Bimatoprost 0.03% for the Treatment of Eyebrow Hypotrichosis.

BACKGROUND: Eyebrow loss may have substantial negative functional and social consequences. OBJECTIVE: Evaluate the safety and efficacy of bimatoprost 0.03% in subjects with eyebrow hypotrichosis. METHODS: This multicenter, double-masked study randomized adult females or males with eyebrow hypotrichosis to receive bimatoprost 0.03% twice (BID) or once daily (QD) or vehicle BID for 7 months. Primary endpoint was overall eyebrow fullness at Month 7. Secondary endpoints included eyebrow fullness (mm), darkness (intensity units), and subject satisfaction with treatment. Safety was also assessed. RESULTS: At Month 7, the proportion of subjects with improvement was significantly higher in bimatoprost groups versus vehicle (both, p < .001). Improvements occurred in both bimatoprost groups versus vehicle after Month 1 and continued through follow-up; eyebrow fullness and darkness improved as early as Months 2 and 1, respectively (both, p < .001). Greater satisfaction was reported with bimatoprost versus vehicle at Month 2 and all subsequent time points. Overall, 38.1%, 42.4%, and 35.5% of subjects in the bimatoprost BID, QD, and vehicle groups, respectively, experienced ≥1 treatment-emergent adverse event (TEAE). Most frequent TEAEs were similar across groups. No skin or iris hyperpigmentation or conjunctival hyperemia occurred. CONCLUSION: Bimatoprost 0.03% BID and QD is safe, well tolerated, and effective for eyebrow hypotrichosis.

Dose response with onabotulinumtoxinA for post-stroke spasticity: a pooled data analysis.

Clinical trials demonstrate that onabotulinumtoxinA reduces upper limb post-stroke spasticity, with therapeutic response influenced by injected dose. Individual studies provide limited insight regarding muscle group-specific dose-response relationships. Our objective was to characterize dose-response relationships between onabotulinumtoxinA and muscle tone in specific upper limb muscles. Individual patient data from seven multicenter, randomized, double-blind, placebo-controlled trials were pooled. Of 544 post-stroke patients enrolled, 362 received onabotulinumtoxinA and 182 received placebo, injected into the flexor carpi radialis (FCR), flexor carpi ulnaris (FCU), flexor digitorum superficialis (FDS), flexor digitorum profundus (FDP), and/or biceps brachii (BB). Ashworth Scale score change at week 6 (AshworthCBL) was the primary outcome measure for muscle tone. For a broader analysis of response, AshworthCBL/onabotulinumtoxinA dosage relationships were characterized using three techniques: (1) AshworthCBL plotted as a function of onabotulinumtoxinA dose in Units (U) [dose-response curve]; (2) mean AshworthCBL per onabotulinumtoxinA dose depicting the responses seen with specific dose injection clusters/groups for each specific muscle group; and (3) onabotulinumtoxinA dose estimated to produce a mean 1-point decrease in AshworthCBL as an indicator of clinically meaningful benefit of treatment. Increasing onabotulinumtoxinA doses produced greater AshworthCBLs (muscle tone improvements). The maximal week 6 response (E(max)) model indicated a saturating dose-response relationship, with mean E(max) AshworthCBL values of -1.48, -1.48, -0.63, -0.77, and -0.61 in the FCR, FCU, FDS, FDP, and BB, respectively. OnabotulinumtoxinA doses estimated to produce a mean 1-point decrease in AshworthCBL were: 22.5U, 18.4U, 66.3U, 42.5U in the FCR, FCU, FDS, and FDP, respectively, and not determinable in the BB. These analyses demonstrate a saturating effect of greater muscle tone improvements with increasing onabotulinumtoxinA doses in post-stroke spasticity patients. These findings suggest potentially effective onabotulinumtoxinA doses in selected muscle groups in this study population.

