- Email: [email protected]
Correlations between spasticity, goal attainment, and global assessment of benefits in patients with upper limb spasticity treated with botulinum toxin A
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Abstracts / Toxicon 123 (2016) S2eS90
Keywords: Botulinum toxin; Clean intermittent catheterization; Neurogenic detrusor overactivity; OnabotulinumtoxinA; Patient-reported outcome; Urinary incontinence 50. CLINICAL RELEVANCE OF TREATMENT WITH ONABOTULINUMTOXINA IN PATIENTS WITH CERVICAL DYSTONIA: RESULTS FROM THE CD PROBE STUDY Khashayar Dashtipour a, *, Zoltan Mari b, Joseph Jankovic c, Charles H. Adler d, Marc Schwartz e, Mitchell F. Brin f. a Loma Linda University School of Medicine, Loma Linda, CA, USA; b Johns Hopkins Hospital, Baltimore, MD, USA; c Baylor College of Medicine, Houston, TX, USA; d Mayo Clinic College of Medicine, Scottsdale, AZ, USA; e MedNet Solutions, Minnetonka, MN, USA; f Allergan, Irvine, CA, USA * Corresponding author: Loma Linda University School of Medicine, 11370 Anderson Street, Suite B-100, Loma Linda, CA 92354, USA. E-mail address:kdashtipour@llu. edu.
Introduction and objectives: Data from the Cervical Dystonia Patient Registry for Observation of OnabotulinumtoxinA Efficacy (CD PROBE) study were analyzed to explore the minimal clinically important change that patients perceive as beneficial based on the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). Methods: CD PROBE is a multicenter, prospective clinical registry that recruited patients with cervical dystonia (CD) from 88 US sites (Jankovic 2011, 2015). Patients with CD who were new to botulinum toxin therapy or had not received it for 16 weeks and were deemed suitable for onabotulinumtoxinA treatment received 3 cycles of the drug. Changes from baseline in TWSTRS scores were correlated with clinical improvement as assessed by the Patient or Clinician Global Impression of Change (PGIC or CGIC) scale. The discrimination of the model was determined using logistic regression; good discrimination was defined as 70% correct classification of PGIC or CGIC based on TWSTRS scores. We report on the 479 patients who completed the study. Results: The mean TWSTRS score significantly decreased from baseline to the final visit (from 39.2 to 27.1; P<0.0001). The point (percentage) reduction in total TWSTRS score that correlated with “very much improved,” “much improved” or better, and “minimally improved” or better on the PGIC were 11 (27.1%; n¼121), 9 (21.2%; n¼307), and 8 (19.1%; n¼436) respectively; for CGIC, point (percentage) reductions were 10 (24.1%; n¼139), 8 (16.3%; n¼356), and 7 (11.8%; n¼454) (Table). Total TWSTRS score had a good level of discrimination and correlated with PGIC and CGIC better than any TWSTRS subscale scores, although the contribution of the “minimally improved” group was limited by small sample size (PGIC, n¼129; CGIC, n¼98). Conclusions: Change in total TWSTRS score correlated well with patientand clinician-based evaluations (PGIC and CGIC, respectively) of onabotulinumtoxinA-treated patients with CD. These results approximate definitions of response used in other studies (Comella 2011; Truong 2005). Keywords: CD PROBE; Cervical dystonia; Clinical effectiveness; OnabotulinumtoxinA Funding: Allergan References Comella CL, Jankovic J, Truong DD, Hanschmann A, Grafe S. 