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Clinical Trial
. 2016 Jun;75(6):1081-91.
doi: 10.1136/annrheumdis-2015-207628. Epub 2015 Oct 28.

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 Mitchell  7
Affiliations
Clinical Trial

Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial

Gerd R Burmester et al. Ann Rheum Dis. 2016 Jun.

Abstract

Objectives: The efficacy of tocilizumab (TCZ), an anti-interleukin-6 receptor antibody, has not previously been evaluated in a population consisting exclusively of patients with early rheumatoid arthritis (RA).

Methods: In a double-blind randomised controlled trial (FUNCTION), 1162 methotrexate (MTX)-naive patients with early progressive RA were randomly assigned (1:1:1:1) to one of four treatment groups: 4 mg/kg TCZ+MTX, 8 mg/kg TCZ+MTX, 8 mg/kg TCZ+placebo and placebo+MTX (comparator group). The primary outcome was remission according to Disease Activity Score using 28 joints (DAS28-erythrocyte sedimentation rate (ESR) <2.6) at week 24. Radiographic and physical function outcomes were also evaluated. We report results through week 52.

Results: The intent-to-treat population included 1157 patients. Significantly more patients receiving 8 mg/kg TCZ+MTX and 8 mg/kg TCZ+placebo than receiving placebo+MTX achieved DAS28-ESR remission at week 24 (45% and 39% vs 15%; p<0.0001). The 8 mg/kg TCZ+MTX group also achieved significantly greater improvement in radiographic disease progression and physical function at week 52 than did patients treated with placebo+MTX (mean change from baseline in van der Heijde-modified total Sharp score, 0.08 vs 1.14 (p=0.0001); mean reduction in Health Assessment Disability Index, -0.81 vs -0.64 (p=0.0024)). In addition, the 8 mg/kg TCZ+placebo and 4 mg/kg TCZ+MTX groups demonstrated clinical efficacy that was at least as effective as MTX for these key secondary endpoints. Serious adverse events were similar among treatment groups. Adverse events resulting in premature withdrawal occurred in 20% of patients in the 8 mg/kg TCZ+MTX group.

Conclusions: TCZ is effective in combination with MTX and as monotherapy for the treatment of patients with early RA.

Trial registration number: ClinicalTrials.gov, number NCT01007435.

Keywords: DMARDs (biologic); Early Rheumatoid Arthritis; Methotrexate.

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Figures

Figure 1
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.
Figure 2
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.
Figure 2
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.
Figure 3
Figure 3
Inhibition of joint damage over 52 weeks. (A) Mean change in radiographic scores from baseline to week 52 (ITT population). Missing 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.
Figure 4
Figure 4
Mean serum TCZ concentrations. MTX, methotrexate; TCZ, tocilizumab.
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