OnabotulinumtoxinA for treatment of chronic migraine: pooled analyses of the 56-week PREEMPT clinical program.

OBJECTIVE: To evaluate safety and efficacy of onabotulinumtoxinA (BOTOX(®) ) as headache prophylaxis in adults with chronic migraine. BACKGROUND: Chronic migraine is a prevalent, disabling, and undertreated neurological disorder. OnabotulinumtoxinA is the only approved prophylactic therapy in this highly disabled patient population. DESIGN AND METHODS: Two phase III, 24-week, double-blind, parallel-group, placebo-controlled studies, followed by a 32-week, open-label, single-treatment, onabotulinumtoxinA phase, were conducted (January 23, 2006 to August 11, 2008). Qualified subjects were randomized (1:1) to injections of onabotulinumtoxinA (155-195 U) or placebo every 12 weeks for 5 cycles (double-blind: 2, open-label: 3). The pooled primary variable was mean change from baseline in frequency of headache days. Secondary variables included proportion of patients with severe Headache Impact Test-6 score (≥ 60) and mean changes from baseline in frequencies of migraine days, moderate/severe headache days, and migraine episodes; cumulative hours of headache on headache days; and acute headache medication intakes. The primary time point was week 24. Assessments for the open-label phase (all patients treated with onabotulinumtoxinA) compared double-blind treatment groups (onabotulinumtoxinA/onabotulinumtoxinA vs placebo/onabotulinumtoxinA) and are summarized to give a descriptive view of consistent study results, with inferences regarding statistical significance only examined for week 56. RESULTS: A total of 1384 patients were randomized to onabotulinumtoxinA (n = 688) or placebo (n = 696) in the double-blind phase; 607 (88.2%) onabotulinumtoxinA/onabotulinumtoxinA and 629 (90.4%) placebo/onabotulinumtoxinA patients continued into the open-label phase. OnabotulinumtoxinA/onabotulinumtoxinA treatment statistically significantly reduced headache-day frequency vs placebo/onabotulinumtoxinA in patients with chronic migraine at week 56 (-11.7 onabotulinumtoxinA/onabotulinumtoxinA, -10.8 placebo/onabotulinumtoxinA; P = .019). Statistically significant reductions also favored onabotulinumtoxinA/onabotulinumtoxinA for several secondary efficacy variables at week 56, including frequencies of migraine days (-11.2 onabotulinumtoxinA/onabotulinumtoxinA, -10.3 placebo/onabotulinumtoxinA; P = .018) and moderate/severe headache days (-10.7 onabotulinumtoxinA/onabotulinumtoxinA, -9.9 placebo/onabotulinumtoxinA; P = .027) and cumulative headache hours on headache days (-169.1 onabotulinumtoxinA/onabotulinumtoxinA, -145.7 placebo/onabotulinumtoxinA; P = .018). After the open-label phase (all treated with onabotulinumtoxinA), statistically significant within-group changes from baseline were observed for all efficacy variables. Most patients (72.6%) completed the open-label phase; few discontinued because of adverse events. No new safety or tolerability issues emerged. CONCLUSIONS: Repeated treatment with ≤ 5 cycles of onabotulinumtoxinA was effective, safe, and well tolerated in adults with chronic migraine.

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. © 2010 Movement Disorder Society.

An evaluation of the safety and efficacy of bimatoprost for eyelash growth in pediatric subjects.

