Mitchell F. Brin

OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial.

Objectives: This is the first of a pair of studies designed to assess efficacy, safety and tolerability of onabotulinumtoxinA (BOTOX®) as headache prophylaxis in adults with chronic migraine. Methods: The Phase III REsearch Evaluating Migraine Prophylaxis Therapy 1 (PREEMPT 1) is a phase 3 study, with a 24-week, double-blind, parallel-group, placebo-controlled phase followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections every 12 weeks of onabotulinumtoxinA (155 U–195 U; n = 341) or placebo (n = 338) (two cycles). The primary endpoint was mean change from baseline in headache episode frequency at week 24. Results: No significant between-group difference for onabotulinumtoxinA versus placebo was observed for the primary endpoint, headache episodes (−5.2 vs. −5.3; p = 0.344). Large within-group decreases from baseline were observed for all efficacy variables. Significant between-group differences for onabotulinumtoxinA were observed for the secondary endpoints, headache days (p = .006) and migraine days (p = 0.002). OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few subjects discontinued due to adverse events. Conclusions: There was no between-group difference for the primary endpoint, headache episodes. However, significant reductions from baseline were observed for onabotulinumtoxinA for headache and migraine days, cumulative hours of headache on headache days and frequency of moderate/severe headache days, which in turn reduced the burden of illness in adults with disabling chronic migraine.

OnabotulinumtoxinA for Treatment of Chronic Migraine: Pooled Results From the Double‐Blind, Randomized, Placebo‐Controlled Phases of the PREEMPT Clinical Program

(Headache 2010;50:921‐936)

Efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity: a randomised, double-blind, placebo-controlled trial.

BACKGROUND Neurogenic detrusor overactivity (NDO) frequently results in urinary incontinence (UI) which impairs quality of life (QOL) and puts the upper urinary tract at risk. OBJECTIVE To assess the effects of onabotulinumtoxinA (BOTOX(®), Allergan, Inc.) on UI, urodynamic variables, and QOL in incontinent patients with NDO. DESIGN, SETTING, AND PARTICIPANTS This multicentre, randomised, double-blind, placebo-controlled study enrolled patients with multiple sclerosis (MS; n=154) or spinal cord injury (SCI; n=121) with UI due to NDO (≥14 UI episodes per week). INTERVENTION Patients received 30 intradetrusor injections of onabotulinumtoxinA 200 U (n=92), 300 U (n=91), or placebo (n=92), avoiding the trigone. MEASUREMENTS Primary end point was change from baseline in UI episodes per week (week 6). Secondary end points included urodynamics (maximum cystometric capacity [MCC], maximum detrusor pressure during first involuntary detrusor contraction [P(detmaxIDC)]), and Incontinence Quality of Life (I-QOL) total score. Adverse events (AEs) were assessed. RESULTS AND LIMITATIONS At baseline, mean UI episodes per week (33.5) were similar across groups. At week 6, onabotulinumtoxinA 200 U and 300 U significantly reduced UI episodes per week (-21.8 and -19.4, respectively) compared with placebo (-13.2; p<0.01); onabotulinumtoxinA benefit was observed by the first posttreatment study visit at week 2. Improvements in MCC, P(detmaxIDC), and I-QOL at week 6 were significantly greater with both onabotulinumtoxinA doses than with placebo (p<0.001). Benefits were observed in both the MS and SCI populations. The median time to patient request for retreatment was the same for both onabotulinumtoxinA doses (42.1 wk) and greater than placebo (13.1 wk; p<0.001). Most frequent AEs were localised urologic events (urinary tract infections and urinary retention, which were dose related in patients not using clean intermittent catheterisation [CIC] at baseline). Significant increases in postvoid residual were observed in patients not using CIC prior to treatment, and 12%, 30%, and 42% of patients in the placebo, 200-U, and 300-U groups, respectively, initiated CIC posttreatment. CONCLUSIONS OnabotulinumtoxinA significantly reduced UI and improved urodynamics and QOL in MS and SCI patients with NDO. Both doses were well tolerated with no clinically relevant differences in efficacy or duration of effect between the two doses (http://www.clinicaltrials.gov; NCT00461292).

