCZ concentrations. MTX, methotrexate; TCZ, tocilizumab.
kg TCZ+placebo and placebo+MTX patients, respectively). No Although the study was not powered to detect differences in
associations between neutropenia and serious infections or treatment effects between the TCZ arms and all doses/regimens
between thrombocytopenia and bleeding events were observed. of TCZ demonstrated clinical benefit compared with MTX
Increases in low-density lipoprotein cholesterol from <160 mg/ alone, the 8 mg/kg TCZ+MTX group consistently achieved the
dL at baseline to ≥160 mg/dL were reported in 8.0%, 12.1%, best outcomes across all efficacy measures. For the duration of
15.1% and 3.2% of 4 mg/kg TCZ+MTX, 8 mg/kg TCZ the 52-week study, the 8 mg/kg TCZ+MTX regimen (the
+MTX, 8 mg/kg TCZ+placebo and placebo+MTX patients, primary comparator) significantly improved clinical outcomes
respectively. and functional ability (measured by HAQ-DI score) and inhib-
Thirteen malignancies were reported (five before day 50); ited joint damage progression compared with the MTX-alone
incidences were similar among all groups. Breast cancer was the regimen. The primary endpoint was met: 45% of 8 mg/kg TCZ
most commonly reported malignancy (three patients; see online +MTX patients achieved DAS28 remission at 24 weeks com-
supplementary appendix table S6). Nine deaths occurred: two pared with 15% of placebo+MTX patients. Of interest, in con-
in the 8 mg/kg TCZ+MTX group, one in the 8 mg/kg TCZ trast to the humanised monoclonal anti-TNF antibody
+placebo group, four in the 4 mg/kg TCZ+MTX group and adalimumab,18 the addition of MTX to TCZ did not result in
two in the placebo+MTX group. The underlying cause of TCZ serum levels significantly higher than levels attained with
death varied across treatment groups (see online supplementary TCZ monotherapy. Although the underlying mechanisms that
appendix table S7). Three of four deaths in the 4 mg/kg TCZ drive serum levels of a biological treatment in the context of
+MTX group were in patients who were older than 80 years. combination with MTX versus monotherapy are not fully eluci-
dated, our findings suggest that synergy between IL-6 inhibition
DISCUSSION and MTX action, rather than higher serum drug levels, drives
FUNCTION is the first trial to examine the effects of inhibiting the higher clinical response observed with TCZ+MTX.
IL-6 signalling as a first-line therapeutic option for RA. The Exploratory analyses across other disease remission measures
study entry criteria specifically targeted patients with active (ACR/EULAR Boolean and Index remission, CDAI remission),
disease and features of progressive disease (baseline mean which were of clinical importance despite their not being vali-
DAS28-ESR ranged from 6.6 to 6.7; approximately 90% of dated in a clinical trial setting, also showed that improvement
enrolled patients were seropositive for RF and/or anti-CCP anti- with 8 mg/kg TCZ+MTX was at least equal to improvement
bodies), which is the target population for whom early use of with MTX alone. Analysis of CDAI remission is of particular
intensive therapy, such as with a biological agent, may be interest because this composite disease activity measure does not
appropriate.5 include an acute-phase reactant, and it demonstrates that control
Table 3 Summary of safety findings (safety population)
Placebo+MTX 4 mg/kg TCZ+MTX 8 mg/kg TCZ+MTX 8 mg/kg TCZ+placebo
n=282 n=289 n=290 n=292
Patients with one or more event, n (%)
Any AEs 235 (83.3) 256 (88.6) 256 (88.3) 250 (85.6)
Infections 136 (48.2) 155 (53.6) 137 (47.2) 138 (47.3)
AEs resulting in premature withdrawal from the study 21 (7.4) 35 (12.1) 59 (20.3) 34 (11.6)
Any SAEs 24 (8.5) 29 (10.0) 31 (10.7) 25 (8.6)
SAEs of special interest
Infections 6 (2.1) 11 (3.8) 10 (3.4) 8 (2.7)
Malignancies 3 (1.1) 4 (1.4) 1 (0.3) 2 (0.7)
Myocardial infarctions 0 3 (1.0) 1 (0.3) 1 (0.3)
Strokes 2 (0.7) 2 (0.7) 0 0