PURPOSE: Evaluate the safety and effectiveness of bimatoprost 0.03% for treatment of eyelash hypotrichosis in a pediatric population. PATIENTS AND METHODS: This multicenter, randomized, double-masked, parallel-group study was conducted at seven sites in the US and Brazil. Subjects with eyelash hypotrichosis caused by chemotherapy or alopecia areata (aged 5-17 years) or healthy adolescents aged 15-17 years were enrolled (N=71). Subjects applied bimatoprost 0.03% or vehicle to upper eyelid margins once nightly for 4 months and were followed for 1 month post-treatment. Eyelash prominence was assessed using the validated 4-grade Global Eyelash Assessment scale with photonumeric guide. Changes in eyelash length, thickness, and darkness were measured by digital image analysis. Safety was assessed by adverse events and ophthalmic observations. RESULTS: Eyelash prominence improved in a significantly greater proportion of subjects treated with bimatoprost compared with vehicle at month 4 (70.8% versus 26.1%; P<0.001). This benefit was sustained at month 5 post-treatment assessment. Digital image analysis measures were significantly improved with bimatoprost. Significant treatment benefits with bimatoprost versus vehicle were evident among the healthy adolescents but not in the postchemotherapy or alopecia areata subgroups. The safety profile of bimatoprost was consistent with previous studies in adults. CONCLUSION: Bimatoprost was safe and well tolerated in pediatric subjects with eyelash hypotrichosis. In this study with limited sample size, subgroup analyses showed that treatment was effective in healthy adolescents with no concurrent contributing medical condition, but not in those with eyelash hypotrichosis due to chemotherapy or alopecia areata.

Bimatoprost 0.03% for the Treatment of Eyelash Hypotrichosis: A Pooled Safety Analysis of Six Randomized, Double-masked Clinical Trials.

OBJECTIVE: Describe the safety profile of bimatoprost 0.03% ophthalmic solution as once-daily topical treatment for idiopathic or chemotherapy-induced eyelash hypotrichosis. DESIGN: Pooled data from six randomized, multicenter, double-masked, parallel-group clinical studies of at least three-months' duration with at least one bimatoprost treatment group. SETTING: Study sites in the United States, Canada, United Kingdom, and Japan from 2007 to 2012. PARTICIPANTS: Adults with eyelash hypotrichosis, defined as baseline Global Eyelash Assessment of minimal or moderate, who received bimatoprost 0.03% (n=680) or vehicle, with no prior exposure to bimatoprost (n=379). MEASUREMENTS: Safety assessments included adverse events, vital sign measurements, and physical examinations. Common (≥2%) and treatment-related adverse events were analyzed at time points up to four months and through end of treatment, up to 12 months. RESULTS: Similar overall adverse events incidence was reported in bimatoprost and vehicle groups for subjects with idiopathic hypotrichosis; a higher incidence in both groups was reported for postchemotherapy subjects. Common adverse events included conjunctival hyperemia, eyelid pruritus, blepharal pigmentation, nasopharyngitis, eyelid erythema, and punctate keratitis. Most adverse events occurred early in treatment, were mild in intensity, localized to treatment site, and reversible with treatment cessation. Discontinuations due to adverse events were low (3.2% for bimatoprost and 2.4% for vehicle). CONCLUSION: Adverse events were consistent with the known pharmacologic mechanism of bimatoprost. The safety profile was similar across the studies and no new safety signals were observed. Once-daily bimatoprost 0.03% for treatment of eyelid hypotrichosis has a favorable safety and tolerability profile when applied topically to the upper eyelid margin.

One-year, randomized study comparing bimatoprost and timolol in glaucoma and ocular hypertension.

OBJECTIVE: To compare bimatoprost with timolol maleate in patients with glaucoma or ocular hypertension. METHODS: In 2 identical, multicenter, randomized, double-masked, 1-year clinical trials, patients were treated with 0.03% bimatoprost once daily (QD) (n = 474), 0.03% bimatoprost twice daily (BID) (n = 483), or 0.5% timolol maleate BID (n = 241). MAIN OUTCOME MEASURES: Diurnal intraocular pressure (IOP) at 8 AM, 10 AM, and 4 PM and safety variables (IOP was also measured at 8 PM at selected sites). RESULTS: Bimatoprost QD provided significantly lower mean IOP than timolol at every time of the day at each study visit (P<.001). This was also true for bimatoprost BID at most time points, but the efficacy was not as good as that of the QD regimen. At 10 AM (peak timolol effect) at month 12, the mean reduction in IOP from baseline was 7.6 mm Hg (30%) with bimatoprost and 5.3 mm Hg (21%) with timolol (P<.001). A significantly higher percentage of patients receiving bimatoprost QD (58%) than timolol (37%) achieved IOPs at or below 17 mm Hg (10 AM, month 12; P<.001). The most common adverse effect with bimatoprost was hyperemia (significantly higher with bimatoprost QD than timolol; P<.001). CONCLUSIONS: Bimatoprost QD provides sustained IOP lowering superior to timolol or bimatoprost BID and achieves low target IOPs in significantly more patients.

