title: Safety and efficacy of incobotulinumtoxinA doses up to 800 U in limb spasticity: The TOWER study.
abstract: OBJECTIVE
  To evaluate safety (primary objective) and efficacy of increasing doses (400 U up to 800 U) of incobotulinumtoxinA (Xeomin, Merz Pharmaceuticals GmbH) for patients with limb spasticity.
  
  
  METHODS
  In this prospective, single-arm, dose-titration study (NCT01603459), patients (18-80 years) with spasticity due to cerebral causes, who were clinically deemed to require total doses of 800 U incobotulinumtoxinA, received 3 consecutive injection cycles (ICs) with 400 U, 600 U, and 600-800 U incobotulinumtoxinA, respectively, each followed by 12-16 weeks' observation. Outcomes included adverse events (AEs), antibody testing, Resistance to Passive Movement Scale (REPAS; based on the Ashworth Scale), and Goal Attainment Scale.
  
  
  RESULTS
  In total, 155 patients were enrolled. IncobotulinumtoxinA dose escalation did not lead to an increased incidence of treatment-related AEs (IC1: 4.5%; IC2: 5.3%; IC3: 2.9%). No treatment-related serious AEs occurred. The most frequent AEs overall were falls (7.7%), nasopharyngitis, arthralgia, and diarrhea (6.5% each). Five patients (3.2%) discontinued due to AEs. No patient developed secondary nonresponse due to neutralizing antibodies. Mean (SD) REPAS score improvements from each injection to 4 weeks postinjection increased throughout the study (IC1: -4.6 [3.9]; IC2: -5.9 [4.2]; IC3: -7.1 [4.8];p< 0.0001 for all). The proportion of patients achieving ≥3 (of 4) treatment goals also increased (IC1: 25.2%; IC2: 50.7%; IC3: 68.6%).
  
  
  CONCLUSIONS
  Escalating incobotulinumtoxinA doses (400 U up to 800 U) did not compromise safety or tolerability, enabled treatment in a greater number of muscles/spasticity patterns, and was associated with increased treatment efficacy, improved muscle tone, and goal attainment.
  
  
  BACKGROUND
  NCT01603459.
  
  
  METHODS
  This study provides Class IV evidence that, for patients with limb spasticity, escalating incobotulinumtoxinA doses (400 U up to 800 U) increases treatment efficacy without compromising safety or tolerability.
authors.affiliation: From Neurorehabilitation (J.W.), Department of Neurology, Vivantes Hospital Spandau, Berlin, Germany; Raymond-Poincaré Hospital (D.B.), AP-HP, University of Versailles Saint Quentin, Garches, France; Instituto de Medicina Molecular (J.J.F.), Faculty of Medicine, University of Lisbon, Portugal; Villa Beretta (F.M.), Rehabilitation Center, Valduce Hospital, Como, Italy; Division of Physical Medicine and Rehabilitation (L.S.), University of Alberta, Edmonton, Canada; Department of Physical Medicine and Rehabilitation (S.M.), University Hospital La Paz, Madrid, Spain; Department of Neurology (T.R.), Haukeland University Hospital, Bergen, Norway; Medical College of Wisconsin (J.M.), Milwaukee; Merz Pharmaceuticals GmbH (A.S., B.F.-B., O.S.), Frankfurt am Main, Germany; Complete Medical Communications (E.T.J.R.), Macclesfield, UK; Movement Disorders Section (D.D.), Department of Neurology, Hannover Medical School, Hannover, Germany; and Icahn School of Medicine at Mount Sinai (D.M.S.), New York, NY. joerg.wissel@vivantes.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Wissel
authors.affiliation: From Neurorehabilitation (J.W.), Department of Neurology, Vivantes Hospital Spandau, Berlin, Germany; Raymond-Poincaré Hospital (D.B.), AP-HP, University of Versailles Saint Quentin, Garches, France; Instituto de Medicina Molecular (J.J.F.), Faculty of Medicine, University of Lisbon, Portugal; Villa Beretta (F.M.), Rehabilitation Center, Valduce Hospital, Como, Italy; Division of Physical Medicine and Rehabilitation (L.S.), University of Alberta, Edmonton, Canada; Department of Physical Medicine and Rehabilitation (S.M.), University Hospital La Paz, Madrid, Spain; Department of Neurology (T.R.), Haukeland University Hospital, Bergen, Norway; Medical College of Wisconsin (J.M.), Milwaukee; Merz Pharmaceuticals GmbH (A.S., B.F.-B., O.S.), Frankfurt am Main, Germany; Complete Medical Communications (E.T.J.R.), Macclesfield, UK; Movement Disorders Section (D.D.), Department of Neurology, Hannover Medical School, Hannover, Germany; and Icahn School of Medicine at Mount Sinai (D.M.S.), New York, NY.