Hypersensitivity reactions 0 1 (0.3) 0 1 (0.3)
Gastrointestinal perforations 1 (0.4) 0 0 0
Hepatic events 0 0 0 0
Deaths, n (%) 2 (0.7) 4 (1.4) 2 (0.7) 1 (0.3)
Clinical laboratory abnormalities
Neutropenia
Grade −3 (<1.0–0.5×109/L) 1 (0.4) 2 (0.7) 10 (3.4) 8 (2.7)
Grade −4 (<0.5×109/L) 0 0 0 1 (0.3)
Thrombocytopenia (based on platelet count)
Grade −3 (<50–25×109/L) 1 (0.4) 1 (0.3) 0 0
Grade −4 (<25×109/L) 1 (0.4) 0 1 (0.3) 0
ALT elevations
Grade 1 (>ULN–2.5× ULN) 120 (42.6) 125 (43.3) 136 (46.9) 115 (39.4)
Grade 2 (>2.5–5× ULN) 21 (7.4) 35 (12.1) 59 (20.3) 19 (6.5)
Grade 3 (>5.0–20× ULN) 3 (1.1) 10 (3.5) 10 (3.4) 5 (1.7)
Grade 4 (>20× ULN) 0 0 0 0
AST elevations
Grade 1 (>ULN–2.5× ULN) 88 (31.2) 95 (32.9) 137 (47.2) 86 (29.5)
Grade 2 (>2.5–5× ULN) 11 (3.9) 12 (4.2) 18 (6.2) 9 (3.1)
Grade 3 (>5.0–20× ULN) 1 (0.4) 1 (0.3) 5 (1.7) 3 (1.0)
Grade 4 (>20× ULN) 0 0 0 0
All values are n (%).
ALT ULN=55 U/L.
AST ULN=40 U/L.
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; MTX, methotrexate; SAE, serious adverse event; TCZ, tocilizumab; ULN, upper limit of normal.
of disease activity in TCZ-treated patients with early RA was RA population. Both 8 mg/kg TCZ+placebo and 4 mg/kg TCZ
independent of the direct pharmacodynamic effect of TCZ in +MTX achieved DAS28 and ACR efficacy responses consist-
suppressing the synthesis of acute-phase reactant proteins.19 ently at least equal to those observed with placebo+MTX.
Early radiographic progression contributes to long-term dis- These regimens also demonstrated suppression of radiographic
ability, and prevention of structural joint damage is an important structural joint damage, with 77% (8 mg/kg TCZ+placebo) and
therapeutic goal early in and throughout the course of the 63% (4 mg/kg TCZ+MTX) relative reduction in mTSS to week
disease.20 21 Baseline radiographic joint damage was low in all 52 compared with rates seen in the MTX+placebo group.
treatment groups, reflecting the early stage of RA in the study Numerically greater inhibition in structural joint damage was
population. This finding is consistent with other trials in early observed with 8 mg/kg TCZ+MTX than with 8 mg/kg TCZ
RA populations.1 22–24 Throughout 52 weeks, patients treated monotherapy or 4 mg/kg TCZ+MTX. Therefore, although
with TCZ experienced less radiographic progression than 8 mg/kg TCZ+MTX is the most effective treatment, both 4
patients treated with MTX monotherapy, with the greatest joint mg/kg TCZ+MTX and 8 mg/kg TCZ monotherapy represent
damage inhibition in the 8 mg/kg TCZ+MTX group. Of note, good alternative treatments for subsets of patients, such as those
mTSS progression was low overall, even in the comparator unable to tolerate MTX or the higher 8 mg/kg dose because of
MTX monotherapy arm, as has been observed in other early RA contraindications or adverse reactions.
trials. Several other biological agents have proven efficacy in the
The recommended starting dose for intravenous TCZ in the early RA population. Because of differences in study design,
USA and Canada is 4 mg/kg,25 in contrast to 8 mg/kg used in comparisons across trials are difficult. Nevertheless, TCZ
the rest of the world; 8 mg/kg TCZ monotherapy has also appears to demonstrate benefits in patients with early RA (in
demonstrated efficacy in patients with RA.11 15 16 Therefore, it regard to DAS28 remission, ACR responses and radiographic
was of interest to evaluate these TCZ dose regimens in the early endpoints), compared with patients treated with MTX alone,
that are generally consistent with those observed in previous radiographic outcomes and the long-term safety of TCZ in
studies of biological therapies in similar populations.1 3 22 26 patients with early RA and poor prognostic features.
Although a number of head-to-head comparison studies of dif-
ferent biological agents have recently been published,15 27 these Author affiliations
1
