Efficacy and Safety of DaxibotulinumtoxinA for Injection in Cervical Dystonia
Cynthia Comella, Joseph Jankovic, Robert A. Hauser, Atul T. Patel, Marta Banach, Edvard Ehler, Domenico Vitarella, Roman G. Rubio, Todd M. Gross, on behalf of the ASPEN-1 Study Group, Philipp Albrecht, Richard L. Barbano, Norman Bettle, Sylvia Bösch, Françoise Bouhour, James Boyd, Giovanni Castelnovo, Pratap Chand, Christine Cooper, Susan R. Criswell, Khashayar Dashtipour, Andres Deik, Aaron Ellenbogen, Virgilio Gerald H. Evidente, Danielle Feigenbaum, Susan H. Fox, Karen Frei, Jeffrey Gitt, John L. Goudreau, Behzad Habibi, Timothy Harrower, Bernhard Haslinger, Peter Hedera, Daragh Heitzman, Neal Hermanowicz, Jorge Hernández‐Vara, David Isaacs, Stuart Isaacson, Robert Jech, Hyder A. Jinnah, Christopher Kobylecki, Katja Kollewe, Aikaterini Kompoliti, Dariusz Koziorowski, Alexandre Kreisler, Rajeev Kumar, Andreas Kupsch, Mark S. LeDoux, Peter A. LeWitt, Ebba Lohmann, Lydia López Manzanares, Irene A. Malaty, Janice M. Massey, Peter McAllister, Peter Moore, Elena Moro, William G. Ondo, Javier Pagonabarraga Mora, Sebastian Paus, Elizabeth Peckham, Rekha Pillai, Monika Rudzińska, Harvey Schwartz, Carlos Singer, Jarosław Sławek, Thomas Sycha, Dariusz A Szabela, Jessica Tate, N. Thakur, D. F. Torres, José M. Trejo, Daniel Truong, Winona Tse, Andrzej Tutaj, Alberto Vásquez, Oldřich Vyšata, Ivana Woznicová, Sharon Yegiaian
Abstract
BACKGROUND AND OBJECTIVES: ASPEN-1 was a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, duration of response, and safety of 2 doses of DaxibotulinumtoxinA for Injection (DAXI), a novel botulinum toxin type A formulation in participants with cervical dystonia (CD). METHODS: Adults (aged 18-80 years) with moderate-to-severe CD (Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] total score ≥20) were enrolled at 60 sites across 9 countries in Europe and North America. Participants were randomized (3:3:1) to single-dose intramuscular DAXI 125U, 250U, or placebo and followed for up to 36 weeks after injection. The primary end point was change from baseline in TWSTRS total score averaged across weeks 4 and 6. Key secondary end points included duration of effect, Clinical and Patient Global Impression of Change (CGIC, PGIC), TWSTRS subscale scores, and safety. Multiplicity-adjusted intent-to-treat hypothesis tests with multiple imputation were performed using ANCOVA and Cochran-Mantel-Haenszel analyses. RESULTS: = 0.0006). The median duration of effect (time from treatment until loss of ≥80% of the peak improvement in average TWSTRS total score achieved at weeks 4 and 6) was 24.0 (95% confidence interval 20.3-29.1) weeks with DAXI 125U and 20.3 (16.7-24.0) weeks with DAXI 250U. Significant improvements were also observed with DAXI in CGIC and PGIC responder rates and TWSTRS subscales. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.6% of participants with DAXI 125U, 23.8% with DAXI 250U, and 17.4% with placebo, with injection site pain being the most common overall. The most frequently reported treatment-related TEAEs of interest in DAXI 125U, DAXI 250U, and placebo, respectively, were muscular weakness (4.8%, 2.3%, 0%), musculoskeletal pain (2.4%, 3.1%, 0%), and dysphagia (1.6%, 3.8%, 0%). DISCUSSION: This study demonstrated that DAXI, at doses of 125U and 250U, is an effective, safe, long-acting, and well-tolerated treatment for CD. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier (NCT03608397, submitted July 11, 2018) and EU Clinical Trials Register (ClinicalTrialsRegister.eu EudraCT identifier 2018-000446-19, submitted September 13, 2018). First participant enrolled on June 11, 2018. Trial registration was performed in accordance with the Food and Drug Administration Amendments Act (FDAAA 801), which stipulates that the responsible party register an applicable clinical trial not later than 21 calendar days after enrolling the first human participant (42 CFR 11.24). CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in adults with moderate-to-severe idiopathic cervical dystonia, DAXI reduces dystonia more effectively than placebo.