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. Jankovic J, Adler CH, Charles PD, et al. Rationale and design of a prospective study: Cervical Dystonia Patient Registry for Observation of OnaBotulinumtoxinA Efficacy (CD PROBE). BMC Neurol. 2011;11:140. Jankovic J, Adler CH, Charles D, et al. Primary results from the cervical dystonia patient registry for observation of onabotulinumtoxina efficacy (CD PROBE). J Neurol Sci. 2015;349(1-2):84-93. Truong D, Duane DD, Jankovic J, et al. Efficacy and safety of botulinum
Table Correlation of Changes in Total TWSTRSs With Changes in PGIC and CGIC From Baseline to Final Visit (N¼479) Mean Change Area Output Under Change in Curve TWSTRS Score
Sensitivity Specificity Correctly Classified, %
Change in Total TWSTRSs Correlated With Changes in PGIC* Point 0.860 e11.00 0.80 0.77 “Very much improved” change % 0.893 e27.12 0.83 0.84 (n¼121) change Point 0.783 e9.00 0.72 0.72 “Much improved” change or better % 0.810 e21.21 0.76 0.74 (n¼307) change Point 0.723 e8.00 0.66 0.67 “Minimally improved” change or better % 0.746 e19.05 0.67 0.67 (n¼436) change Change in Total TWSTRSs Correlated With Changes in CGICy Point 0.903 e10.00 0.83 0.84 “Very much improved” change (n¼139) % 0.924 e24.14 0.83 0.84 change Point 0.835 e8.00 0.74 0.76 “Much improved” change or better % 0.857 e16.28 0.80 0.80 (n¼356) change Point 0.784 e7.00 0.69 0.72 “Minimally improved” change or better % 0.806 e11.76 0.76 0.76 (n¼454) change
79.3 83.5 72.3 75.4 66.0 67.4
82.9 83.5 74.0 80.1 68.7 76.2
CGIC¼Clinician Global Impression of Change; PGIC¼Patient Global Impression of Change; TWSTRSs¼Toronto Western Spasmodic Torticollis Rating Scale score. Values in bold met the indicators of good cutoffs for discrimination of the model: area under curve 0.7 or percentage correctly classified 70%. *PGIC ratings: no change or worse, n¼43; “minimally improved,” n¼129; “much improved,” n¼186; “very much improved,” n¼121. y CGIC ratings: no change or worse, n¼25; “minimally improved,” n¼98; “much improved,” n¼217; “very much improved,” n¼139.
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. 51. CORRELATIONS BETWEEN SPASTICITY, GOAL ATTAINMENT, AND GLOBAL ASSESSMENT OF BENEFITS IN PATIENTS WITH UPPER LIMB SPASTICITY TREATED WITH BOTULINUM TOXIN A Khashayar Dashtipour a, Jovita Balcaitiene b, *, Stephen Ashford c, Jorge Jacinto d, Klemens Fheodoroff e, Pascal Maisonobe b, Lynne TurnerStokes c. a Department of Neurology/Movement Disorders, School of Medicine, Loma Linda University, California, USA; b Ipsen Pharma, Boulogne-Billancourt, France; c King’s College London School of Medicine, Palliative Care, Policy and Rehabilitation and Regional Rehabilitation Unit, Northwick Park ~o de Alcoita ~o, Hospital, London, UK; d Centro de Medicina de Reabilitaça ~o de Adultos, Estoril, Portugal; e Department of Serviço de Reabilitaça Neurorehabilitation, Gailtal-Klinik, Hermagor, Austria * Corresponding author: IPSEN Pharma, Boulogne-Billancourt, France. E-mail address:[email protected].
