Treatment of adult spasticity with Botox (onabotulinumtoxinA): Development, insights, and impact.

Upper and lower limb spasticity (ULS, LLS) often occur following a stroke or in patients with other neurological disorders, leading to difficulties in mobility and daily living and decreased quality of life. Prior to the use of onabotulinumtoxinA, antispastic medications had limited efficacy and often caused sedation. Phenol injections were difficult for physicians to perform, painful, and led to tissue destruction. The success of onabotulinumtoxinA in treating cervical dystonia led to its use in spasticity. However, many challenges characterized the development of onabotulinumtoxinA for adult spasticity. The wide variability in the presentation of spasticity among patients rendered it difficult to determine which muscles to inject and how to measure improvement. Another challenge was the initial refusal of the Food and Drug Administration to accept the Ashworth Scale as a primary endpoint. Additional scales were designed to incorporate a goal-oriented, patient-centered approach that also accounted for the variability of spasticity presentations. Several randomized, double-blind, placebo-controlled trials of post-stroke spasticity of the elbow, wrist, and/or fingers showed significantly greater improvements in the modified Ashworth Scale and patient treatment goals and led to the approval of onabotulinumtoxinA for the treatment of ULS in adult patients. Lessons learned from the successful ULS trials were applied to design an LLS trial that led to approval for the latter indication. Additional observational trials mimicking real-world treatment have shown continued effectiveness and patient satisfaction. The use of onabotulinumtoxinA for spasticity has ushered in a more patient-centered treatment approach that has vastly improved patients' quality of life.

Treatment of pediatric spasticity, including children with cerebral palsy, with Botox (onabotulinumtoxinA): Development, insights, and impact.

Spasticity is a velocity-dependent increase in muscle tone that has a negative effect on quality of life and hinders the ability of others to provide care. In children, most cases are caused by cerebral palsy. Traditionally, many children are treated with surgery, sometimes performed before their limbs had grown sufficiently to permit long-term success. Nonsurgical treatment comprises oral pharmacological options, but their efficacy is limited and side effects such as drowsiness and decreased short-term memory are common; nerve block procedures can cause painful dysesthesias and muscle scarring. OnabotulinumtoxinA was first approved for the treatment of pediatric lower limb spasticity in Europe in the 1990s and is now licensed for use in pediatric patients in over 80 countries worldwide, based on a large body of clinical evidence demonstrating its efficacy and safety. In 2019 the U.S. Food and Drug Administration approved onabotulinumtoxinA for the treatment of pediatric patients with upper or lower limb spasticity. This approval represents 3 decades of work to refine the dose, measurements, patient selection, and muscle selection. The availability of onabotulinumtoxinA as a treatment for pediatric spasticity can have a substantial impact on a patient's quality of life. The use of onabotulinumtoxinA in combination with orthoses and occupational/physical therapy can postpone corrective surgery until growth is nearly complete and minimize the number of corrective surgeries.

Efficacy and safety of onabotulinumtoxinA with standardized physiotherapy for the treatment of pediatric lower limb spasticity: A randomized, placebo-controlled, phase III clinical trial.

BACKGROUND: Spasticity is common in cerebral palsy and can result in pain and diminished health-related quality of life. OBJECTIVE: To evaluate the safety and efficacy of onabotulinumtoxinA for lower limb spasticity treatment in children with cerebral palsy. METHODS: In this registrational phase 3, multinational, randomized, double-blind, placebo-controlled trial (NCT01603628), children (2-< 17 years) with cerebral palsy and ankle spasticity (Modified Ashworth Scale-Bohannon [MAS] score≥2) were randomized 1 : 1 : 1 to standardized physical therapy and onabotulinumtoxinA (4 or 8 U/kg), or placebo. Primary endpoint was average change from baseline at weeks 4 and 6 in MAS ankle score. Secondary endpoints included the Modified Tardieu Scale (MTS) and Global Attainment Scale (GAS). RESULTS: 381 participants were randomized. MAS scores averaged at weeks 4 and 6 were significantly reduced with both onabotulinumtoxinA doses (8 U/kg: -1.06, p = 0.010; 4 U/kg: -1.01, p = 0.033) versus placebo (-0.8). Significant improvements in average dynamic component of spasticity, measured by MTS, and in function, measured by GAS, were observed at several time points with both onabotulinumtoxinA doses versus placebo. Most adverse events were mild or moderate. CONCLUSIONS: OnabotulinumtoxinA was well tolerated and effective in reducing lower limb spasticity and improving functional outcomes versus placebo in children.