Double‐blind, placebo‐controlled trial of botulinum toxin injections for the treatment of spasmodic torticollis

We enrolled 55 patients in a double-blind, placebo-controlled, parallel design study of the effectiveness of botulinum toxin (Botox) injections for the treatment of spasmodic torticollis. Patients received a standard series of injections, either placebo or Botox. We determined the sites of injection and dose per muscle by the nature of head deviation. Compared with placebo, Botox produced statistically significant improvement in the severity of torticollis, disability, pain, and degree of head turning. There were no serious side effects. During the double-blind phase, 61% of patients injected with Botox improved; 74% of patients subsequently improved during a later open phase at a higher dose of Botox. Direction of head turning, severity of torticollis, and presence or absence of jerky movements did not significantly influence the response rate. We conclude that Botox is a valuable treatment for spasmodic torticollis.

Botulinum toxin management of spasmodic dysphonia (laryngeal dystonia) : A 12-year experience in more than 900 patients

Objectives: This paper reviews a 12-year experience in more than 900 patients with spasmodic dysphonia who have been treated with botulinum toxin. Study Design: This is a retrospective analysis of patients with adductor spasmodic dysphonia (strainstrangled voice), abductor spasmodic dysphonia (whispering voice), and adductor breathing dystonia (paradoxical vocal fold motion), all of whom have been treated with botulinum toxin injections for relief of symptom. Methods: All of the patients were studied with a complete head and neck and neurologic examination; fiberoptic laryngostroboscopy; acoustic and aerodynamic measures; and a speech evaluation including the Universal spasmodic dysphonia rating scale. Some were given electromyography. All patients received botulinum toxin injections into the affected muscles under electromyographic guidance. Results: The adductor patients had an average benefit of 90% of normal function lasting an average of 15.1 weeks. The abductor patients had an average benefit of 66.7% of normal function lasting an average of 10.5 weeks. Adverse effects included mild breathiness and coughing on fluids in the adductor patients, and mild stridor in a few of the abductor patients. Conclusion: Botulinum toxin A injection of the laryngeal hyperfunctional muscles has been found over the past 12 years to be the treatment of choice to control the dystonic symptoms in most patients with spasmodic dysphonia. Laryngoscope, 108:1435–1441, 1998

Botulinum toxin type a for the prophylaxis of chronic daily headache: subgroup analysis of patients not receiving other prophylactic medications: a randomized double-blind, placebo-controlled study.

Objective.—To assess the efficacy and safety of botulinum toxin type A (BoNT‐A; BOTOX®, Allergan, Inc., Irvine, CA) for the prophylaxis of headaches in patients with chronic daily headache (CDH) without the confounding factor of concurrent prophylactic medications.

Phase 3 efficacy and tolerability study of onabotulinumtoxinA for urinary incontinence from neurogenic detrusor overactivity.

PURPOSE We assessed the efficacy, safety and effects on quality of life of onabotulinumtoxinA in patients with neurogenic detrusor overactivity. MATERIALS AND METHODS In this 52-week, international, multicenter, double-blind, randomized, placebo controlled trial 416 patients with neurogenic detrusor overactivity and urinary incontinence (14 or more episodes per week) resulting from multiple sclerosis (227) and spinal cord injury (189) were treated with intradetrusor injections of onabotulinumtoxinA (200 or 300 U) or placebo. The primary end point was the change from baseline in the mean number of urinary incontinence episodes per week at week 6. Maximum cystometric capacity, maximum detrusor pressure during the first involuntary detrusor contraction and Incontinence Quality of Life total score were secondary end points. Adverse events were monitored. RESULTS OnabotulinumtoxinA at a dose of 200 U in 135 patients and 300 U in 132 decreased mean urinary incontinence at week 6 by 21 and 23 episodes per week, respectively, vs 9 episodes per week in 149 on placebo (each dose p<0.001). Also, maximum cystometric capacity, maximum detrusor pressure during the first involuntary detrusor contraction and Incontinence Quality of Life score were significantly improved over values in the placebo group (each dose p<0.001). Median time to patient re-treatment request was greater for onabotulinumtoxinA 200 and 300 U than for placebo (256 and 254 days, respectively, vs 92). The most common adverse events were urinary tract infection and urinary retention. Of patients who did not catheterize at baseline 10% on placebo, 35% on 200 U and 42% on 300 U initiated catheterization due to urinary retention. CONCLUSIONS OnabotulinumtoxinA significantly improved neurogenic detrusor overactivity symptoms vs placebo. Clean intermittent catheterization initiation due to urinary retention appeared to increase in a dose dependent fashion. No clinically relevant benefit in efficacy or duration was identified for the 300 U dose over the 200 U dose.