24-Hour IOP control with once-daily bimatoprost, timolol gel-forming solution, or latanoprost: a 1-month, randomized, comparative clinical trial.

PURPOSE: To compare the efficacy and safety of once-daily (QD) bimatoprost, latanoprost, and timolol gel-forming solution in providing 24-hour intraocular pressure (IOP) control. DESIGN: This was a randomized, multicenter, investigator-masked, prospective, parallel-group, clinical trial. PARTICIPANTS: Patients with open-angle glaucoma or ocular hypertension. INTERVENTION: After washout of any previous ocular hypotensive medications, patients were randomly assigned to treatment with bimatoprost 0.03% ophthalmic solution QD (n=38) or latanoprost 0.005% ophthalmic solution QD (n=38) between 7 and 9 pm, or timolol maleate 0.5% gel-forming ophthalmic solution QD (n=39) between 7 and 9 am for 1 month. MAIN OUTCOME MEASURES: The primary outcome measure, circadian IOP, was measured at eight time points over the course of 24 hours beginning at 8 am on day 28 and with the last measurement at 8 am on day 29. IOP was also measured at 8 am and 10 am at baseline and at 8 am on day 14. Safety measures included adverse events, biomicroscopy, visual acuity, heart rate, and blood pressure. RESULTS: At 10 am (peak drug effect) on day 28, the mean IOP reduction from baseline was significantly greater with bimatoprost (9.3 mm Hg, 40.3%) than with timolol gel (7.1 mm Hg, 31.1%; P=.024, Wilcoxon rank sum test) or latanoprost (7.4 mm Hg, 33.3%). In the overall analysis of IOP measured over the course of 24 hours, mean IOP was significantly lower with bimatoprost or latanoprost than with timolol gel (P<.001; analysis of repeated measures). The analysis of repeated measures also showed a significant difference between bimatoprost and latanoprost (P=.003). In the area-under-the-curve analysis, bimatoprost and latanoprost were superior to timolol gel (P< or =.018) but comparable to each other (P> or =.223). All treatment regimens were well tolerated, with few discontinuations due to adverse events. There were no significant effects on systemic safety parameters. CONCLUSION: Once-daily bimatoprost or latanoprost provided significantly better 24-hour IOP control than timolol gel in patients with glaucoma or ocular hypertension. Some measurements suggested a trend for greater efficacy of bimatoprost over latanoprost. All three treatments were well tolerated.

Two-year double-masked comparison of bimatoprost with timolol in patients with glaucoma or ocular hypertension.