Introduction: ULIS-II was an 18-month, international, noninterventional study in 456 poststroke adults (from 84 centres in 22 countries) with upper limb spasticity (ULS) receiving 1 cycle of botulinum toxin A (BoNTA) in accordance with routine local clinical practice. In this study, a
Abstracts / Toxicon 123 (2016) S2eS90
clinically significant impact on attainment of person-centered goals (measured by Goal Attainment Scaling; GAS), was demonstrated. Methods: This was a post hoc analysis to investigate correlations between change in Modified Ashworth Scale (MAS) and Goal Attainment Scaling (GAS) or global assessment of benefits. Correlations were determined between MAS, reported benefit and GAS T scores, using Spearman’s rank correlation coefficient. Results: Weak but significant correlations were observed between change in MAS scores and investigator- or patient-assessed benefit (rho¼0.28 and 0.20, respectively; P<0.01). Change in MAS score correlated better with investigator-reported benefits than with patient-reported benefits; a correlation was demonstrated between investigator and patient assessment of benefit (rho¼0.66; P<0.01). Significant correlations were observed between change from baseline in GAS T scores and investigator- or patientassessed benefit (rho¼0.39 and 0.47, respectively; P<0.01). A significant correlation was also demonstrated between MAS change score and change from baseline in GAS T-score (rho¼-0.28; P<0.01). Conclusions: In patients receiving BoNT-A treatment in the ULIS-II study, MAS change scores at follow-up correlated with investigator and patient global assessment of benefits, as well as GAS T scores. Correlations between MAS and investigator-assessed benefits were stronger compared with the correlation between MAS and patient-assessed benefits, which suggests that MAS change does not necessarily translate to patient benefits, whereas goal attainment may provide a more patient-centered reflection of outcome. Funding: Sponsored by Ipsen Keywords: Botulinum toxin A; Goal attainment scaling (GAS); Upper limb spasticity 52. SWITCHING BOTULINUM TOXIN FORMULATIONS FROM ONABOTULINUMTOXINA (BOTOX) TO INCOBOTULINUMTOXINA (XEOMIN): EXPERIENCE FROM A SPASTICITY OUTPATIENT CLINIC Prabal K. Datta*, Adrian Robertson. Mid Yorkshire Hospitals NHS Trust, Wakefield, UK * Corresponding author: Mid Yorkshire Hospitals NHS Trust, Aberford Road, Wakefield, WF1 4AD, UK. E-mail address:[email protected].
Introduction and objectives: This retrospective case review evaluated outcomes, doses, and treatment intervals in patients with spasticity due to any neurologic condition after switching botulinum neurotoxin type A (BoNT-A) formulations from onabotulinumtoxinA (Botox) to incobotulinumtoxinA (Xeomin). Methods: BoNT-A was injected into the affected muscles of the upper and/or lower limb, occasionally guided by electromyography, electrostimulation, or ultrasonography. Treatment regimens were continually adjusted based on clinical need and previous outcomes without changes in practice over the study period. Switching from onabotulinumtoxinA to incobotulinumtoxinA (both reconstituted to the same volume) was generally initiated at a 1:1 unit dose ratio. Patient records documented treatment intervals, doses, muscles treated, injection technique, and adverse reactions. Results: Of 254 consecutive patients, 93 met the inclusion criteria. Mean age at start of treatment was 46.5 (range,16 to 82) years. Spasticity was mainly due to stroke (40.9%), cerebral palsy (25.8%), or multiple sclerosis (18.3%). Patients had been treated with onabotulinumtoxinA for 3 to 55 (mean, 16) months before receiving incobotulinumtoxinA for 7 to 73 (mean, 39) months. Mean doses at the last 3 onabotulinumtoxinA treatments were 143.3 units (U), 147.2 U, and 143.9 U, given on average 125.2,141.5, and 194.2 days after previous treatment. After switching, mean doses at the first 3 incobotulinumtoxinA treatments were 152.4 U,140.9 U, and 136.9 U, given on average 163.8,167.4, and 135.5 days after previous treatment. No adverse reactions occurred with any formulation. Conclusions: In our spasticity outpatient clinic, switching from onabotulinumtoxinA to incobotulinumtoxinA at a 1:1 unit dose ratio did not affect dose requirements or treatment intervals, indicating similar efficacy of both formulations. Tolerability was also similar, with no adverse reactions for either formulation. Editorial support funded by: Merz Pharmaceuticals Keywords: Botulinum toxin type A; IncobotulinumtoxinA; OnabotulinumtoxinA; Spasticity
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53. NONPARALYTIC BOTULINUM MOLECULES FOR CHRONIC PAIN MANAGEMENT Bazbek Davletov a, *, Stephen Hunt b, Stefania Mangione b, Anna Andreou c. a University of Sheffield, Sheffield, UK; b University College London, London, UK; c Imperial College, London, UK * Corresponding author: University of Sheffield, Sheffield S10 2TN, UK. E-mail address:b.davletov@sheffield.ac.uk.