Efficacy and safety of onabotulinumtoxinA with standardized occupational therapy for treatment of pediatric upper limb spasticity: Phase III placebo-controlled randomized trial.

BACKGROUND: This is the first large study of onabotulinumtoxinA as treatment for pediatric upper limb spasticity. OBJECTIVE: Evaluate efficacy and safety of a single treatment with onabotulinumtoxinA plus occupational therapy (OT). METHODS: In this registrational phase III, multinational study (NCT01603602), participants were randomized 1:1:1 to onabotulinumtoxinA 3 U/kg/OT, 6 U/kg/OT, or placebo/OT. Primary endpoint was average change from baseline at weeks 4 and 6 in Modified Ashworth Scale-Bohannon (MAS) score. Secondary endpoints included Modified Tardieu Scale (MTS), Clinical Global Impression of Change (CGI) and functional Goal Attainment Scale (GAS). RESULTS: 235 participants were randomized. At weeks 4 and 6, onabotulinumtoxinA groups had greater mean reductions in MAS (both -1.9; p < 0.001) versus placebo (-1.2). OnabotulinumtoxinA doses improved dynamic tone per MTS. Mean CGI at weeks 4 and 6 was unchanged in the overall population, but improved in a post hoc analysis of patients with a single affected upper limb (UL) muscle group (elbow or wrist). GAS score for passive goals was significantly higher for 6 U/kg versus placebo at week 12. Most AEs were mild/moderate in severity; overall incidence was similar between groups. CONCLUSIONS: OnabotulinumtoxinA (3 and 6 U/kg) was safe and effective in reducing upper limb spasticity in pediatric participants.

Safety and Stability of Pulmonary Function in Patients with Decreased Respiratory Function Treated for Spasticity with OnabotulinumtoxinA.

Two randomized, placebo-controlled studies evaluated the pulmonary function safety of onabotulinumtoxinA (onabotA) for treatment of upper and/or lower limb spasticity. Patients with stable baseline respiratory status received one or two treatments with placebo, 240 U, or 360 U of onabotA. Pulmonary function tests, adverse events, and efficacy were measured at least every 6 weeks for 18 weeks (Study 1) or 30 weeks (Study 2). Study 1 enrolled 109 patients (n = 36-37/group) and Study 2 enrolled 155 patients (n = 48-54/group). Mean baseline forced vital capacity (FVC) was 76-78% of predicted per group in Study 1 and 71% of predicted per group in Study 2. In Study 1, change from baseline FVC values were significantly (p < 0.05) decreased vs. placebo at weeks 3 (240 U -57 mL vs. placebo +110 mL) and 12 (360 U -6 mL vs. +167 mL placebo). In Study 2, change from baseline FVC values were significantly decreased in the 360 U group vs. placebo at weeks 6 (-78 mL vs. +49 mL placebo), 13 (-60 mL vs. +119 mL placebo), 18 (-128 mL vs. +80 mL placebo), and 24 (-82 mL vs. +149 mL placebo). Individual pulmonary function-related adverse events were not correlated with PFT decreases. The most frequent pulmonary-related adverse events were nasopharyngitis (Study 1) and upper respiratory tract infection (Study 2). Ashworth scores were significantly improved at multiple time points in both studies. Injection of onabotA for spasticity in patients with decreased pulmonary function, at single and repeated doses of up to 360 U, was associated with small but statistically significant decreases in FVC or forced expiratory volume 1 s (FEV1) (>12% and 200 mL) that were subclinical and not correlated with any adverse clinical pulmonary events.