The object of this study was to compare the long term efficacy and safety of bimatoprost with timolol in patients with glaucoma or ocular hypertension. In a 12-month extension of two identically designed 1-year, multicenter, randomized, double-masked clinical trials, patients were treated topically with bimatoprost 0.03% QD (n=167), bimatoprost 0.03% BID (n=131), or timolol 0.5% BID (n=81). Main outcome measures were IOP at 8 am and 10 am and safety parameters. Bimatoprost QD provided significantly greater mean reduction from baseline IOP than did timolol at both measurements at each study visit (P< or =.001). At 10 am (peak timolol effect) at month 24, the mean reduction from baseline IOP was 7.8 mm Hg with bimatoprost QD and 4.6 mm Hg with timolol (P<.001). Patients treated with bimatoprost QD also sustained significantly lower mean IOP than timolol-treated patients at every follow-up visit throughout the 2-year study period (P< or =.006). At 10 am at month 24, a significantly greater proportion of bimatoprost QD than timolol patients achieved target pressures of < or =13-18 mm Hg (P< or =.010). Bimatoprost sustained an excellent safety profile during the second year of treatment. Most adverse events were mild, and there were no reports of increased iris pigmentation, uveitis, or CME. The incidence of hyperemia was significantly higher with bimatoprost QD (13.8%) than with timolol (2.5%) (P=.006). Mean reduction from baseline IOP with bimatoprost BID was not significantly different from that with timolol at month 24 at 10 am (P=.474). We conclude that bimatoprost QD provides superior IOP lowering to timolol, and is safe and well tolerated over 24 months of treatment.

Safety and efficacy of ketorolac tromethamine 0.4% ophthalmic solution in post-photorefractive keratectomy patients.

PURPOSE: To evaluate the safety and analgesic efficacy of ketorolac tromethamine 0.4% ophthalmic solution in postoperative photorefractive keratectomy (PRK) patients. SETTING: Fifteen clinical sites in the eastern and southern United States. METHODS: This pooled analysis of 2 multicenter, randomized, double-masked, vehicle-controlled, parallel-group studies comprised 313 patients having unilateral PRK. After surgery, patients were treated with 1 drop of ketorolac tromethamine 0.4% ophthalmic solution (Acular(R) LS) (n = 156) or vehicle (n = 157) 4 times daily for up to 4 days. Pain intensity, pain relief, use of escape medication, and severity of ocular symptoms were assessed. Adverse events, epithelial healing, and visual acuity were recorded. RESULTS: There was significantly less pain intensity experienced by patients in the ketorolac group (P<.001). During the first 12 hours post PRK, 50% fewer patients in the ketorolac group than in the vehicle group had severe to intolerable pain (41.6% [64/154] and 84.5% [131/155], respectively). The median time to no pain was 30 hours in the ketorolac group and 54 hours in the vehicle group (P<.001, survival analysis). Ketorolac patients reported significantly greater pain relief than vehicle patients throughout the study (P<.001). Ketorolac patients used significantly less escape medication than vehicle patients for 48 hours post PRK (P< or =.008). Treatment-related adverse events occurred in 2.6% (4/156) of ketorolac patients and 6.4% (10/157) of vehicle patients. CONCLUSION: Ketorolac 0.4% ophthalmic solution is safe and effective in reducing ocular pain when used 4 times daily for up to 4 days post PRK.

Relationship between disability and health-related quality of life and caregiver burden in patients with upper limb poststroke spasticity.

OBJECTIVE: To evaluate the relationship between disability and both health-related quality of life (HRQoL) and caregiver burden in patients with upper limb poststroke spasticity. DESIGN: Multicenter open-label study. SETTING: Thirty-five sites in North America. PARTICIPANTS: Patients (N = 279) with upper limb poststroke spasticity. METHODS: Post hoc analyses of data from an open-label study were performed to estimate HRQoL and caregiver burden at study baseline across levels of disability in 4 problem domains: hygiene, dressing, limb posture, and pain. Disability severity in these areas was determined by using the 4-point Disability Assessment Scale rated by the physicians. MAIN OUTCOME MEASUREMENTS: HRQoL measured by the patient-reported EuroQol 5 Dimensions questionnaire and the Stroke-Adapted Sickness Impact Profile and caregiver burden. RESULTS: At study baseline, increasing disability in the hygiene, dressing, and pain domains of the Disability Assessment Scale was associated with diminishing HRQoL scores (P < .002) measured by the EuroQol 5 Dimensions. By using the Stroke-Adapted Sickness Impact Profile, greater disability scores in all problem domains were significantly associated with higher overall dysfunction scores (P ≤ .05). Within the physical dimension of the Stroke-Adapted Sickness Impact Profile, significant associations also were observed in all domains. At baseline, caregiver burden was significantly related to increasing levels of hygiene and dressing domain severity (P ≤ .05). Caregiver assistance requirement increased from approximately 9.0-28.2 hours per week in the hygiene domain and 3.3-32.1 hours per week in the dressing domain as disability increased from "none" to "severe." CONCLUSIONS: In patients with upper limb poststroke spasticity, increasing disability in the hygiene, dressing, and pain domains of the Disability Assessment Scale were associated with diminishing HRQoL. Furthermore, these patients required caregiver assistance proportionally related to the severity of their disability in the hygiene and dressing domains.