authors.forename: Djamel
authors.initials: D
authors.lastname: Bensmail
authors.affiliation: From Neurorehabilitation (J.W.), Department of Neurology, Vivantes Hospital Spandau, Berlin, Germany; Raymond-Poincaré Hospital (D.B.), AP-HP, University of Versailles Saint Quentin, Garches, France; Instituto de Medicina Molecular (J.J.F.), Faculty of Medicine, University of Lisbon, Portugal; Villa Beretta (F.M.), Rehabilitation Center, Valduce Hospital, Como, Italy; Division of Physical Medicine and Rehabilitation (L.S.), University of Alberta, Edmonton, Canada; Department of Physical Medicine and Rehabilitation (S.M.), University Hospital La Paz, Madrid, Spain; Department of Neurology (T.R.), Haukeland University Hospital, Bergen, Norway; Medical College of Wisconsin (J.M.), Milwaukee; Merz Pharmaceuticals GmbH (A.S., B.F.-B., O.S.), Frankfurt am Main, Germany; Complete Medical Communications (E.T.J.R.), Macclesfield, UK; Movement Disorders Section (D.D.), Department of Neurology, Hannover Medical School, Hannover, Germany; and Icahn School of Medicine at Mount Sinai (D.M.S.), New York, NY.
authors.forename: Joaquim J
authors.initials: JJ
authors.lastname: Ferreira
authors.affiliation: From Neurorehabilitation (J.W.), Department of Neurology, Vivantes Hospital Spandau, Berlin, Germany; Raymond-Poincaré Hospital (D.B.), AP-HP, University of Versailles Saint Quentin, Garches, France; Instituto de Medicina Molecular (J.J.F.), Faculty of Medicine, University of Lisbon, Portugal; Villa Beretta (F.M.), Rehabilitation Center, Valduce Hospital, Como, Italy; Division of Physical Medicine and Rehabilitation (L.S.), University of Alberta, Edmonton, Canada; Department of Physical Medicine and Rehabilitation (S.M.), University Hospital La Paz, Madrid, Spain; Department of Neurology (T.R.), Haukeland University Hospital, Bergen, Norway; Medical College of Wisconsin (J.M.), Milwaukee; Merz Pharmaceuticals GmbH (A.S., B.F.-B., O.S.), Frankfurt am Main, Germany; Complete Medical Communications (E.T.J.R.), Macclesfield, UK; Movement Disorders Section (D.D.), Department of Neurology, Hannover Medical School, Hannover, Germany; and Icahn School of Medicine at Mount Sinai (D.M.S.), New York, NY.
authors.forename: Franco
authors.initials: F
authors.lastname: Molteni
authors.affiliation: From Neurorehabilitation (J.W.), Department of Neurology, Vivantes Hospital Spandau, Berlin, Germany; Raymond-Poincaré Hospital (D.B.), AP-HP, University of Versailles Saint Quentin, Garches, France; Instituto de Medicina Molecular (J.J.F.), Faculty of Medicine, University of Lisbon, Portugal; Villa Beretta (F.M.), Rehabilitation Center, Valduce Hospital, Como, Italy; Division of Physical Medicine and Rehabilitation (L.S.), University of Alberta, Edmonton, Canada; Department of Physical Medicine and Rehabilitation (S.M.), University Hospital La Paz, Madrid, Spain; Department of Neurology (T.R.), Haukeland University Hospital, Bergen, Norway; Medical College of Wisconsin (J.M.), Milwaukee; Merz Pharmaceuticals GmbH (A.S., B.F.-B., O.S.), Frankfurt am Main, Germany; Complete Medical Communications (E.T.J.R.), Macclesfield, UK; Movement Disorders Section (D.D.), Department of Neurology, Hannover Medical School, Hannover, Germany; and Icahn School of Medicine at Mount Sinai (D.M.S.), New York, NY.