We are using our recently gained knowledge of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins and botulinum neurotoxins (BoNTs) to develop innovative longlasting pain therapeutics. BoNTs efficiently trigger local neuromuscular paralysis for several months, but they are also known to provide partial relief for sufferers with severe migraine and intractable neuropathic pain. It would be highly advantageous to develop new BoNTs that do not paralyze but still possess their antinociceptive properties. Unfortunately, BoNTs are the most lethal paralytic toxins known, and working with these proteins presents great danger. We developed new technology that solves the safety issues and also allows production of new, nonparalytic botulinum products for long-lasting neuronal silencing. Specifically, BoNT type A was split into 2 parts that can be expressed as innocuous fragments and then “stapled” together with a peptide (Darios 2010). Using this approach, we developed a unique panel of neuronal targeting and blocking molecules that can silence specific neurons for months, allowing reliable management of chronic pain. We are investigating targeting of known subpopulations of nociceptive neurons by tailor-made botulinum molecules and testing them in well-characterized pain models. The novel synthetic molecules have the potential to underpin treatment of different types of chronic pain in which localized injections of subimmunogenic, nanogram amounts of very potent, safe medicines will alleviate pain without side effects. Our protein stapling technology allowed production of an elongated botulinum molecule, Bitox (Ferrari 2011). We tested Bitox in several rodent pain models and found that it can, without any paralysis, efficiently alleviate mechanical allodynia in a rat model of neuropathic pain (Mangione 2016). In addition, nonparalytic Bitox increased the activation threshold of the trigeminovascular system in migraine models (Torres-Perez 2015), potentially offering a significant advancement in therapeutic options for patients. Keywords: Allodynia; Botulinum neurotoxin; Migraine; Nociceptive pain; Nonparalytic; SNARE protein References Darios F, Niranjan D, Ferrari E, et al. SNARE tagging allows step-wise assembly of a multimodular medicinal toxin. Proc Natl Acad Sci USA. 2010;107:18197-18201. Ferrari E, Maywood E, Restani L, et al. Re-assembled botulinum neurotoxin inhibits CNS functions without systemic toxicity. Toxins (Basel). 2011;3:345-355. Mangione AS, Obara I, Maiarú M, et al. Non-paralytic botulinum molecules for the control of pain. Pain. 2016;157:1045-1055. Torres-Perez JV, Chamberlain J, Miedzik AA, Nagy I, Davletov B, Andreou AP. Non-paralytic botulinum chimeras increase the activation threshold of the trigeminovascular system in migraine models. Cephalalgia. 2015;35:4. 54. PHASE 3 TRIAL TO EVALUATE ABOBOTULINUMTOXINA (DYSPORT®) INJECTIONS IN CHILDREN WITH UPPER LIMB SPASTICITY DUE TO CEREBRAL PALSY: A STUDY DESIGN Mauricio R. Delgado a,*, Ann Tilton b, Jorge Carranza c, Marcin Bonikowski d, Nigar Dursun e, France Catus f, Philippe Picaut f. a Texas Scottish Rite Hospital for Children, Dallas, TX, USA; b Louisiana State University Health Center and Children’s Hospital New Orleans, New Orleans, e Celaya, Celaya, Guanajuato, Mexico; Louisiana, USA; c Hospital San Jos d Non-Public Healthcare Unit, Mazovian Neurorehabilitation and Psychiatry Center in Zagorze, Wiazowna, Poland; e Kocaeli University Medical Faculty, Izmit, Turkey; f Ipsen, Les Ulis, France