have generally been performed in patients who have more estab- Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin
Berlin, Free University and Humboldt University of Berlin, Berlin, Germany
lished RA and who have responded inadequately to previous 2
Department of Medicine-Rheumatology, Dartmouth-Hitchcock Medical Center and
DMARDs. It would be of interest to conduct such studies in Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA
3
more treatment-naive patients with early RA. Department of Medicine, Karolinska Institute, Stockholm, Sweden
4
AEs observed in the TCZ groups were consistent with the Rheumatology Center, University of Massachusetts Medical School and UMass
Memorial Medical Center, Worcester, Massachusetts, USA
known safety profile of TCZ; no additional safety signals were 5
Department of Internal Medicine I, University of Cologne, Cologne, Germany
observed, and the most frequently reported AE was infection in 6
Genentech, South San Francisco, California, USA
7
all TCZ groups and in the placebo+MTX group. However, a Roche Products Ltd., Welwyn Garden City, UK
numerically higher incidence of certain events (infections, malig-
Acknowledgements The first draft of the manuscript was prepared by the
nancies, myocardial infarctions and deaths) was reported in the
authors, with professional writing and editorial assistance provided by Sara Duggan,
4 mg/kg TCZ+MTX group than the other groups. Although PhD, Karen Stauffer, PhD, Maribeth Bogush, PhD, and Meryl Mandle, who provided
patients in the 4 mg/kg TCZ+MTX group were marginally writing services on behalf of F Hoffmann-La Roche Ltd. Revisions to the manuscript
older than the other patients, there were no imbalances in any were performed by the authors, with professional writing and editorial assistance
other baseline demographic or disease characteristics. The sig- provided by Sara Duggan, PhD, and Meryl Mandle, on behalf of F Hoffmann-La
Roche Ltd. The authors thank Emma Healy and Susanna Grzeschik of F Hoffmann-La
nificance of, and reason for, these small numerical differences Roche Ltd., who contributed to the analysis and interpretation of the data. The
are unclear. Changes in laboratory parameters (eg, increased authors vouch for the completeness and accuracy of the data and data analyses and
hepatic transaminase levels and decreased neutrophil and plate- for the fidelity of the study to the protocol.
let counts) have been reported for TCZ.10–14 Consistent with Contributors GRB and WFR contributed to the conception and design of the
the known effects of TCZ and of MTX on transaminase levels, study. GRB, WFR, RFvV, JK and AR-R contributed to data acquisition. GRB, WFR,
more patients in the TCZ+MTX groups than in either mono- RFvV, JK, AR-R, AK, SD and NM analysed and interpreted the data. NM conducted
the literature search. GRB, WFR, JK, AK, SD and NM drafted the manuscript. All
therapy group experienced ALT elevations, though AST eleva-
authors revised the manuscript critically for important intellectual content. All
tions were similar between TCZ+MTX and TCZ monotherapy. authors contributed to, reviewed and approved the final manuscript.
Importantly, most elevations occurred at a single time point,
Funding This study was funded by Roche. Funding for manuscript preparation was
were not sustained and did not result in any clinical sequelae provided by F Hoffmann-La Roche Ltd.
(no serious hepatic events were reported). Thrombocytopenia
Competing interests GRB reports grants paid to his institution from Roche and
was similar between TCZ+MTX and TCZ monotherapy personal fees for lectures and consulting from AbbVie, Bristol-Myers Squibb, Merck
groups. Consistent with intravenous TCZ dosing, one hypersen- Sharp & Dohme, Pfizer and UCB Pharma outside the submitted work. WFR reports
sitivity reaction was reported in the 4 mg/kg TCZ+MTX grants and personal fees from Roche outside the submitted work. RFvV reports grants