authors.forename: Lalith
authors.initials: L
authors.lastname: Satkunam
authors.affiliation: From Neurorehabilitation (J.W.), Department of Neurology, Vivantes Hospital Spandau, Berlin, Germany; Raymond-Poincaré Hospital (D.B.), AP-HP, University of Versailles Saint Quentin, Garches, France; Instituto de Medicina Molecular (J.J.F.), Faculty of Medicine, University of Lisbon, Portugal; Villa Beretta (F.M.), Rehabilitation Center, Valduce Hospital, Como, Italy; Division of Physical Medicine and Rehabilitation (L.S.), University of Alberta, Edmonton, Canada; Department of Physical Medicine and Rehabilitation (S.M.), University Hospital La Paz, Madrid, Spain; Department of Neurology (T.R.), Haukeland University Hospital, Bergen, Norway; Medical College of Wisconsin (J.M.), Milwaukee; Merz Pharmaceuticals GmbH (A.S., B.F.-B., O.S.), Frankfurt am Main, Germany; Complete Medical Communications (E.T.J.R.), Macclesfield, UK; Movement Disorders Section (D.D.), Department of Neurology, Hannover Medical School, Hannover, Germany; and Icahn School of Medicine at Mount Sinai (D.M.S.), New York, NY.
authors.forename: Susana
authors.initials: S
authors.lastname: Moraleda
authors.affiliation: From Neurorehabilitation (J.W.), Department of Neurology, Vivantes Hospital Spandau, Berlin, Germany; Raymond-Poincaré Hospital (D.B.), AP-HP, University of Versailles Saint Quentin, Garches, France; Instituto de Medicina Molecular (J.J.F.), Faculty of Medicine, University of Lisbon, Portugal; Villa Beretta (F.M.), Rehabilitation Center, Valduce Hospital, Como, Italy; Division of Physical Medicine and Rehabilitation (L.S.), University of Alberta, Edmonton, Canada; Department of Physical Medicine and Rehabilitation (S.M.), University Hospital La Paz, Madrid, Spain; Department of Neurology (T.R.), Haukeland University Hospital, Bergen, Norway; Medical College of Wisconsin (J.M.), Milwaukee; Merz Pharmaceuticals GmbH (A.S., B.F.-B., O.S.), Frankfurt am Main, Germany; Complete Medical Communications (E.T.J.R.), Macclesfield, UK; Movement Disorders Section (D.D.), Department of Neurology, Hannover Medical School, Hannover, Germany; and Icahn School of Medicine at Mount Sinai (D.M.S.), New York, NY.
authors.forename: Tiina
authors.initials: T
authors.lastname: Rekand
authors.affiliation: From Neurorehabilitation (J.W.), Department of Neurology, Vivantes Hospital Spandau, Berlin, Germany; Raymond-Poincaré Hospital (D.B.), AP-HP, University of Versailles Saint Quentin, Garches, France; Instituto de Medicina Molecular (J.J.F.), Faculty of Medicine, University of Lisbon, Portugal; Villa Beretta (F.M.), Rehabilitation Center, Valduce Hospital, Como, Italy; Division of Physical Medicine and Rehabilitation (L.S.), University of Alberta, Edmonton, Canada; Department of Physical Medicine and Rehabilitation (S.M.), University Hospital La Paz, Madrid, Spain; Department of Neurology (T.R.), Haukeland University Hospital, Bergen, Norway; Medical College of Wisconsin (J.M.), Milwaukee; Merz Pharmaceuticals GmbH (A.S., B.F.-B., O.S.), Frankfurt am Main, Germany; Complete Medical Communications (E.T.J.R.), Macclesfield, UK; Movement Disorders Section (D.D.), Department of Neurology, Hannover Medical School, Hannover, Germany; and Icahn School of Medicine at Mount Sinai (D.M.S.), New York, NY.