Impact of early intervention with onabotulinumtoxinA treatment in adult patients with post-stroke lower limb spasticity: results from the double-blind, placebo-controlled, phase 3 REFLEX study.

The aim of this study in patients with post-stroke lower limb spasticity (PSLLS) was to evaluate the relationship between time of onabotulinumtoxinA treatment relative to stroke and efficacy outcomes. This was a phase 3, international, multicenter, randomized, 12-week, double-blind study, followed by a repeated treatment, open-label extension. Patients were aged 18-85 years with PSLLS (Modified Ashworth Scale [MAS] ≥ 3) of the ankle with the most recent stroke occurring ≥ 3 months before screening. Patients (double-blind phase) were randomized (n = 468) to onabotulinumtoxinA 300-400 U (300 U, mandatory ankle muscles (gastrocnemius, soleus, tibialis posterior); and ≤ 100 U, optional lower limb muscles (flexor digitorum longus, flexor hallucis longus, flexor digitorum brevis, extensor hallucis, and rectus femoris]) or placebo. Primary endpoint: MAS change from baseline (average score of weeks 4 and 6). Secondary endpoints: physician-assessed Clinical Global Impression of Change (CGI) average score of weeks 4 and 6 and physician-assessed Goal Attainment Scale (GAS; active and passive, weeks 8 and 12). When stratified by time since stroke (≤ 24 months, n = 153; > 24 months, n = 315, post hoc), patients treated ≤ 24 months post-stroke experienced greater improvements from baseline versus placebo in MAS (- 0.31 vs - 0.17), CGI (0.49 vs 0.12), and passive GAS scores (week 12, 0.37 vs 0.26). A ≥ - 1-point improvement in active (week 12; p = 0.04) and passive (week 8; p = 0.02) GAS scores versus placebo was achieved by more patients treated ≤ 24 months post-stroke; in patients treated > 24 months post-stroke, improvements were only observed in active scores (week 8; p = 0.04). OnabotulinumtoxinA 300-400 U was well tolerated, with no new safety findings.

Safety of OnabotulinumtoxinA with Concomitant Antithrombotic Therapy in Patients with Muscle Spasticity: A Retrospective Pooled Analysis of Randomized Double-Blind Studies.

BACKGROUND: OnabotulinumtoxinA is approved as a treatment across multiple indications. For the treatment of spasticity, onabotulinumtoxinA is injected directly into affected muscles. Intramuscular injections may result in local bleeding and related complications, especially in patients receiving anticoagulant therapy. Despite anticoagulants being commonly used, there is limited information in the medical literature regarding the safety of intramuscular medications in patients receiving oral anticoagulants. This retrospective analysis included pooled safety data from Allergan-sponsored studies evaluating onabotulinumtoxinA for the treatment of patients with muscle spasticity. OBJECTIVE: The objective of this study was to determine the risk of bleeding complications in patients with post-stroke spasticity receiving antithrombotic therapy and intramuscular onabotulinumtoxinA. METHODS: We conducted a retrospective analysis of pooled safety data from 16 randomized, double-blind, placebo-controlled Allergan-sponsored studies of onabotulinumtoxinA for the treatment of post-stroke upper or lower limb muscle spasticity, including adult patients with at least moderate upper or lower limb spasticity and receiving at least one dose of the study drug. Bleeding-related adverse events starting within 4 weeks of study treatment were assessed. The incidence rates of bleeding complications were compared for patients receiving classes of antithrombotic therapy vs those not receiving antithrombotic therapy and for those receiving onabotulinumtoxinA vs placebo (with or without antithrombotic therapy). RESULTS: Of 1877 patients, 1182 received antithrombotic therapy. The overall incidence of bleeding complications was < 2%. In those receiving any antithrombotic therapy, the incidence of bleeding was 1.0% vs 1.4% (no antithrombotic therapy); after onabotulinumtoxinA, it was 0.9% for those receiving antithrombotic therapy vs 1.4% (no antithrombotic therapy), and for placebo 1.2% vs 1.4%, respectively. Subgroup results were similar. CONCLUSIONS: No apparent increased risk of bleeding complications was observed following administration of onabotulinumtoxinA to patients receiving antithrombotic therapy. Nonetheless, patient education and careful observation of the injection site in patients receiving antithrombotic therapy remains warranted.

