Pain Reduction in Cervical Dystonia Following Treatment with IncobotulinumtoxinA: A Pooled Analysis.

This analysis pooled pain severity data from four phase 3 and 4 studies of incobotulinumtoxinA (incoBoNT-A) for the treatment of cervical dystonia (CD) in adults. CD-related pain severity was assessed at baseline, each injection visit, and 4 weeks after each injection of incoBoNT-A using the Toronto Western Spasmodic Torticollis Rating Scale pain severity subscale or a pain visual analog scale. Both were analyzed using a score range of 0-10 and pain was categorized as mild, moderate, or severe. Data for 678 patients with pain at baseline were assessed and sensitivity analyses evaluated pain responses in the subgroup not taking concomitant pain medication (n = 384 at baseline). At Week 4 after the first injection, there was a mean change of -1.25 (standard deviation 2.04) points from baseline pain severity (p < 0.0001), with 48.1% showing ≥ 30% pain reduction from baseline, 34.4% showing ≥50% pain reduction from baseline, and 10.3% becoming pain free. Pain responses were sustained over five injection cycles with a trend to incremental improvements with each successive cycle. Pain responses in the subgroup not taking concomitant pain medication demonstrated the lack of confounding effects of pain medications. These results confirmed the pain relief benefits of long-term treatment with incoBoNT-A.

Improvement in Quality-of-Life-Related Outcomes Following Treatment with IncobotulinumtoxinA in Adults with Limb Spasticity: A Pooled Analysis.

A strong correlation has been reported between patient-reported quality of life (QoL) and the investigator-rated Disability Assessment Scale (DAS) in patients with spasticity. The current analysis evaluates the effect of incobotulinumtoxinA on QoL-related outcomes (limb position abnormality, as well as dressing- and hygiene-related disability, measured with the DAS) in adults with upper limb spasticity, using pooled data from six studies. Separate analyses for each DAS domain were performed using data from patients with disabilities for that domain (DAS score ≥1). Results showed that a significantly greater proportion of incobotulinumtoxinA-treated compared with placebo-treated patients achieved a ≥1-point reduction from baseline in each of the DAS domains (improvement) 4 weeks after the first injection. The benefits of incobotulinumtoxinA were observed regardless of the baseline severity of DAS impairment and of the time elapsed since stroke. The effects of incobotulinumtoxinA 4 weeks after injection were maintained or enhanced over multiple injection cycles for all three DAS domains, supporting the use of repeated injection cycles to provide sustained QoL benefit. IncobotulinumtoxinA represents an important treatment option to achieve better QoL-related outcomes for patients with upper limb spasticity, irrespective of the duration of their condition.

Efficacy and safety of two incobotulinumtoxinA injection intervals in cervical dystonia patients with inadequate benefit from standard injection intervals of botulinum toxin: Phase 4, open-label, randomized, noninferiority study.

IntroductionSome patients with cervical dystonia (CD) receiving long-term botulinum neurotoxin (BoNT) therapy report early waning of treatment benefit before the typical 12-week reinjection interval. Methods: This phase 4, open-label, randomized, noninferiority study (CD Flex; NCT01486264) compared 2 incobotulinumtoxinA injection schedules (Short Flex: 8 ± 2 weeks; Long Flex: 14 ± 2 weeks) in CD patients. Previous BoNT-responsive subjects who reported acceptable clinical benefit lasting < 10 weeks were recruited. Efficacy and safety were evaluated after 8 injection cycles. The primary endpoint was change in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) severity subscale 4 weeks after the eighth injection. Secondary endpoints included TWSTRS total and subscale scores. Immunogenicity was assessed in a subset of patients. Results: Two hundred eighty-two CD patients were randomized and treated (Short Flex, N = 142; Long Flex, N = 140), and 207 completed the study. Significant improvements in TWSTRS severity from study baseline to 4 weeks after cycle 8 were observed in both the Short Flex (4.1 points; P < 0.0001) and Long Flex (2.4 points; P = 0.002) groups; Short Flex was noninferior to Long Flex (LS mean difference = 1.4 points; 95% CI = [-2.9, 0.1] < Δ = 2.0). Key secondary endpoints favored Short Flex intervals. Adverse events (AEs) were comparable between groups. There was no secondary loss of treatment effect. Conclusion: Injection cycles < 10 weeks for incobotulinumtoxinA are effective (and noninferior to longer intervals) for treating CD patients with early waning of clinical benefit. Shorter injection intervals did not increase AEs or lead to loss of treatment effect.