Electromyographic Findings in Focal Laryngeal Dystonia (Spastic Dysphonia)

Spastic dysphonia is a clinical speech disorder characterized by spasms of the laryngeal muscles during phonation, producing a broken pattern of speech sometimes termed laryngeal stuttering. Fourteen patients with the diagnosis of spastic dysphonia based on voice quality were referred for evaluation; detailed clinical and electrophysiologic evaluations were performed. Laryngeal electromyographic (EMG) testing failed to demonstrate any spontaneous activity in the 14 patients tested. Seven patients (50 %) had normal number and amplitude of motor unit potentials. Four of these had disparate amplitudes when compared with the other side, and two had complex motor unit potentials. The other seven patients (50 %) had abnormal findings, including three patients with abnormally increased amplitude. Two patients had asynchronous activity characteristic of a tremor disorder. One patient had synchronous bursts of activity also affecting the diaphragm, later diagnosed as pyramidal and extrapyramidal disease. One patient had bursts of activity, and later presented with diffuse myoclonus. Laryngeal EMG therefore seemed to be a more precise way of evaluating patients presenting with a tremulous voice pattern termed spastic dysphonia. Clinical observation and EMG data demonstrated that spastic dysphonia is not a “spastic” disease. We identified patients with tremor (2), pyramidal and extrapyramidal disease (1), and myoclonic disorders (1). The remainder of the patients had clinical and EMG findings consistent with dystonia, a neurologic disorder characterized by abnormal, often action-induced, involuntary movements or uncontrolled spasms. We classify these patients as having “focal laryngeal dystonia” when the disorder occurs in isolation. It may also present as a component of a generalized dystonic syndrome.

Long-term treatment with botulinum toxin type A in cervical dystonia has low immunogenicity by mouse protection assay†

To evaluate the immunogenicity of botulinum toxin type A (BoNTA; BOTOX) in cervical dystonia (CD). Subjects diagnosed with CD for ≥1 year and previously naïve to BoNTs were treated with BoNTA in a prospective, open‐label, multicenter study. Serum samples were analyzed for BoNTA neutralizing antibodies using the Mouse Protection Assay (MPA). Clinical resistance was assessed with a test injection of 20 U BoNTA placed unilaterally into the frontalis (Frontalis Antibody Test; FTAT) or corrugator muscle (Unilateral Brow Injection; UBI). Efficacy was assessed and adverse events were recorded. Of 326 subjects enrolled, 251 (77%) completed the study. Subjects received a median of 9 BoNTA treatments (mean dose per session ranged from 148.4 to 213.0 U over a mean of 2.5 years [range: 3.2 months–4.2 years]). Only 4 of 326 subjects (1.2%) tested positive for antibodies in the MPA; three of these subjects stopped responding clinically to BoNTA (of whom one also showed clinical resistance in the FTAT) and one continued to respond. Consistent improvements in the signs/symptoms of CD were noted. The most frequent treatment‐related adverse events were mild to moderate weakness, dysphagia, neck pain, and injection‐site pain. The current formulation of BoNTA rarely causes neutralizing antibody formation in CD subjects treated ≤4 years.

Meta-analysis of neutralizing antibody conversion with onabotulinumtoxinA (BOTOX®) across multiple indications.

This meta‐analysis evaluated the frequency of neutralizing antibody (nAb) conversion with onabotulinumtoxinA (BOTOX®; Allergan) across five studied indications. The analysis was based on large, controlled or prospective, open‐label trials (durations 4 months to ≥2 years). Serum samples were analyzed for nAbs using the Mouse Protection Assay. Subjects who were antibody negative at baseline and had at least one analyzable postbaseline antibody assay result were included. The 16 clinical studies included 3,006 subjects; of these, 2,240 met the inclusion criteria for this analysis. Subjects received 1–15 treatments (mean 3.8 treatments) with onabotulinumtoxinA. Total doses per treatment cycle ranged from 10 or 20 units in glabellar lines to 20–500 units in cervical dystonia. The numbers of subjects who converted from an antibody‐negative status at baseline to antibody‐positive status at any post‐treatment time point were: cervical dystonia 4/312 (1.28%), glabellar lines 2/718 (0.28%), overactive bladder 0/22 (0%), post‐stroke spasticity 1/317 (0.32%), and primary axillary hyperhidrosis 4/871 (0.46%). Across all indications, 11/2,240 subjects (0.49%) converted from antibody negative at baseline to positive at one or more post‐treatment time points, but only three subjects became clinically unresponsive to onabotulinumtoxinA at some point following a positive assay. Based on these large trials, the frequency of antibody conversion after onabotulinumtoxinA treatment is very low, and infrequently leads to loss of efficacy.