Optimal Muscle Selection for OnabotulinumtoxinA Injections in Poststroke Lower-Limb Spasticity: A Randomized Trial.

OBJECTIVE: The aim of the study was to identify optimal muscle selection patterns for onabotulinumtoxinA treatment of poststroke lower-limb spasticity. DESIGN: Adults with poststroke lower-limb spasticity (ankle Modified Ashworth Scale ≥3) were randomized to onabotulinumtoxinA (300 U, mandatory ankle plantar flexors; ≤100 U, optional lower-limb muscles) or placebo. Post hoc analysis assessed the impact of muscle selection patterns on ankle Modified Ashworth Scale and physician-assessed Clinical Global Impression of Change based on change from baseline to average of weeks 4/6 versus placebo. RESULTS: Among 468 patients randomized, onabotulinumtoxinA improved ankle Modified Ashworth Scale (-0.81 vs -0.61, P = 0.01) and Clinical Global Impression of Change (0.86 vs 0.65, P = 0.012) versus placebo. Injection of mandatory muscles alone was not sufficient in improving ankle Modified Ashworth Scale (P = 0.255) or Clinical Global Impression of Change (P = 0.576) versus placebo but was adequate 24 mos or less after stroke (Modified Ashworth Scale, -1.13 vs -0.62, P = 0.019; Clinical Global Impression of Change, 1.24 vs 0.68, P = 0.006). Additional injections into toe muscles (flexor digitorum longus, flexor hallucis longus) improved ankle Modified Ashworth Scale (-0.98 vs -0.52, P = 0.002) and Clinical Global Impression of Change (0.80 vs 0.38, P = 0.023) versus placebo regardless of time since stroke. OnabotulinumtoxinA was well tolerated, with no new safety findings. CONCLUSIONS: Post hoc analyses suggested additional injections of onabotulinumtoxinA into toe flexors improved ankle Modified Ashworth Scale and Clinical Global Impression of Change scores versus mandatory muscles alone overall and with treatment initiation more than 24 mos after stroke.

OnabotulinumtoxinA for the Treatment of Poststroke Distal Lower Limb Spasticity: A Randomized Trial.

BACKGROUND: Poststroke distal lower limb spasticity impairs mobility, limiting activities of daily living and requiring additional caregiver time. OBJECTIVE: To evaluate the efficacy, safety, and sustained benefit of onabotulinumtoxinA in adults with poststroke lower limb spasticity (PSLLS). DESIGN: A multicenter, randomized, double-blind, phase 3, placebo-controlled trial (NCT01575054). SETTING: Sixty study centers across North America, Europe, Russia, the United Kingdom, and South Korea. PATIENTS: Adult patients (18-65 years of age) with PSLLS (Modified Ashworth Scale [MAS] ≥3) of the ankle plantar flexors and the most recent stroke ≥3 months before study enrollment. INTERVENTIONS: During the open-label phase, patients received ≤3 onabotulinumtoxinA treatments (≤400 U) or placebo at approximately 12-week intervals. Treatments were into the ankle plantar flexors (onabotulinumtoxinA 300 U into ankle plantar flexors; ≤100 U, optional lower limb muscles). MAIN OUTCOME MEASUREMENTS: The double-blind primary endpoint was MAS change from baseline (average score at weeks 4 and 6). Secondary measures included physician-assessed Clinical Global Impression of Change (CGI), MAS change from baseline in optional muscles, Goal Attainment Scale (GAS), and pain scale. RESULTS: Of 468 patients enrolled, 450 (96%) completed the double-blind phase and 413 (88%) completed the study. Small improvements in MAS observed with onabotulinumtoxinA during the double-blind phase (onabotulinumtoxinA, -0.8; placebo, -0.6, P = .01) were further enhanced with additional treatments through week 6 of the third open-label treatment cycle (onabotulinumtoxinA/onabotulinumtoxinA, -1.2; placebo/onabotulinumtoxinA, -1.4). Small improvements in CGI observed during the double-blind phase (onabotulinumtoxinA, 0.9; placebo, 0.7, P = .01) were also further enhanced through week 6 of the third open-label treatment cycle (onabotulinumtoxinA/onabotulinumtoxinA, 1.6; placebo/onabotulinumtoxinA, 1.6). Physician- and patient-assessed GAS scores improved with each subsequent treatment. No new safety signals emerged. CONCLUSIONS: OnabotulinumtoxinA significantly improved ankle MAS, CGI, and GAS scores compared with placebo; improvements were consistent and increased with repeated treatments of onabotulinumtoxinA over 1 year in patients with PSLLS. LEVEL OF EVIDENCE: I.

