title: Clinical endpoint sensitivity in rheumatoid arthritis: modeling and simulation.
abstract: The commonly used efficacy endpoints in Rheumatoid Arthritis (RA) clinical trials are American College of Rheumatology 20 % improvement criteria (ACR20), ACR50, and ACR70 response rates, and the 28-joint disease activity score (DAS28). Longitudinal models to quantitate the exposure-response relationships for ACRs and DAS28 score were developed for four biologics used for the management of RA. The models were then used to simulate the clinical outcome at various time points following different treatment regimens. Discriminative sensitivity of these endpoints was assessed using a power analysis. The trial simulation and subsequent power analysis showed that both ACR20 and DAS28 exhibit much lower power in distinguishing between two doses investigated compared with distinguishing treatment effect over placebo/Methotrexate (MTX) control. ACR20 response rate is generally more powerful in detecting treatment effect over placebo/MTX control as compared to DAS28. The findings of current study provide useful information which will help future clinical trial design for the treatment of patients with RA.
authors.affiliation: Division of Pharmacometrics, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Lian
authors.initials: L
authors.lastname: Ma
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.forename: Yun
authors.initials: Y
authors.lastname: Xu
authors.forename: Sarah
authors.initials: S
authors.lastname: Yim
authors.forename: Suresh
authors.initials: S
authors.lastname: Doddapaneni
authors.forename: Chandrahas G
authors.initials: CG
authors.lastname: Sahajwalla
authors.forename: Yaning
authors.initials: Y
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: Ji
mesh_terms: D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D003198:Computer Simulation; D018849:Controlled Clinical Trials as Topic / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006801:Humans; D008727:Methotrexate / Q000627:therapeutic use; D008954:Models, Biological; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D008727:Methotrexate