Abstracts / Toxicon 123 (2016) S2eS90
Keywords: Botulinum toxin; Clean intermittent catheterization; Neurogenic detrusor overactivity; OnabotulinumtoxinA; Patient-reported outcome; Urinary incontinence 50. CLINICAL RELEVANCE OF TREATMENT WITH ONABOTULINUMTOXINA IN PATIENTS WITH CERVICAL DYSTONIA: RESULTS FROM THE CD PROBE STUDY Khashayar Dashtipour a, *, Zoltan Mari b, Joseph Jankovic c, Charles H. Adler d, Marc Schwartz e, Mitchell F. Brin f. a Loma Linda University School of Medicine, Loma Linda, CA, USA; b Johns Hopkins Hospital, Baltimore, MD, USA; c Baylor College of Medicine, Houston, TX, USA; d Mayo Clinic College of Medicine, Scottsdale, AZ, USA; e MedNet Solutions, Minnetonka, MN, USA; f Allergan, Irvine, CA, USA * Corresponding author: Loma Linda University School of Medicine, 11370 Anderson Street, Suite B-100, Loma Linda, CA 92354, USA. E-mail address:kdashtipour@llu. edu.
Introduction and objectives: Data from the Cervical Dystonia Patient Registry for Observation of OnabotulinumtoxinA Efficacy (CD PROBE) study were analyzed to explore the minimal clinically important change that patients perceive as beneficial based on the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). Methods: CD PROBE is a multicenter, prospective clinical registry that recruited patients with cervical dystonia (CD) from 88 US sites (Jankovic 2011, 2015). Patients with CD who were new to botulinum toxin therapy or had not received it for 16 weeks and were deemed suitable for onabotulinumtoxinA treatment received 3 cycles of the drug. Changes from baseline in TWSTRS scores were correlated with clinical improvement as assessed by the Patient or Clinician Global Impression of Change (PGIC or CGIC) scale. The discrimination of the model was determined using logistic regression; good discrimination was defined as 70% correct classification of PGIC or CGIC based on TWSTRS scores. We report on the 479 patients who completed the study. Results: The mean TWSTRS score significantly decreased from baseline to the final visit (from 39.2 to 27.1; P<0.0001). The point (percentage) reduction in total TWSTRS score that correlated with “very much improved,” “much improved” or better, and “minimally improved” or better on the PGIC were 11 (27.1%; n¼121), 9 (21.2%; n¼307), and 8 (19.1%; n¼436) respectively; for CGIC, point (percentage) reductions were 10 (24.1%; n¼139), 8 (16.3%; n¼356), and 7 (11.8%; n¼454) (Table). Total TWSTRS score had a good level of discrimination and correlated with PGIC and CGIC better than any TWSTRS subscale scores, although the contribution of the “minimally improved” group was limited by small sample size (PGIC, n¼129; CGIC, n¼98). Conclusions: Change in total TWSTRS score correlated well with patientand clinician-based evaluations (PGIC and CGIC, respectively) of onabotulinumtoxinA-treated patients with CD. These results approximate definitions of response used in other studies (Comella 2011; Truong 2005). Keywords: CD PROBE; Cervical dystonia; Clinical effectiveness; OnabotulinumtoxinA Funding: Allergan References Comella CL, Jankovic J, Truong DD, Hanschmann A, Grafe S. 