Efficacy and Safety of DaxibotulinumtoxinA for Injection in Cervical Dystonia: ASPEN-1 Phase 3 Randomized Controlled Trial
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu randomizované kontrolované studie, klinické zkoušky, fáze III, časopisecké články
PubMed
38295339
PubMed Central
PMC10962918
DOI
10.1212/wnl.0000000000208091
Knihovny.cz E-zdroje
- MeSH
- botulotoxiny typu A * škodlivé účinky MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- dystonické poruchy * farmakoterapie MeSH
- injekce intramuskulární MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nervosvalové látky * škodlivé účinky MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- tortikolis * farmakoterapie chemicky indukované MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- randomizované kontrolované studie MeSH
- Názvy látek
- botulotoxiny typu A * MeSH
- nervosvalové látky * MeSH
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: Of 444 individuals screened, 301 were randomized to DAXI 125U (n = 125) or 250U (n = 130) or placebo (n = 46). DAXI 125U and 250U significantly improved the mean TWSTRS total score vs placebo (least squares mean [standard error] difference vs placebo: DAXI 125U, -8.5 [1.93], p < 0.0001; DAXI 250U, -6.6 [1.92], p = 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.
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Balint B, Mencacci NE, Valente EM, et al. . Dystonia. Nat Rev Dis Primers. 2018;4(1):25. doi:10.1038/s41572-018-0023-6 PubMed DOI
Junker J, Berman BD, Hall J, et al. . Quality of life in isolated dystonia: non-motor manifestations matter. J Neurol Neurosurg Psychiatry. 2021:jnnp-2020-325193. doi: 10.1136/jnnp-2020-325193 PubMed DOI PMC
Vu JP, Lee HY, Chen Q, et al. . Head tremor and pain in cervical dystonia. J Neurol. 2021;268(5):1945-1950. doi:10.1007/s00415-020-10378-5 PubMed DOI PMC
Medina Escobar A, Pringsheim T, Goodarzi Z, Martino D. The prevalence of depression in adult onset idiopathic dystonia: systematic review and metaanalysis. Neurosci Biobehav Rev. 2021;125:221-230. doi:10.1016/j.neubiorev.2021.02.036 PubMed DOI
Tomic S, Petkovic I, Pucic T, Resan B, Juric S, Rotim T. Cervical dystonia and quality of life. Acta Neurol Belg. 2016;116(4):589-592. doi:10.1007/s13760-016-0634-1 PubMed DOI
Simpson DM, Hallett M, Ashman EJ, et al. . Practice guideline update summary: botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2016;86(19):1818-1826. doi:10.1212/wnl.0000000000002560 PubMed DOI PMC
Contarino MF, Van Den Dool J, Balash Y, et al. . Clinical practice: evidence-based recommendations for the treatment of cervical dystonia with botulinum toxin. Front Neurol. 2017;8:35. doi:10.3389/fneur.2017.00035 PubMed DOI PMC
Marsili L, Bologna M, Jankovic J, Colosimo C. Long-term efficacy and safety of botulinum toxin treatment for cervical dystonia: a critical reappraisal. Expert Opin Drug Saf. 2021;20(6):695-705. doi:10.1080/14740338.2021.1915282 PubMed DOI
Comella C, Bhatia K. An international survey of patients with cervical dystonia. J Neurol. 2015;262(4):837-848. doi:10.1007/s00415-014-7586-2 PubMed DOI PMC
Comella C, Ferreira JJ, Pain E, Azoulai M, Om S. Patient perspectives on the therapeutic profile of botulinum neurotoxin type A in cervical dystonia. J Neurol. 2021;268(3):903-912. doi:10.1007/s00415-020-10217-7 PubMed DOI PMC
Colosimo C, Charles D, Misra VP, Maisonobe P, Om S, INTEREST IN CD2 Study Group. Cumulative effects of long-term treatment with abobotulinumtoxinA in cervical dystonia: findings from a prospective, observational study. J Neurol Sci. 2020;416:117015. doi:10.1016/j.jns.2020.117015 PubMed DOI
Allergan. BOTOX® (onabotulinumtoxinA) for injection, for intramuscular, intradetrusor, or intradermal use prescribing information. Accessed July 19, 2023. rxabbvie.com/pdf/botox_pi.pdf.
