Sustained functional benefits after a single set of injections with abobotulinumtoxinA using a 2-mL injection volume in adults with cervical dystonia: 12-week results from a randomized, double-blind, placebo-controlled phase 3b study

Abstract

Cervical dystonia (CD) is primarily treated with botulinum toxin, at intervals of ≥ 12 weeks. We present efficacy, patient-reported outcomes (PROs), and safety in adults with CD at the last available visit after a single set of abobotulinumtoxinA (aboBoNT-A) injections versus placebo using 500 U in a 2-mL injection volume. In this 12-week, randomized, double-blind trial, patients were ≥ 18 years of age with primary idiopathic CD, had a Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score ≥ 20, and TWSTRS-Severity subscale score > 10 at baseline. Patients (N = 134) were randomized (2:1) to aboBoNT-A (n = 89) or placebo (n = 45), with aboBoNT-A patients treated with 500 units (U) if toxin-naïve, and 250 to 500 U based on previous onabotulinumtoxinA dose if non-naïve. Endpoints included total TWSTRS, Pain Numeric Rating Scale (NRS-Pain; 24-hour), Treatment Satisfaction Questionnaire for Medication, and other PROs for pain, depression, and global health. Results are for the intent-to-treat population, with "Week 12" (Wk12) comprising the last available post-baseline assessment (end-of-study or early withdrawal). Mean TWSTRS total scores improved from 42.5 at baseline to 35.4 at Wk12 with aboBoNT-A and 42.4 to 40.4 with placebo (treatment difference: -4.8; 95% confidence interval [CI]: -8.5, -1.1; p = 0.011). At Wk12, mean (95% CI) change from baseline in NRS-Pain was -1.0 (-1.59, -0.45) for aboBoNT-A and -0.2 (-0.96, 0.65) for placebo. AboBoNT-A demonstrated numeric improvements in other PROs. More aboBoNT-A-treated patients than patients receiving placebo reported being at least "somewhat satisfied" with treatment (60.4% vs 42.2%, respectively), symptom relief (57.0% vs 40.0%), and time for treatment to work (55.8% vs 33.3%). No new adverse events were reported. Results indicate that in patients with CD, treatment with aboBoNT-A using a 2-mL injection provided sustained improvement in the TWSTRS total score and patient-perceived benefits up to 12 weeks. Trial registration: Clinicaltrials.gov Identified: NCT01753310.