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. Jankovic J, Adler CH, Charles PD, et al. Rationale and design of a prospective study: Cervical Dystonia Patient Registry for Observation of OnaBotulinumtoxinA Efficacy (CD PROBE). BMC Neurol. 2011;11:140. Jankovic J, Adler CH, Charles D, et al. Primary results from the cervical dystonia patient registry for observation of onabotulinumtoxina efficacy (CD PROBE). J Neurol Sci. 2015;349(1-2):84-93. Truong D, Duane DD, Jankovic J, et al. Efficacy and safety of botulinum
Table Correlation of Changes in Total TWSTRSs With Changes in PGIC and CGIC From Baseline to Final Visit (N¼479) Mean Change Area Output Under Change in Curve TWSTRS Score
Sensitivity Specificity Correctly Classified, %
Change in Total TWSTRSs Correlated With Changes in PGIC* Point 0.860 e11.00 0.80 0.77 “Very much improved” change % 0.893 e27.12 0.83 0.84 (n¼121) change Point 0.783 e9.00 0.72 0.72 “Much improved” change or better % 0.810 e21.21 0.76 0.74 (n¼307) change Point 0.723 e8.00 0.66 0.67 “Minimally improved” change or better % 0.746 e19.05 0.67 0.67 (n¼436) change Change in Total TWSTRSs Correlated With Changes in CGICy Point 0.903 e10.00 0.83 0.84 “Very much improved” change (n¼139) % 0.924 e24.14 0.83 0.84 change Point 0.835 e8.00 0.74 0.76 “Much improved” change or better % 0.857 e16.28 0.80 0.80 (n¼356) change Point 0.784 e7.00 0.69 0.72 “Minimally improved” change or better % 0.806 e11.76 0.76 0.76 (n¼454) change
79.3 83.5 72.3 75.4 66.0 67.4
82.9 83.5 74.0 80.1 68.7 76.2
CGIC¼Clinician Global Impression of Change; PGIC¼Patient Global Impression of Change; TWSTRSs¼Toronto Western Spasmodic Torticollis Rating Scale score. Values in bold met the indicators of good cutoffs for discrimination of the model: area under curve 0.7 or percentage correctly classified 70%. *PGIC ratings: no change or worse, n¼43; “minimally improved,” n¼129; “much improved,” n¼186; “very much improved,” n¼121. y CGIC ratings: no change or worse, n¼25; “minimally improved,” n¼98; “much improved,” n¼217; “very much improved,” n¼139.
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. 51. CORRELATIONS BETWEEN SPASTICITY, GOAL ATTAINMENT, AND GLOBAL ASSESSMENT OF BENEFITS IN PATIENTS WITH UPPER LIMB SPASTICITY TREATED WITH BOTULINUM TOXIN A Khashayar Dashtipour a, Jovita Balcaitiene b, *, Stephen Ashford c, Jorge Jacinto d, Klemens Fheodoroff e, Pascal Maisonobe b, Lynne TurnerStokes c. a Department of Neurology/Movement Disorders, School of Medicine, Loma Linda University, California, USA; b Ipsen Pharma, Boulogne-Billancourt, France; c King’s College London School of Medicine, Palliative Care, Policy and Rehabilitation and Regional Rehabilitation Unit, Northwick Park ~o de Alcoita ~o, Hospital, London, UK; d Centro de Medicina de Reabilitaça ~o de Adultos, Estoril, Portugal; e Department of Serviço de Reabilitaça Neurorehabilitation, Gailtal-Klinik, Hermagor, Austria * Corresponding author: IPSEN Pharma, Boulogne-Billancourt, France. E-mail address:[email protected].