Pain Reduction in Adults with Limb Spasticity Following Treatment with IncobotulinumtoxinA: A Pooled Analysis.

Some studies have shown that incobotulinumtoxinA reduces spasticity-associated pain, but further evidence is needed. This exploratory analysis pooled pain-relief data from six Phase 2 or 3 studies of incobotulinumtoxinA (four placebo-controlled studies) for treating upper limb spasticity in adults. Spasticity-associated pain was assessed at baseline and 4 weeks post incobotulinumtoxinA injection using the disability assessment scale (DAS) for pain. Only data for patients with pain at baseline were analysed. Overall, 544 (incobotulinumtoxinA, N = 415; placebo, N = 129) of 937 patients (58.1%) experienced pain at baseline. At Week 4, a significantly greater proportion of incobotulinumtoxinA- (52.1%) than placebo-treated patients (28.7%; Chi-square p < 0.0001) showed a response (≥1-point improvement in DAS pain score). In logistic regression analysis, incobotulinumtoxinA-treated patients were 2.6 times more likely to achieve this endpoint than placebo-treated patients. A significant difference between incobotulinumtoxinA and placebo was observed regardless of baseline pain severity. Additionally, 27.1% of incobotulinumtoxinA- versus 12.4% of placebo-treated patients reported complete pain relief at Week 4 (p = 0.0006). Pain relief increased with multiple injection cycles. To achieve patient-centred care, pain relief may be considered a treatment goal in adults with spasticity-associated pain regardless of pain severity. This study contributes to understanding the benefits of incobotulinumtoxinA in treating limb spasticity-associated pain.

Spasticity in practice (SPACE): an international non-interventional study of botulinum neurotoxin type A in treatment-naïve subjects with spasticity.

AIM OF THE STUDY: SPACE, a prospective, non-interventional, open-label, multinational study, investigated physicians' and subjects' assessment of safety, efficacy, and health-related quality of life (HRQoL) following botulinum neurotoxin type A (BoNT-A) treatment to understand real-world clinical usage for the management of focal and multifocal spasticity. CLINICAL RATIONALE FOR THE STUDY: Treatment guidelines recommend the use of BoNT-A for the management of spasticity in adults. This study assessed how physicians use BoNT-A therapy in real-world clinical practice, and provided evidence on long-term safety and efficacy over a period of up to 2 years. MATERIALS AND METHODS: BoNT treatment-naïve adults with spasticity of any aetiology received any BoNT-A formulation at their physician's discretion, and were observed for ≤ 8 treatment cycles (≤ 2 years). Daily practice information, physician's global assessments of tolerability and efficacy, and HRQoL were documented. Incidences of adverse drug reactions or all adverse events were documented for non-Mexican subjects and for Mexican subjects, respectively, due to protocol differences based on local regulatory requirements. RESULTS: A total of 701 subjects were enrolled (safety population; nine countries). Physicians rated the tolerability of BoNT-A as 'very good' or 'good' for 88.2-97.4% of subjects throughout the study (subject numbers declined throughout this non-interventional study). Adverse drug reactions were reported for 16/600 (2.7%) of the non-Mexican subjects, with two considered to be 'definitely related' to treatment (injection-site haematoma, n = 1; botulism, n = 1). For 687 subjects, efficacy was rated 'very good' or 'good' by most physicians and subjects. Improvements in HRQoL were observed. CONCLUSIONS AND CLINICAL IMPLICATIONS: Throughout this 2-year study, BoNT-A treatment was generally well-tolerated, effective, and associated with an improved HRQoL. This study makes a valuable contribution to the broader understanding of how physicians use BoNT-A therapy to manage spasticity in real-world clinical practice.

Efficacy and safety of treatment with incobotulinum toxin A (botulinum neurotoxin type A free from complexing proteins; NT 201) in post-stroke upper limb spasticity.

