Background/Purpose:  Anti-TNF plus methotrexate (MTX) is more effective than either as monotherapy. Thus far, no controlled data are available on the benefit:risk of different doses of MTX in combination with anti-TNF. The purpose of this study was to determine the effect of MTX dose in combination with adalimumab (ADA) on efficacy, pharmacokinetics, and safety in patients (pts) with early rheumatoid arthritis (RA).

Methods:  CONCERTO was a 26-week (wk), double-blind, parallel-arm trial in MTX and biologic-naive pts with active RA [DAS28(CRP) ≥3.2; CRP ≥1.5 mg/dL or ESR ≥28 mm/hr; ≥1 erosion or RF+ or ACPA+] of <1 year duration. Pts were randomized 1:1:1:1 to wkly oral MTX (2.5, 5, 10, or 20 mg) and received open-label (OL) ADA 40 mg every other wk (eow). Pts in the 20 mg arm began 10 mg and escalated 2.5 mg eow to 20 mg. The primary endpoint was the achievement of low disease activity [LDA, defined as DAS28(CRP) <3.2] at wk 26. Secondary endpoints included DAS28(CRP) (<2.6), ACR50/70/90, SDAI (≤3.3)/CDAI (≤2.8) remission, radiographic nonprogression (ΔmTSS ≤0.5), and ΔHAQ-DI ≤-0.22 at wk 26. Dose-response was assessed via Cochran-Armitage linear trend test. Non-responder imputation was used for missing data. Serum samples for pharmacokinetics were collected prior to baseline and at all study visits. Safety was assessed in terms of adverse events (AEs) for all pts who received ≥1 dose of study drug.

Results:  Of the 395 randomized pts, 358 (83, 93, 93, and 89 from the 2.5, 5, 10, and 20 mg arms, respectively) completed 26 wks. At wk 26, there was a statistically significant trend in the proportion of pts achieving DAS28(CRP) <3.2 with increasing dose of MTX in combination with OL ADA (Table). Significant trends were noted as early as wk 12 and sustained through wk 26. Similar results were observed for ACR50/70/90 and DAS28(CRP) < 2.6, SDAI/CDAI remission. Numerically increasing trends were also apparent in the proportions achieving radiographic nonprogression and ΔHAQ-DI ≤-0.22 at wk 26. Clinical and radiographic outcomes generally appeared comparable between the 10 and 20 mg arms. ADA serum concentrations were similar in the 10 and 20 mg MTX arms, with slightly lower mean ADA serum concentrations in the 2.5 and 5 mg arms. AEs were consistent with the known profile of anti-TNF and were generally consistent between arms, occurring most frequently in the 20 mg arm.

 

Parametera	2.5 mg MTX + OL ADA	5 mg MTX + OL ADA	10 mg MTX + OL ADA	20 mg MTX + OL ADA	P value
DAS28(CRP) <3.2, n/N (%)	42/98 (43)	44/100 (44)	56/99 (57)	59/98 (60)	.005
DAS28(CRP) <2.6, n/N (%)	27/98 (28)	32/100 (32)	37/99 (37)	44/98 (45)	.008
SDAI ≤3.3, n/N (%)	11/98 (11)	22/100 (22)	28/99 (28)	29/98 (30)	.005
CDAI ≤2.8, n/N (%)	12/98 (12)	22/100 (22)	29/99 (29)	27/98 (28)	.02
ACR50/70/90, %	46/24/7	51/34/10	54/41/17	62/46/16	.02/.003/.04
ΔmTSS ≤0.5, n/N (%)	63/98 (64)	72/100 (72)	76/99 (77)	76/98 (78)	.06
ΔHAQ-DI ≤-0.22, n/N (%)	67/98 (68)	70/100 (70)	73/99 (74)	76/98 (78)	.12
aNon-responder imputation.

Conclusion: MTX and biologic-naïve pts with early RA demonstrated robust and dose-dependent clinical responses with increasing doses of MTX in combination with OL ADA through 26 wks. Interestingly, clinical responses and ADA serum concentrations generally appeared similar between the 10 and 20 mg MTX arms.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/efficacy-pharmacokinetics-and-safety-of-different-doses-of-methotrexate-in-combination-with-adalimumab-results-from-the-concerto-trial/