Meta-Analysis of the Time Course of the Response to Adalimumab Plus Methotrexate or Methotrexate Monotherapy in Clinical Trials of Patients with Rheumatoid Arthritis

Xin Wang¹, Arthur Kavanaugh², Désirée van der Heijde³, Maxime Dougados⁴, Stefan Florentinus¹, Yihan Li¹, Iain Sainsbury¹ and Josef S. Smolen⁵, ¹AbbVie Inc., North Chicago, IL, ²University of California San Diego, La Jolla, CA, ³Leiden University Medical Center, Leiden, Netherlands, ⁴René Descartes University and Hôpital Cochin, Paris, France, ⁵Medical University of Vienna and Hietzing Hospital, Vienna, Austria

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: C-reactive protein (CRP), methotrexate (MTX), rheumatoid arthritis (RA) and treatment

Session Information

Date: Sunday, November 8, 2015

Title: Rheumatoid Arthritis - Clinical Aspects Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Adalimumab (ADA) plus
methotrexate (MTX) and MTX treatments for rheumatoid arthritis (RA) have been assessed
in phase 2–4 clinical trials. This meta-analysis used 5 such studies to create
a maximum efficacy (Emax) model describing the time course of the change from
baseline in the 28-joint Disease Activity Score (DAS28) based on C-reactive
protein (CRP).

Methods: DAS28(CRP) is a validated, continuous clinical
efficacy endpoint for assessing signs and symptoms in RA patients (pts); change
from baseline was modeled using a 3-parameter, nonlinear Emax model of ADA+MTX or
MTX efficacy over time (up to 52 wks). Emax models for the DAS28(CRP) time
course for each treatment and each study were built using data from pts with
early (n=3 studies) and established (n=2) RA. Contributions of baseline covariates
were assessed using the least absolute shrinkage and selection operator (LASSO)
penalized linear regression model.

Results: Emax model estimates for DAS28(CRP) responses
to ADA+MTX and MTX treatments are in Table 1. Visual inspection
confirmed that modeled time courses for DAS28(CRP) responses to ADA+MTX and MTX
treatments were consistent with observed mean and median values of the combined
studies; residual variability for DAS28(CRP) change was 1.1 in both groups. The
modeled DAS28(CRP) response to MTX appeared to develop more slowly vs response
to ADA+MTX (9.4 vs 3.1 wks for 50% effect). The effects of RA duration on DAS28(CRP)
responses were estimated by modeled time courses for ADA+MTX and MTX in pts
with early (duration=0.4 y, no prior DMARD use) and established (duration=5 y,
prior DMARD use) RA; all other covariates were fixed. The DAS28(CRP) responses
to MTX and ADA+MTX were greater in pts with early vs established RA (Figure
1). When the covariate for baseline disease activity was set to DAS28(CRP)=5.5
(less active RA) vs 6.5 (more active RA), the model predicted greater responses
to either treatment in pts with more active RA (Figure 2).

Conclusion: Time courses of DAS28(CRP) responses to
ADA+MTX and MTX treatments over 52 wks were well characterized by Emax models incorporating
baseline covariates. The models predicted the greatest treatment differences
between ADA+MTX and MTX during the first 24 wks and greater DAS28(CRP) responses
to either treatment in pts with early RA and more active RA at baseline.

Table 1. 52-Week Emax Model Estimates for DAS28(CRP) Responses
	Parameter Estimates
Covariate at Baseline	MTX	ADA+MTX
Body mass index, kg/m²	0.005	0.023**
RA duration, y	0.059**	0.001
DAS28	–0.682**	–0.632**
Prior DMARD use	0.343**	0.661**
CRP	–0.013	–0.034**
Subject Global Assessment of disease activity	–0.008**	–0.005**
Physician Global Assessment of disease activity	0.007**	0.003**
Subject Global Assessment of pain	0.004*	0.004**
Health Assessment Questionnaire	0.276**	0.232**
Model Parameters
b₀	0.304	–0.470**
ED₅₀	9.381**	3.085**
P<0.01; *P<0.001.

Disclosure: X. Wang, AbbVie, 3,AbbVie, 1; A. Kavanaugh, AbbVie, 2,AbbVie, 5; D. van der Heijde, AbbVie, Amgen, AstraZeneca, BMS, Centocor, Chugai, Daiichi, Eli Lilly, GSK, Janssen Biologics, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB, Vertex, 2,AbbVie, Amgen, AstraZeneca, BMS, Centocor, Chugai, Daiichi, Eli Lilly, GSK, Janssen Biologics, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB, Vertex, 5; M. Dougados, AbbVie, Pfizer, UCB, Merck, Lilly, Roche, BMS, 2,AbbVie, Pfizer, UCB, Merck, Lilly, Roche, BMS, 5; S. Florentinus, AbbVie, 3,AbbVie, 1; Y. Li, AbbVie, 3,AbbVie, 1; I. Sainsbury, AbbVie, 3,AbbVie, 1; J. S. Smolen, AbbVie, 2,AbbVie, 5.

To cite this abstract in AMA style:

Wang X, Kavanaugh A, van der Heijde D, Dougados M, Florentinus S, Li Y, Sainsbury I, Smolen JS. Meta-Analysis of the Time Course of the Response to Adalimumab Plus Methotrexate or Methotrexate Monotherapy in Clinical Trials of Patients with Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/meta-analysis-of-the-time-course-of-the-response-to-adalimumab-plus-methotrexate-or-methotrexate-monotherapy-in-clinical-trials-of-patients-with-rheumatoid-arthritis/. Accessed .

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