authors.forename: John
authors.initials: J
authors.lastname: McGuire
authors.affiliation: From Neurorehabilitation (J.W.), Department of Neurology, Vivantes Hospital Spandau, Berlin, Germany; Raymond-Poincaré Hospital (D.B.), AP-HP, University of Versailles Saint Quentin, Garches, France; Instituto de Medicina Molecular (J.J.F.), Faculty of Medicine, University of Lisbon, Portugal; Villa Beretta (F.M.), Rehabilitation Center, Valduce Hospital, Como, Italy; Division of Physical Medicine and Rehabilitation (L.S.), University of Alberta, Edmonton, Canada; Department of Physical Medicine and Rehabilitation (S.M.), University Hospital La Paz, Madrid, Spain; Department of Neurology (T.R.), Haukeland University Hospital, Bergen, Norway; Medical College of Wisconsin (J.M.), Milwaukee; Merz Pharmaceuticals GmbH (A.S., B.F.-B., O.S.), Frankfurt am Main, Germany; Complete Medical Communications (E.T.J.R.), Macclesfield, UK; Movement Disorders Section (D.D.), Department of Neurology, Hannover Medical School, Hannover, Germany; and Icahn School of Medicine at Mount Sinai (D.M.S.), New York, NY.
authors.forename: Astrid
authors.initials: A
authors.lastname: Scheschonka
authors.affiliation: From Neurorehabilitation (J.W.), Department of Neurology, Vivantes Hospital Spandau, Berlin, Germany; Raymond-Poincaré Hospital (D.B.), AP-HP, University of Versailles Saint Quentin, Garches, France; Instituto de Medicina Molecular (J.J.F.), Faculty of Medicine, University of Lisbon, Portugal; Villa Beretta (F.M.), Rehabilitation Center, Valduce Hospital, Como, Italy; Division of Physical Medicine and Rehabilitation (L.S.), University of Alberta, Edmonton, Canada; Department of Physical Medicine and Rehabilitation (S.M.), University Hospital La Paz, Madrid, Spain; Department of Neurology (T.R.), Haukeland University Hospital, Bergen, Norway; Medical College of Wisconsin (J.M.), Milwaukee; Merz Pharmaceuticals GmbH (A.S., B.F.-B., O.S.), Frankfurt am Main, Germany; Complete Medical Communications (E.T.J.R.), Macclesfield, UK; Movement Disorders Section (D.D.), Department of Neurology, Hannover Medical School, Hannover, Germany; and Icahn School of Medicine at Mount Sinai (D.M.S.), New York, NY.
authors.forename: Birgit
authors.initials: B
authors.lastname: Flatau-Baqué
authors.affiliation: From Neurorehabilitation (J.W.), Department of Neurology, Vivantes Hospital Spandau, Berlin, Germany; Raymond-Poincaré Hospital (D.B.), AP-HP, University of Versailles Saint Quentin, Garches, France; Instituto de Medicina Molecular (J.J.F.), Faculty of Medicine, University of Lisbon, Portugal; Villa Beretta (F.M.), Rehabilitation Center, Valduce Hospital, Como, Italy; Division of Physical Medicine and Rehabilitation (L.S.), University of Alberta, Edmonton, Canada; Department of Physical Medicine and Rehabilitation (S.M.), University Hospital La Paz, Madrid, Spain; Department of Neurology (T.R.), Haukeland University Hospital, Bergen, Norway; Medical College of Wisconsin (J.M.), Milwaukee; Merz Pharmaceuticals GmbH (A.S., B.F.-B., O.S.), Frankfurt am Main, Germany; Complete Medical Communications (E.T.J.R.), Macclesfield, UK; Movement Disorders Section (D.D.), Department of Neurology, Hannover Medical School, Hannover, Germany; and Icahn School of Medicine at Mount Sinai (D.M.S.), New York, NY.