OBJECTIVE: To investigate the efficacy and safety of repeated treatment with incobotulinum toxin A (botulinum neurotoxin type A free from complexing proteins; NT 201) in post-stroke upper limb spasticity. PATIENTS AND DESIGN: After completing a double-blind, placebo- controlled, multicentre study (up to 20 weeks), 145 patients received up to 5 additional sets of NT 201 injections for an open-label extension period of up to 69 weeks. METHODS: Upper limb muscle groups were treated as clinically indicated; injection intervals were ≥ 12 weeks. Outcome was assessed 4 weeks after each injection session and at the end of the study. RESULTS: Muscle tone (flexors of wrist, elbow, finger, and thumb, and forearm pronators) improved throughout the study (response rate: up to 80.6%, p < 0.0001, Ashworth Scale). Continuous and significant improvements were also observed in disability (p < 0.05, Disability Assessment Scale). The majority of investigators, patients and caregivers rated NT 201 efficacy as very good or good (56-84%). Adverse events considered treatment-related occurred in 11% of patients. Formation of neutralizing antibodies was not observed in any patient after repeated treatments. CONCLUSION: Treatment with NT 201 showed sustained improvements in muscle tone and functionality (median dose 400 units) over a study duration of up to 89 weeks, and was well tolerated during repeated treatments for post-stroke upper limb spasticity.

Efficacy and safety of botulinum neurotoxin NT 201 in poststroke upper limb spasticity.

OBJECTIVE: To assess the impact of the new botulinum neurotoxin type A preparation NT 201 (Xeomin; Merz Pharmaceuticals GmbH, Frankfurt, Germany) on muscle tone, functional disability, and caregiver burden in patients with poststroke upper limb spasticity in a randomized, placebo-controlled, double-blind study. METHODS: One hundred forty-eight patients with an Ashworth Scale score of 2 or higher for wrist and finger flexors and at least moderate disability in their principal therapeutic target of the Disability Assessment Scale were treated either with NT 201 (median, 320 U) or placebo and followed up for up to 20 weeks. Treatment of the wrist and finger muscles was mandatory. RESULTS: A significantly higher proportion of patients treated with NT 201 were responders (improvement of > or =1 point in the Ashworth Scale score), as observed in comparison to placebo 4 weeks after treatment in wrist flexors (odds ratio, 3.97; 95% confidence interval, 1.9-8.3; P < 0.001, intent to treat). For all treated flexor muscle groups, statistically significant odds ratios in favor of NT 201 were observed at week 4 (P < or = 0.009). Statistically significant results in favor of NT 201 were observed at all postinjection visits until week 12 in the principal therapeutic target (P < or = 0.005), in the global assessment of efficacy (P < 0.001), and in some tasks of the Carer Burden Scale (P < 0.05). Similar numbers of patients in each group experienced at least 1 adverse event (NT 201, n = 21; placebo, n = 20). Importantly, none of the patients developed neutralizing antibodies. CONCLUSIONS: NT 201 led to statistically significant improvements in muscle tone and disability and was well tolerated in patients with poststroke upper limb spasticity.

Neurophysiological double-blind trial of a botulinum neurotoxin type a free of complexing proteins.

OBJECTIVE: Safety and efficacy of botulinum neurotoxin type A preparation NT 201 (Xeomin, Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany) were investigated over 52 weeks in a double-blind, randomized trial with 32 male volunteers. METHODS: Electroneurographic assessments with surface electrodes were performed after single injections of NT 201 (2, 4, 16, or 32 units) into the extensor digitorum brevis (EDB) muscle and the same dose (Botox; Allergan Pharmaceuticals (Ireland) Ltd. Westport, Ireland) into the contralateral EDB. RESULTS: All NT 201 and BTXCo doses achieved a statistically significant reduction of the compound muscle action potential M-wave amplitude in the EDB muscle. At week 4, the highest dose was statistically significantly more effective than the lowest dose (NT 201, P = 0.019; 95% confidence interval, 0.195-1.370; and BTXCo, P = 0.002; 95% confidence interval, 0.309-1.167). Duration of effect was dose dependent. The mean values of compound muscle action potential M-wave amplitudes in the adjacent muscles (abductor digiti quinti and abductor hallucis) were above the predefined threshold of effect, indicating that there was no relevant diffusion-induced reduction of muscle activity. NT 201 and BTXCo were well tolerated. CONCLUSIONS: NT 201 is effective and safe in inducing the desired paretic effect.