OnabotulinumtoxinA Improves Pain in Patients With Post-Stroke Spasticity: Findings From a Randomized, Double-Blind, Placebo-Controlled Trial.

CONTEXT: Patients with post-stroke spasticity (PSS) commonly experience pain in affected limbs, which may impact quality of life. OBJECTIVES: To assess onabotulinumtoxinA for pain in patients with PSS from the BOTOX(®) Economic Spasticity Trial, a multicenter, randomized, double-blind, placebo-controlled trial. METHODS: Patients with PSS (N = 273) were randomized to 22- to 34-week double-blind treatment with onabotulinumtoxinA + standard care (SC) or placebo injection + SC and were eligible to receive open-label onabotulinumtoxinA up to 52 weeks. Assessments included change from baseline on the 11-point pain numeric rating scale, proportion of patients with baseline pain ≥4 achieving ≥30% and ≥50% improvement in pain, and pain interference with work at Week 12, end of double-blind treatment, and Week 52. RESULTS: At baseline, most patients (74.3%) experienced pain and 47.4% had pain ≥4 (pain subgroup). Mean pain reduction from baseline at Week 12 was significantly greater with onabotulinumtoxinA + SC (-0.77, 95% CI -1.14 to -0.40) than placebo + SC (-0.13, 95% CI -0.51 to 0.24; P < 0.05). Higher proportions of patients in the pain subgroup achieved ≥30% and ≥50% reductions in pain at Week 12 with onabotulinumtoxinA + SC (53.7% and 37.0%, respectively) compared with placebo (28.8% and 18.6%, respectively; P < 0.05). Reductions in pain were sustained through Week 52. Compared with placebo + SC, onabotulinumtoxinA consistently reduced pain interference with work. CONCLUSION: This is the first randomized, placebo-controlled trial demonstrating statistically significant and clinically meaningful reductions in pain and pain interference with work with onabotulinumtoxinA in patients with PSS.

Research designs for proof-of-concept chronic pain clinical trials: IMMPACT recommendations.

Proof-of-concept (POC) clinical trials play an important role in developing novel treatments and determining whether existing treatments may be efficacious in broader populations of patients. The goal of most POC trials is to determine whether a treatment is likely to be efficacious for a given indication and thus whether it is worth investing the financial resources and participant exposure necessary for a confirmatory trial of that intervention. A challenge in designing POC trials is obtaining sufficient information to make this important go/no-go decision in a cost-effective manner. An IMMPACT consensus meeting was convened to discuss design considerations for POC trials in analgesia, with a focus on maximizing power with limited resources and participants. We present general design aspects to consider including patient population, active comparators and placebos, study power, pharmacokinetic-pharmacodynamic relationships, and minimization of missing data. Efficiency of single-dose studies for treatments with rapid onset is discussed. The trade-off between parallel-group and crossover designs with respect to overall sample sizes, trial duration, and applicability is summarized. The advantages and disadvantages of more recent trial designs, including N-of-1 designs, enriched designs, adaptive designs, and sequential parallel comparison designs, are summarized, and recommendations for consideration are provided. More attention to identifying efficient yet powerful designs for POC clinical trials of chronic pain treatments may increase the percentage of truly efficacious pain treatments that are advanced to confirmatory trials while decreasing the percentage of ineffective treatments that continue to be evaluated rather than abandoned.

Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations.