authors.forename: Olivier
authors.initials: O
authors.lastname: Simon
authors.affiliation: From Neurorehabilitation (J.W.), Department of Neurology, Vivantes Hospital Spandau, Berlin, Germany; Raymond-Poincaré Hospital (D.B.), AP-HP, University of Versailles Saint Quentin, Garches, France; Instituto de Medicina Molecular (J.J.F.), Faculty of Medicine, University of Lisbon, Portugal; Villa Beretta (F.M.), Rehabilitation Center, Valduce Hospital, Como, Italy; Division of Physical Medicine and Rehabilitation (L.S.), University of Alberta, Edmonton, Canada; Department of Physical Medicine and Rehabilitation (S.M.), University Hospital La Paz, Madrid, Spain; Department of Neurology (T.R.), Haukeland University Hospital, Bergen, Norway; Medical College of Wisconsin (J.M.), Milwaukee; Merz Pharmaceuticals GmbH (A.S., B.F.-B., O.S.), Frankfurt am Main, Germany; Complete Medical Communications (E.T.J.R.), Macclesfield, UK; Movement Disorders Section (D.D.), Department of Neurology, Hannover Medical School, Hannover, Germany; and Icahn School of Medicine at Mount Sinai (D.M.S.), New York, NY.
authors.forename: Edward T J
authors.initials: ET
authors.lastname: Rochford
authors.affiliation: From Neurorehabilitation (J.W.), Department of Neurology, Vivantes Hospital Spandau, Berlin, Germany; Raymond-Poincaré Hospital (D.B.), AP-HP, University of Versailles Saint Quentin, Garches, France; Instituto de Medicina Molecular (J.J.F.), Faculty of Medicine, University of Lisbon, Portugal; Villa Beretta (F.M.), Rehabilitation Center, Valduce Hospital, Como, Italy; Division of Physical Medicine and Rehabilitation (L.S.), University of Alberta, Edmonton, Canada; Department of Physical Medicine and Rehabilitation (S.M.), University Hospital La Paz, Madrid, Spain; Department of Neurology (T.R.), Haukeland University Hospital, Bergen, Norway; Medical College of Wisconsin (J.M.), Milwaukee; Merz Pharmaceuticals GmbH (A.S., B.F.-B., O.S.), Frankfurt am Main, Germany; Complete Medical Communications (E.T.J.R.), Macclesfield, UK; Movement Disorders Section (D.D.), Department of Neurology, Hannover Medical School, Hannover, Germany; and Icahn School of Medicine at Mount Sinai (D.M.S.), New York, NY.
authors.forename: Dirk
authors.initials: D
authors.lastname: Dressler
authors.affiliation: From Neurorehabilitation (J.W.), Department of Neurology, Vivantes Hospital Spandau, Berlin, Germany; Raymond-Poincaré Hospital (D.B.), AP-HP, University of Versailles Saint Quentin, Garches, France; Instituto de Medicina Molecular (J.J.F.), Faculty of Medicine, University of Lisbon, Portugal; Villa Beretta (F.M.), Rehabilitation Center, Valduce Hospital, Como, Italy; Division of Physical Medicine and Rehabilitation (L.S.), University of Alberta, Edmonton, Canada; Department of Physical Medicine and Rehabilitation (S.M.), University Hospital La Paz, Madrid, Spain; Department of Neurology (T.R.), Haukeland University Hospital, Bergen, Norway; Medical College of Wisconsin (J.M.), Milwaukee; Merz Pharmaceuticals GmbH (A.S., B.F.-B., O.S.), Frankfurt am Main, Germany; Complete Medical Communications (E.T.J.R.), Macclesfield, UK; Movement Disorders Section (D.D.), Department of Neurology, Hannover Medical School, Hannover, Germany; and Icahn School of Medicine at Mount Sinai (D.M.S.), New York, NY.
authors.forename: David M
authors.initials: DM
authors.lastname: Simpson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019274:Botulinum Toxins, Type A / Q000009:adverse effects* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005121:Extremities; D005260:Female; D006801:Humans; D008171:Lung Diseases / Q000209:etiology; D008297:Male; D008875:Middle Aged; D009128:Muscle Spasticity / Q000150:complications / Q000188:drug therapy*; D009465:Neuromuscular Agents / Q000009:adverse effects*; D012189:Retrospective Studies; D055986:Vital Signs / Q000187:drug effects; D055815:Young Adult
chemical_list: D009465:Neuromuscular Agents; D019274:Botulinum Toxins, Type A; C545476:incobotulinumtoxinA