Introduction: ULIS-II was an 18-month, international, noninterventional study in 456 poststroke adults (from 84 centres in 22 countries) with upper limb spasticity (ULS) receiving 1 cycle of botulinum toxin A (BoNTA) in accordance with routine local clinical practice. In this study, a
Abstracts / Toxicon 123 (2016) S2eS90
clinically significant impact on attainment of person-centered goals (measured by Goal Attainment Scaling; GAS), was demonstrated. Methods: This was a post hoc analysis to investigate correlations between change in Modified Ashworth Scale (MAS) and Goal Attainment Scaling (GAS) or global assessment of benefits. Correlations were determined between MAS, reported benefit and GAS T scores, using Spearman’s rank correlation coefficient. Results: Weak but significant correlations were observed between change in MAS scores and investigator- or patient-assessed benefit (rho¼0.28 and 0.20, respectively; P<0.01). Change in MAS score correlated better with investigator-reported benefits than with patient-reported benefits; a correlation was demonstrated between investigator and patient assessment of benefit (rho¼0.66; P<0.01). Significant correlations were observed between change from baseline in GAS T scores and investigator- or patientassessed benefit (rho¼0.39 and 0.47, respectively; P<0.01). A significant correlation was also demonstrated between MAS change score and change from baseline in GAS T-score (rho¼-0.28; P<0.01). Conclusions: In patients receiving BoNT-A treatment in the ULIS-II study, MAS change scores at follow-up correlated with investigator and patient global assessment of benefits, as well as GAS T scores. Correlations between MAS and investigator-assessed benefits were stronger compared with the correlation between MAS and patient-assessed benefits, which suggests that MAS change does not necessarily translate to patient benefits, whereas goal attainment may provide a more patient-centered reflection of outcome. Funding: Sponsored by Ipsen Keywords: Botulinum toxin A; Goal attainment scaling (GAS); Upper limb spasticity 52. SWITCHING BOTULINUM TOXIN FORMULATIONS FROM ONABOTULINUMTOXINA (BOTOX) TO INCOBOTULINUMTOXINA (XEOMIN): EXPERIENCE FROM A SPASTICITY OUTPATIENT CLINIC Prabal K. Datta*, Adrian Robertson. Mid Yorkshire Hospitals NHS Trust, Wakefield, UK * Corresponding author: Mid Yorkshire Hospitals NHS Trust, Aberford Road, Wakefield, WF1 4AD, UK. E-mail address:[email protected].
Introduction and objectives: This retrospective case review evaluated outcomes, doses, and treatment intervals in patients with spasticity due to any neurologic condition after switching botulinum neurotoxin type A (BoNT-A) formulations from onabotulinumtoxinA (Botox) to incobotulinumtoxinA (Xeomin). Methods: BoNT-A was injected into the affected muscles of the upper and/or lower limb, occasionally guided by electromyography, electrostimulation, or ultrasonography. Treatment regimens were continually adjusted based on clinical need and previous outcomes without changes in practice over the study period. Switching from onabotulinumtoxinA to incobotulinumtoxinA (both reconstituted to the same volume) was generally initiated at a 1:1 unit dose ratio. Patient records documented treatment intervals, doses, muscles treated, injection technique, and adverse reactions. Results: Of 254 consecutive patients, 93 met the inclusion criteria. Mean age at start of treatment was 46.5 (range,16 to 82) years. Spasticity was mainly due to stroke (40.9%), cerebral palsy (25.8%), or multiple sclerosis (18.3%). Patients had been treated with onabotulinumtoxinA for 3 to 55 (mean, 16) months before receiving incobotulinumtoxinA for 7 to 73 (mean, 39) months. Mean doses at the last 3 onabotulinumtoxinA treatments were 143.3 units (U), 147.2 U, and 143.9 U, given on average 125.2,141.5, and 194.2 days after previous treatment. After switching, mean doses at the first 3 incobotulinumtoxinA treatments were 152.4 U,140.9 U, and 136.9 U, given on average 163.8,167.4, and 135.5 days after previous treatment. No adverse reactions occurred with any formulation. Conclusions: In our spasticity outpatient clinic, switching from onabotulinumtoxinA to incobotulinumtoxinA at a 1:1 unit dose ratio did not affect dose requirements or treatment intervals, indicating similar efficacy of both formulations. Tolerability was also similar, with no adverse reactions for either formulation. Editorial support funded by: Merz Pharmaceuticals Keywords: Botulinum toxin type A; IncobotulinumtoxinA; OnabotulinumtoxinA; Spasticity
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53. NONPARALYTIC BOTULINUM MOLECULES FOR CHRONIC PAIN MANAGEMENT Bazbek Davletov a, *, Stephen Hunt b, Stefania Mangione b, Anna Andreou c. a University of Sheffield, Sheffield, UK; b University College London, London, UK; c Imperial College, London, UK * Corresponding author: University of Sheffield, Sheffield S10 2TN, UK. E-mail address:b.davletov@sheffield.ac.uk.