There has been an increase in the number of chronic pain clinical trials in which the treatments being evaluated did not differ significantly from placebo in the primary efficacy analyses despite previous research suggesting that efficacy could be expected. These findings could reflect a true lack of efficacy or methodological and other aspects of these trials that compromise the demonstration of efficacy. There is substantial variability among chronic pain clinical trials with respect to important research design considerations, and identifying and addressing any methodological weaknesses would enhance the likelihood of demonstrating the analgesic effects of new interventions. An IMMPACT consensus meeting was therefore convened to identify the critical research design considerations for confirmatory chronic pain trials and to make recommendations for their conduct. We present recommendations for the major components of confirmatory chronic pain clinical trials, including participant selection, trial phases and duration, treatment groups and dosing regimens, and types of trials. Increased attention to and research on the methodological aspects of confirmatory chronic pain clinical trials has the potential to enhance their assay sensitivity and ultimately provide more meaningful evaluations of treatments for chronic pain.

Analyzing multiple endpoints in clinical trials of pain treatments: IMMPACT recommendations. Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials.

The increasing complexity of randomized clinical trials and the practice of obtaining a wide variety of measurements from study participants have made the consideration of multiple endpoints a critically important issue in the design, analysis, and interpretation of clinical trials. Failure to consider important outcomes can limit the validity and utility of clinical trials; specifying multiple endpoints for the evaluation of treatment efficacy, however, can increase the rate of false positive conclusions about the efficacy of a treatment. We describe the use of multiple endpoints in the design, analysis, and interpretation of pain clinical trials, and review available strategies and methods for addressing multiplicity. To decrease the probability of a Type I error (i.e., the likelihood of obtaining statistically significant results by chance) in pain clinical trials, the use of gatekeeping procedures and other methods that correct for multiple analyses is recommended when a single primary endpoint does not adequately reflect the overall benefits of treatment. We emphasize the importance of specifying in advance the outcomes and clinical decision rule that will serve as the basis for determining that a treatment is efficacious and the methods that will be used to control the overall Type I error rate.

Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations.

UNLABELLED: A consensus meeting was convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) to provide recommendations for interpreting clinical importance of treatment outcomes in clinical trials of the efficacy and effectiveness of chronic pain treatments. A group of 40 participants from universities, governmental agencies, a patient self-help organization, and the pharmaceutical industry considered methodologic issues and research results relevant to determining the clinical importance of changes in the specific outcome measures previously recommended by IMMPACT for 4 core chronic pain outcome domains: (1) Pain intensity, assessed by a 0 to 10 numerical rating scale; (2) physical functioning, assessed by the Multidimensional Pain Inventory and Brief Pain Inventory interference scales; (3) emotional functioning, assessed by the Beck Depression Inventory and Profile of Mood States; and (4) participant ratings of overall improvement, assessed by the Patient Global Impression of Change scale. It is recommended that 2 or more different methods be used to evaluate the clinical importance of improvement or worsening for chronic pain clinical trial outcome measures. Provisional benchmarks for identifying clinically important changes in specific outcome measures that can be used for outcome studies of treatments for chronic pain are proposed. PERSPECTIVE: Systematically collecting and reporting the recommended information needed to evaluate the clinical importance of treatment outcomes of chronic pain clinical trials will allow additional validation of proposed benchmarks and provide more meaningful comparisons of chronic pain treatments.

A series of three sequential, randomized, controlled studies of repeated treatments with botulinum toxin type A for migraine prophylaxis.

