Articles www.thelancet.com/neurology Vol 9 April 2010 381 Lancet Neurol 2010; 9: 381–90 Published Online February 16, 2010 DOI:10.1016/S1474- 4422(10)70033-8 See Reflection and Reaction page 337 *Investigators listed at end of paper Consultants in Neurology Multiple Sclerosis Center, Northbrook, IL, USA (D Wynn MD); Carolinas Medical Center, Charlotte, NC, USA (M Kaufman MD); Hospital Universitari Vall d’Hebron, Barcelona, Spain (X Montalban MD); University of Colorado Health Sciences Center, Aurora, CO, USA (T Vollmer MD); University of Colorado Bio-Imaging Research Laboratory, Denver, CO, USA (J Simon MD); Biogen Idec, Cambridge, MA, USA (J Elkins MD, G O’Neill MD); Facet Biotech, Redwood City, CA, USA (L Neyer PhD, J Sheridan PhD, C Wang PhD, A Fong PharmD); and University of Utah Center for Advanced Medical Technology, Salt Lake City, UT, USA (J W Rose MD) Correspondence to: John W Rose, Neurovirology Research Laboratory (151B), VA Medical Center, 500 Foothill Drive, Salt Lake City, Utah 84148, USA jrose@genetics.utah.edu Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta Daniel Wynn, Michael Kaufman, Xavier Montalban, Timothy Vollmer, Jack Simon, Jacob Elkins, Gilmore O’Neill, Lauri Neyer, James Sheridan, Chungchi Wang, Alice Fong, John W Rose; for the CHOICE investigators* Summary Background Daclizumab, a humanised monoclonal antibody, reduced multiple sclerosis disease activity in previous non-randomised studies. We aimed to assess whether daclizumab reduces disease activity in patients with active relapsing multiple sclerosis who are receiving interferon beta treatment. Methods We did a phase 2, randomised, double-blind, placebo-controlled study at 51 centres in the USA, Canada, Germany, Italy, and Spain. Patients with active relapsing multiple sclerosis who were taking interferon beta were randomly assigned to receive add-on subcutaneous daclizumab 2 mg/kg every 2 weeks (interferon beta and high-dose daclizumab group), daclizumab 1 mg/kg every 4 weeks (interferon beta and low-dose daclizumab group), or interferon beta and placebo for 24 weeks. The randomisation scheme was generated by Facet Biotech. All patients and assessors were masked to treatment with the exception of Facet Biotech bioanalysts who prepared data for the data safety monitoring board or generated pharmacokinetic or pharmacodynamic data, a drug accountability auditor, and the site pharmacist. The primary endpoint was total number of new or enlarged gadolinium contrast-enhancing lesions measured on brain MRI scans every 4 weeks between weeks 8 and 24. Effects of daclizumab on prespecified subsets of lymphocytes and quantitative T-cell proliferative response were assessed in an exploratory pharmacodynamic substudy. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00109161. Findings From May, 2005, to March, 2006, 288 patients were assessed for eligibility, and 230 were randomly assigned to receive interferon beta and high-dose daclizumab (n=75), interferon beta and low-dose daclizumab (n=78), or interferon beta and placebo (n=77). The adjusted mean number of new or enlarged gadolinium contrast-enhancing lesions was 4·75 in the interferon beta and placebo group compared with 1·32 in the interferon beta and high-dose daclizumab group (difference 72%, 95% CI 34% to 88%; p=0∙004) and 3·58 in the interferon beta and low-dose daclizumab group (25%, −76% to 68%; p=0∙51). In the pharmacodynamic substudy, daclizumab was not associated with significant changes in absolute numbers of T cells, B cells, or natural killer cells, or T-cell proliferative response compared with interferon beta alone. The number of CD56 bright natural killer cells was seven to eight times higher in both daclizumab groups than in the interferon beta and placebo group (interferon beta and low-dose daclizumab group p=0·002; interferon beta and high-dose daclizumab group p<0∙0001). Common adverse events were equally distributed across groups. Interpretation Add-on daclizumab treatment reduced the number of new or enlarged gadolinium contrast-enhancing lesions compared with interferon beta alone and might reduce multiple sclerosis disease activity to a greater extent than interferon beta alone. Funding Facet Biotech and Biogen Idec. Introduction Daclizumab is a humanised monoclonal antibody specific for the α subunit (CD25) of the human high-affinity interleukin-2 receptor. CD25 is expressed at low levels on resting T cells but is rapidly upregulated after T-cell activation, which enhances high-affinity interleukin-2 signal transduction. 1 Because CD25 antagonism selectively inhibits activated T cells, daclizumab treatment has been studied in patients with human autoimmune conditions characterised by abnormal T-cell responses, including multiple sclerosis. 2 Interleukin-2 signalling plays a major part in initiating T-cell proliferation and activation, and CD25 activity has been implicated in autoimmunity because common polymorphisms of CD25 increase risk for multiple sclerosis and type 1 diabetes mellitus. 3–7 Anti-CD25 monoclonal antibodies decrease T-cell activation and proliferation in vitro. 8–11 However, T cells from patients treated with daclizumab have shown normal proliferative responses and cytokine production ex vivo. 12 By contrast, CD25 antagonism causes expansion of a regulatory subset of natural killer cells, CD56 bright natural killer cells, in vivo. 12 This expansion is associated with reductions in multiple sclerosis disease activity, presumably through the CD56 bright natural killer cell-mediated lysis of autologous activated T cells. 12,13 Previous non-randomised studies suggested that daclizumab leads to clinical benefits in patients with multiple sclerosis who have