We are using our recently gained knowledge of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins and botulinum neurotoxins (BoNTs) to develop innovative longlasting pain therapeutics. BoNTs efficiently trigger local neuromuscular paralysis for several months, but they are also known to provide partial relief for sufferers with severe migraine and intractable neuropathic pain. It would be highly advantageous to develop new BoNTs that do not paralyze but still possess their antinociceptive properties. Unfortunately, BoNTs are the most lethal paralytic toxins known, and working with these proteins presents great danger. We developed new technology that solves the safety issues and also allows production of new, nonparalytic botulinum products for long-lasting neuronal silencing. Specifically, BoNT type A was split into 2 parts that can be expressed as innocuous fragments and then “stapled” together with a peptide (Darios 2010). Using this approach, we developed a unique panel of neuronal targeting and blocking molecules that can silence specific neurons for months, allowing reliable management of chronic pain. We are investigating targeting of known subpopulations of nociceptive neurons by tailor-made botulinum molecules and testing them in well-characterized pain models. The novel synthetic molecules have the potential to underpin treatment of different types of chronic pain in which localized injections of subimmunogenic, nanogram amounts of very potent, safe medicines will alleviate pain without side effects. Our protein stapling technology allowed production of an elongated botulinum molecule, Bitox (Ferrari 2011). We tested Bitox in several rodent pain models and found that it can, without any paralysis, efficiently alleviate mechanical allodynia in a rat model of neuropathic pain (Mangione 2016). In addition, nonparalytic Bitox increased the activation threshold of the trigeminovascular system in migraine models (Torres-Perez 2015), potentially offering a significant advancement in therapeutic options for patients. Keywords: Allodynia; Botulinum neurotoxin; Migraine; Nociceptive pain; Nonparalytic; SNARE protein References Darios F, Niranjan D, Ferrari E, et al. SNARE tagging allows step-wise assembly of a multimodular medicinal toxin. Proc Natl Acad Sci USA. 2010;107:18197-18201. Ferrari E, Maywood E, Restani L, et al. Re-assembled botulinum neurotoxin inhibits CNS functions without systemic toxicity. Toxins (Basel). 2011;3:345-355. Mangione AS, Obara I, Maiarú M, et al. Non-paralytic botulinum molecules for the control of pain. Pain. 2016;157:1045-1055. Torres-Perez JV, Chamberlain J, Miedzik AA, Nagy I, Davletov B, Andreou AP. Non-paralytic botulinum chimeras increase the activation threshold of the trigeminovascular system in migraine models. Cephalalgia. 2015;35:4. 54. PHASE 3 TRIAL TO EVALUATE ABOBOTULINUMTOXINA (DYSPORT®) INJECTIONS IN CHILDREN WITH UPPER LIMB SPASTICITY DUE TO CEREBRAL PALSY: A STUDY DESIGN Mauricio R. Delgado a,*, Ann Tilton b, Jorge Carranza c, Marcin Bonikowski d, Nigar Dursun e, France Catus f, Philippe Picaut f. a Texas Scottish Rite Hospital for Children, Dallas, TX, USA; b Louisiana State University Health Center and Children’s Hospital New Orleans, New Orleans, e Celaya, Celaya, Guanajuato, Mexico; Louisiana, USA; c Hospital San Jos d Non-Public Healthcare Unit, Mazovian Neurorehabilitation and Psychiatry Center in Zagorze, Wiazowna, Poland; e Kocaeli University Medical Faculty, Izmit, Turkey; f Ipsen, Les Ulis, France