UNLABELLED: We examined the effects of multiple treatments with low doses of botulinum toxin type A (BoNTA; BOTOX(R), Allergan Inc., Irvine, CA) versus placebo for prophylaxis of episodic migraine. This was a series of 3 sequential, randomized, controlled studies of 418 patients with a history of 4 to 8 moderate to severe migraines per month. In study I, patients were randomized to treatment with placebo or BoNTA (7.5 U, 25 U, or 50 U) in predetermined fixed injection sites on the front and sides of the head only. In study II, patients continued to receive, or were randomized to, 2 consecutive treatments with 25 U or 50 U. In study III, patients were randomized to placebo or continuation of 25 U or 50 U. Injection cycles were each 4 months long. BoNTA and placebo produced comparable decreases from baseline in the frequency of migraines at each time point examined (P >or= .201). No consistent, statistically significant differences were observed for any efficacy variable. Adverse events were similar among the groups within each study. In these exploratory studies of episodic migraine patients, repeated injections of low doses of BoNTA into fixed frontal, temporal, and glabellar sites were not more effective than placebo. BoNTA was safe and well tolerated. PERSPECTIVE: Beneficial effects of BoNTA in the treatment of migraine have been reported, but positive results are not universal, possibly because the optimal patient population and regimen are not yet definitively established. This study explores the effects of multiple injections of low BoNTA doses into fixed sites for episodic migraine.

Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: The objective of this study was to evaluate the safety and efficacy of botulinum toxin type A (BoNT-A; BOTOX, Allergan, Inc.) for the prophylactic treatment of chronic daily headache (CDH). BACKGROUND: Several open-label and small controlled trials suggest that BoNT-A may be effective in the prophylactic treatment of headache. DESIGN AND METHODS: This was an 11-month, randomized double-blind, placebo-controlled study of BoNT-A for the treatment of patients aged 18 to 65 years old with 16 or more headache days per 30 days conducted at 13 North American study centers. Following a 30-day screening period and a 30-day, single-blind, placebo-response period to identify placebo responders, eligible patients from both the placebo responder and placebo nonresponder groups were injected with BoNT-A or placebo every 90 days and assessed every 30 days for 9 months, a period encompassing three treatment cycles. The primary efficacy measure was the change from baseline in the frequency of headache-free days in a 30-day period for the placebo nonresponder group at day 180, the chosen efficacy time point. The secondary efficacy measure was the proportion of patients with a decrease from baseline of 50% or more in the frequency of headache days per 30-day period for the placebo nonresponder group at day 180. The change from baseline in the frequency of headaches (per 30-day period), the proportion of patients with a decrease from baseline of 50% or greater in the frequency of headaches per 30-day period, acute medication use, and adverse events were also assessed. RESULTS: Of 571 patients assessed over the baseline period, 355 (mean age, 43.5 years; 300/355 [84.5%] female) were enrolled and randomized. At the end of the placebo run-in period, 279 patients (79%) were classified as placebo nonresponders and 76 patients (21%) as placebo responders. Subsequently, patients were randomized within each group to receive either BoNT-A or placebo. In the placebo nonresponder stratum, the mean number of headache-free days at baseline was 5.8 (+/-4.7) for BoNT-A- versus 5.5 (+/-4.7) for placebo-treated patients. At day 180, placebo nonresponders treated with BoNT-A had an improved mean change from baseline of 6.7 headache-free days per 30-day period compared to a mean change from baseline of 5.2 headache-free days for placebo-treated patients. The between-group difference of 1.5 headache-free days favored BoNT-A treatment, although the difference between the groups was not statistically significant. However, a statistically significant difference was observed at day 180 endpoint for the secondary efficacy measure. A significantly higher percentage of BoNT-A patients had a decrease from baseline of 50% or greater in the frequency of headache days per 30-day period at day 180 (32.7% vs. 15.0%, P=.027). Also, the mean change from baseline in the frequency of headaches per 30-day period at day 180 was -6.1 for BoNT-A patients vs. -3.1 for the placebo patients (P=.013). Only 4 of 173 BoNT-A patients (2.3%) discontinued the study due to adverse events. The majority of treatment-related adverse events were transient and mild to moderate in severity. CONCLUSIONS: BoNT-A treatment resulted in patients having, on average, approximately seven more (1 week) headache-free days compared to baseline. Although at the primary time point (day 180) the BoNT-A treatment resulted in a 1.5 between-group difference compared to placebo, this difference was not statistically significant. The treatment met secondary efficacy outcome measures, including the percentage of patients experiencing a 50% or more decrease in the frequency of headache days, in addition to statistically significant reductions in headache frequency. BoNT-A was also well tolerated in patients with CDH.