Conflict of interest statement

I, A. T. Patel, have read the journal’s policy and the authors of this manuscript have the following competing interests: Speaker: Allergan, Ipsen, Merz, Revance; Research support: Allergan, Ipsen, Revance. I, M. F. Lew, have read the journal’s policy and the authors of this manuscript have the following competing interests: Advisor/consultant/speaker: AbbVie, ACADIA, Acorda, Adamas, Cynapsus, Kyowa Kirin, Lundbeck, Neurocrine, Revance, Teva, US WorldMeds; Researcher: Biotie, Enterin Inc., Michael J. Fox Foundation, Parkinson Study Group, Pharm2B; I, A. Brashear, have read the journal’s policy and the authors of this manuscript have the following competing interests: Consulting: Ipsen, Revance; Research support: paid to Wake Forest (institution) and conflicts were managed by Wake Forest. I, K. Dashtipour, have read the journal’s policy and the authors of this manuscript have the following competing interests: Advisor/consultant, and/or speaker: AbbVie, ACADIA, Acorda, Adamas, Allergan, Amneal, Impax, Ipsen, Lundbeck, Neurocrine, Revance, Sunovion, Teva, US WorldMeds. I, S. Isaacson, have read the journal’s policy and the authors of this manuscript have the following competing interests: Honoraria for CME/consultant/promotional speaker: AbbVie, ACADIA, Acorda, Adamas, Addex, Allergan, Amarantus, Axovant, Biogen, Britannia, Eli Lilly, Enterin, GE Healthcare, Global Kinetics, Impax, Intec Pharma, Ipsen, Kyowa, Lundbeck, Michael J. Fox Foundation, Neurocrine, Neuroderm, Parkinson Study Group, Pharma2B, Roche, Sanofi, Sunovion, Teva, UCB, US WorldMeds, Zambon; Honoraria for research grants: AbbVie, ACADIA, Acorda, Adamas, Addex, Allergan, Amarantus, Axovant, Biogen, Britannia, Eli Lilly, Enterin, GE Healthcare, Global Kinetics, Impax, Intec Pharma, Ipsen, Kyowa, Lundbeck, Michael J. Fox Foundation, Neurocrine, Neuroderm, Parkinson Study Group, Pharma2B, Roche, Sanofi, Sunovion, Teva, UCB, US WorldMeds. I, R. A. Hauser, have read the journal’s policy and the authors of this manuscript have the following competing interests: Consulting: AbbVie, Academy for Continued Healthcare Learning, ACADIA, Acorda, Adamas, AstraZeneca, Back Bay Life Science, Biotie, Bracket, Cerecor, ClearView Healthcare Partners, ClinicalMind Medical and Therapeutic Communications, Cowen and Company, Cynapsus Therapeutics, Decision Resources Group, Eli Lilly, eResearch Technology, Expert Connect, Extera Partners, GE Healthcare, Gerson Lehrman Group, Globe Life Sciences, Guidepoint Global, Health Advances, Health and Wellness Partners, HealthLogix, Huron Consulting Group, Impax, Intec Pharma, Jazz Pharmaceuticals, Kyowa Kirin Pharmaceutical Development, LCN Consulting, LifeMax, The Lockwood Group, Lundbeck, MEDACorp, Medscape, Medtronic, Michael J. Fox Foundation, Movement Disorder Society, National Institutes of Health (NIH), Neurocrine Biosciences, Neuroderm, Neuropore Therapies, Outcomes Insights, Parkinson Foundation, Peerview Press, Pennside Partners, Pfizer, Pharma2B, Phase Five Communications, Piper Jaffray & Co, Prexton Therapeutics, Projects in Knowledge, Putnam Associates, Quintiles, RMEI Medical Education for Better Outcomes, Sarepta Therapeutics, Schlesinger Associates, Scion Neurostim, Seagrove Partners, Slingshot Insights, Sun Pharma, Sunovion, Teva, US WorldMeds, Vista Research, WebMD, Windrose Consulting Group; Research support: AbbVie, Acorda Therapeutics, AstraZeneca, Axovant Sciences, Biogen, Cavion, Dart NeuroScience, Enterin, F. Hoffman-La Roche, Impax, Intec Pharma, Jazz Pharmaceuticals, Lundbeck, Michael J. Fox Foundation, NeuroDerm, Parkinson’s Foundation, Prexton Therapeutics, Revance, Sunovion. I, W. Ondo, have read the journal’s policy and the authors of this manuscript have the following competing interests: Advisor/consultant/speaker: ACADIA, Acorda, Adamas, Jazz Pharmaceuticals, Neurocrine, Teva, UCB, US WorldMeds; Research support: Biogen, Lilly, Lundbeck, Sun Pharmaceuticals, Sunovian. I, P. Maisonobe, have read the journal’s policy and the authors of this manuscript have the following competing interests: Employment: Ipsen. I, S. Wietek, have read the journal’s policy and the authors of this manuscript have the following competing interests: Employment: Ipsen. I, B. Rubin, have read the journal’s policy and the authors of this manuscript have the following competing interests: Employment (former): Ipsen.

Figures

Fig 1. CONSORT diagram.

aboBoNT-A = abobotulinumtoxinA; HCP = healthcare provider; mITT = modified intent-to-treat; OLE = open-label extension; PP = per protocol; TWSTRS = Toronto Western Spasmodic Torticollis Rating Scale. *Entered NCT01753336 (OLE) to continue active treatment.

Fig 2. Mean TWSTRS total score.

aboBoNT-A = abobotulinumtoxinA; ITT = intent-to-treat (all randomized patients); last available* = last available post-baseline (end of study or early withdrawal); TWSTRS = Toronto Western Spasmodic Torticollis Rating Scale; Δ = weighted overall treatment difference. Error lines indicate standard deviation. *Last available = last available post-baseline (end of study or early withdrawal), mean (SD) study drug exposure: 62.6 (37.8) days.

Fig 3

Patient-reported outcomes (ITT population): A) PGIC across time points. B) Mean NRS-Pain scores across time points. C) Mean BPI scores across time points. D) Level of depressive (PHQ-9) mood across time points. E) Change from baseline in CDIP-58 scaled sum total score across time points. BPI = Brief Pain Inventory; CDIP-58 = Cervical Dystonia Impact Profile-58; ITT = intent-to-treat (all randomized patients); Improved = minimally, much, or very much improved; Last available* = last available post-baseline (end of study or early withdrawal); Mild/moderate = mild depression (5‒9) or moderate depression (10‒14); No/minimal = no depression (0) or minimal depression (1‒4); NRS-Pain = numeric rating scale for pain; Worse = minimally, much, or very much worse; PGIC = Patient Global Impression of Change; PHQ-9 = Patient Health Questionnaire-9; Severe = moderately severe depression (15‒19) or severe depression (20–27). * Last available = last available post-baseline (end of study or early withdrawal), mean (SD) study drug exposure: 62.6 (37.8) days.