Jog M, Wein T, Bhogal M, et al. . Real-world, long-term quality of life following therapeutic onabotulinumtoxinA treatment. Can J Neurol Sci. 2016;43(5):687-696. doi:10.1017/cjn.2016.262 PubMed DOI
Misra VP, Trosch RM, Maisonobe P, Om S. Spectrum of practice in the routine management of cervical dystonia with abobotulinumtoxinA: findings from three prospective open-label observational studies. J Clin Mov Disord. 2018;5:4. doi:10.1186/s40734-018-0072-8 PubMed DOI PMC
Sethi KD, Rodriguez R, Olayinka B. Satisfaction with botulinum toxin treatment: a cross-sectional survey of patients with cervical dystonia. J Med Econ. 2012;15(3):419-423. doi:10.3111/13696998.2011.653726 PubMed DOI
Evidente VG, Pappert EJ. Botulinum toxin therapy for cervical dystonia: the science of dosing. Tremor Other Hyperkinet Mov (N Y). 2014;4:273. doi:10.7916/D84X56BF PubMed DOI PMC
Poliziani M, Koch M, Liu X. Striving for more good days: patient perspectives on botulinum toxin for the treatment of cervical dystonia. Patient Prefer Adherence. 2016;10:1601-1608. doi:10.2147/PPA.S106560 PubMed DOI PMC
Ipsen. DYSPORT (abobotulinumtoxinA) for injection, for intramuscular use prescribing information. Accessed July 19, 2023. ipsen.com/websites/Ipsen_Online/wp-content/uploads/sites/9/2019/01/21084019/Dysport_Full_Prescribing_Information.pdf.
Merz. XEOMIN (incobotulinumtoxinA) for injection, for intramuscular or intraglandular use prescribing information. Accessed July 19, 2023. xeominaesthetic.com/wp-content/uploads/2019/05/XEOMIN-Full-Prescribing-Information-including-MedGuide.pdf.
Solstice Neurosciences. MYOBLOC® (rimabotulinumtoxinB) injection, for intramuscular or intraglandular use prescribing information. Accessed July 19, 2023. accessdata.fda.gov/drugsatfda_docs/label/2019/103846s5190lbl.pdf.
Bertucci V, Solish N, Kaufman-Janette J, et al. . DaxibotulinumtoxinA for injection has a prolonged duration of response in the treatment of glabellar lines: pooled data from two multicenter, randomized, double-blind, placebo-controlled, phase 3 studies (SAKURA 1 and SAKURA 2). J Am Acad Dermatol. 2020;82(4):838-845. doi:10.1016/j.jaad.2019.06.1313 PubMed DOI
Carruthers JD, Fagien S, Joseph JH, et al. . DaxibotulinumtoxinA for injection for the treatment of glabellar lines: results from each of two multicenter, randomized, double-blind, placebo-controlled, phase 3 studies (SAKURA 1 and SAKURA 2). Plast Reconstr Surg. 2020;145(1):45-58. doi:10.1097/PRS.0000000000006327 PubMed DOI PMC
Fabi SG, Cohen JL, Green LJ, et al. . DaxibotulinumtoxinA for Injection for the treatment of glabellar lines: efficacy results from SAKURA 3, a large, open-label, phase 3 safety study. Dermatol Surg. 2021;47(1):48-54. doi:10.1097/dss.0000000000002531 PubMed DOI PMC
Green JB, Mariwalla K, Coleman K, et al. . A large, open-label, phase 3 safety study of DaxibotulinumtoxinA for injection in glabellar lines: a focus on safety from the SAKURA 3 study. Dermatol Surg. 2021;47(1):42-46. doi:10.1097/dss.0000000000002463 PubMed DOI PMC
Stone HF, Zhu Z, Thach TQ, Ruegg CL. Characterization of diffusion and duration of action of a new botulinum toxin type A formulation. Toxicon 2011;58(2):159-167. doi:10.1016/j.toxicon.2011.05.012 PubMed DOI
Jankovic J, Truong D, Patel AT, et al. . Injectable DaxibotulinumtoxinA in cervical dystonia: a phase 2 dose-escalation multicenter study. Mov Disord Clin Pract. 2018;5(3):273-282. doi:10.1002/mdc3.12613 PubMed DOI PMC
Patel AT, Munin M, Ayyoub Z, Gross TM, Rubio RG, Kesslak P. DaxibotulinumtoxinA for Injection in adults with upper limb spasticity after stroke or traumatic brain injury: a randomized placebo-controlled study (JUNIPER). MDS International Congress, September 15-18, 2022; Madrid, Spain.