group and one was reported in the TCZ monotherapy group. from the Karolinska University Hospital during the conduct of the study; grants and
personal fees from AbbVie, Bristol-Myers Squibb, GSK, Pfizer, Roche and UCB
Rates of AEs resulting in premature withdrawal in this study Pharma outside the submitted work; and personal fees from Biotest, Janssen, Lilly,
ranged from 12% in the 4 mg/kg and TCZ monotherapy arms Merck and Vertex outside the submitted work. JK reports grants paid to his
to 20% in the 8 mg/kg TCZ+MTX arm; these proportions institution from Abbott Laboratories, Roche Laboratories and Sanofi-Aventis during
were higher than in previous studies of TCZ,10–14 which were the conduct of the study and personal fees from Amgen, Inc., AbbVie Inc.,
conducted in more treatment-experienced populations. The Bristol-Myers Squibb Company, Eli Lilly and Company, Epirus Biopharmaceuticals,
Inc., Genentech, Inc., Hospira, Inc., Janssen Biotech, Inc., Pfizer Inc, Roche
higher withdrawal rates might have resulted from the protocol- Laboratories, Inc. and UCB Pharma outside the submitted work. AR-R reports grants
mandated requirement for withdrawal in response to transamin- from Chugai, Roche and Pfizer and honoraria for lectures and advisory boards from
ase elevations (if three consecutive doses of intravenous study Abbott, Bristol-Myers Squibb, Chugai, Merck Sharp & Dohme, Pfizer, Roche and UCB
drug were missed because of transaminase elevations, the Pharma. AK is a full-time employee of Genentech, a member of the Roche Group.
SD is a full-time employee of Roche Products Ltd. NM was a full-time employee of
patient was withdrawn). Roche Products Ltd. at the time this study was conducted.
This study had some limitations. The blinded nature pre-
Patient consent Obtained.
cluded dose modification of intravenous TCZ/placebo, MTX
dose was limited to 20 mg/week and laboratory abnormalities Ethics approval This trial was conducted in accordance with the principles of the
Declaration of Helsinki and Good Clinical Practice. All patients provided written
were managed, according to protocol, by interruption or discon- informed consent.
tinuation of intravenous dosing. These conditions may not
Provenance and peer review Not commissioned; externally peer reviewed.
reflect actual clinical practice. Furthermore, it is unclear
whether these results are generalisable to patients with early RA Open Access This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
that is less severe. permits others to distribute, remix, adapt, build upon this work non-commercially,
Overall, the results of this study support the effectiveness and and license their derivative works on different terms, provided the original work is
clinical benefit of TCZ in MTX-naive patients with early pro- properly cited and the use is non-commercial. See: http://creativecommons.org/
gressive RA. The greatest benefit was afforded by 8 mg/kg TCZ licenses/by-nc/4.0/
+MTX; the other TCZ regimens were at least as effective as
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Clinical and epidemiological research

Tocilizumab in early progressive rheumatoid

Handling editor Tore K Kvien ABSTRACT antirheumatic drugs (DMARDs) in combination or

Data are presented as mean±SD (median) unless stated otherwise.

Table 2 Proportions of patients achieving DAS28-ESR remission at week 24 and week 52

1084 Burmester GR, et al. Ann Rheum Dis 2016;75:1081–1091. doi:10.1136/annrheumdis-2015-207628

Burmester GR, et al. Ann Rheum Dis 2016;75:1081–1091. doi:10.1136/annrheumdis-2015-207628 1085

Burmester GR, et al. Ann Rheum Dis 2016;75:1081–1091. doi:10.1136/annrheumdis-2015-207628

1090 Burmester GR, et al. Ann Rheum Dis 2016;75:1081–1091. doi:10.1136/annrheumdis-2015-207628

Burmester GR, et al. Ann Rheum Dis 2016;75:1081–1091. doi:10.1136/annrheumdis-2015-207628 1091

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