Comella CL, Jankovic J, Truong DD, Hanschmann A, Grafe S, U.S. XEOMIN Cervical Dystonia Study Group. Efficacy and safety of incobotulinumtoxinA (NT 201, XEOMIN®, botulinum neurotoxin type A, without accessory proteins) in patients with cervical dystonia. J Neurol Sci. 2011;308(1-2):103-109. doi:10.1016/j.jns.2011.05.041 PubMed DOI
Pappert EJ, Germanson T, Myobloc/Neurobloc European Cervical Dystonia Study Group. Botulinum toxin type B vs. type A in toxin-naïve patients with cervical dystonia: randomized, double-blind, noninferiority trial. Mov Disord. 2008;23(4):510-517. doi:10.1002/mds.21724 PubMed DOI
Slawek J, McAllister P, Paus S, et al. . A phase 3, open-label, multi-center trial to evaluate the long-term safety and efficacy of repeat treatments of DaxibotulinumtoxinA for Injection in adults with isolated cervical dystonia. AAN 2022; April 2-7 and April 24-26 (virtual); Seattle, USA.
Lew MF, Brashear A, Dashtipour K, et al. . A 500 U/2 mL dilution of abobotulinumtoxinA vs. placebo: randomized study in cervical dystonia. Int J Neurosci. 2018;128(7):619-626. doi:10.1080/00207454.2017.1406935 PubMed DOI
Solish N, Carruthers J, Kaufman J, Rubio RG, Gross TM, Gallagher CJ. Overview of DaxibotulinumtoxinA for injection: a novel formulation of botulinum toxin type A. Drugs. 2021;81(18):2091-2101. doi:10.1007/s40265-021-01631-w PubMed DOI PMC
Pulkoski-Gross MJ, Fang C, Shai R, Too P. A cell-penetrating peptide (CPP) binds directly to and enhances membrane binding of the core toxin of Botulinum toxin type A (BoNTA). TOXINS 2022. July 27-30, New Orleans, Louisiana.
Weisemann J, Rummel A, Oliyai C, Too P, Joshi A. Novel peptide excipient RTP004 enhances the binding of botulinum neurotoxin type A cell binding domain HC to rat brain synaptosomes. Toxicon. 2018;156(suppl 1):S113. doi:10.1016/j.toxicon.2018.11.273 DOI
Ramirez-Castaneda J, Jankovic J, Comella C, Dashtipour K, Fernandez HH, Mari Z. Diffusion, spread, and migration of botulinum toxin. Mov Disord. 2013;28(13):1775-1783. doi:10.1002/mds.25582 PubMed DOI
AEON Biopharma Reports Positive Topline Results from Phase 2 Clinical Trial of ABP-450 (prabotulinumtoxinA) in Cervical Dystonia [online]. Accessed June 21, 2023. aeonbiopharma.com/2022/09/aeon-biopharma-reports-positive-topline-results-from-phase-2-clinical-trial-of-abp-450-prabotulinumtoxina-in-cervical-dystonia/.
Truong D, Brodsky M, Lew M, et al. . Long-term efficacy and safety of botulinum toxin type A (Dysport) in cervical dystonia. Parkinsonism Relat Disord. 2010;16(5):316-323. doi:10.1016/j.parkreldis.2010.03.002 PubMed DOI
Truong D, Duane D, Jankovic J, et al. . Efficacy and safety of botulinum type A toxin (Dysport) in cervical dystonia: results of the first US randomized, double-blind, placebo-controlled study. Mov Disord. 2005;20(7):783-791. doi:10.1002/mds.20403 PubMed DOI
Charles D, Brashear A, Hauser RA, et al. . Efficacy, tolerability, and immunogenicity of onabotulinumtoxina in a randomized, double-blind, placebo-controlled trial for cervical dystonia. Clin Neuropharmacol. 2012;35(5):208-214. doi:10.1097/WNF.0b013e31826538c7 PubMed DOI
ClinicalTrials.gov
NCT03608397