Long-term safety evaluation of bimatoprost ophthalmic solution 0.03%: a pooled analysis of six double-masked, randomized, active-controlled clinical trials.

BACKGROUND: Bimatoprost ophthalmic solution 0.03% was approved in the US for reducing intraoccular pressure (IOP) based on two double-masked, active-controlled clinical trials. Four additional long-term studies (≥12 months) were conducted; however, the aggregate safety profile of the six studies has not been reported. METHODS: Adverse events (AEs) were pooled from six double-masked, active-controlled, long-term clinical trials in which subjects received bimatoprost 0.03% once daily (QD) or twice daily (BID) as an eyedrop. AE terms were converted to MedDRA (V.11.0) Preferred Terms and analyzed. RESULTS: In total, 1409 patients received more than one dose of bimatoprost 0.03% QD or BID. Most AEs were mild in severity and reported by 86.7% (QD) and 94.8% (BID) of subjects (≤12 months of treatment). AEs reported through month 12 (aggregate incidence of ≥5%) were conjunctival hyperemia, increased eyelash growth, eye pruritus, periocular skin hyperpigmentation, eye irritation, dry eye, and hypertrichosis. AE onset was generally reported within four months of treatment. The cumulative incidence of common AEs in the QD treatment group at 24-48 months was similar to that measured at 12 months of treatment. CONCLUSION: Bimatoprost 0.03% has a favorable safety and tolerability profile as characterized by six long-term studies. Common AEs were due to the known pharmacological activity of bimatoprost and reversible with treatment cessation.

A double-blind, randomized, placebo-controlled comparison of botulinum toxin type a injection sites and doses in the prevention of episodic migraine.

BACKGROUND: Several randomized, controlled studies have reported benefits of botulinum toxin type A (BoNTA; Allergan Inc., Irvine, CA, USA) over placebo in the treatment of migraine. Some studies reported significant benefits at dosages as low as 16 U, while other studies reported safety, tolerability, and efficacy at dosages up to 260 U. However, the optimal treatment paradigm and patient population have yet to be defined. OBJECTIVE: To compare different injection sites and doses of BoNTA in the prevention of episodic migraine. DESIGN AND METHODS: This was a randomized, double-blind, placebo-controlled study of 232 patients with a history of four to eight moderate to severe migraines per month, with or without aura. Patients were randomized to placebo or one of four BoNTA groups that received injections into different muscle regions: frontal (10 U), temporal (6 U), glabellar (9 U), or all three areas (total dose 25 U). For 3 months following a single treatment, patients recorded migraine-related variables in a daily diary. RESULTS: BoNTA and placebo produced comparable decreases from baseline in the frequency of migraines (P > or = 0.411). In general, no statistically significant differences were observed for any efficacy variable. The overall rates of adverse events (any type) or treatment-related adverse events were similar among the groups. CONCLUSIONS: In this exploratory study of episodic migraine patients, low-dose injections of BoNTA into the frontal, temporal, and/or glabellar muscle regions were not more effective than placebo. BoNTA was safe and well tolerated. Future studies may examine higher BoNTA doses, flexible injection sites, multiple treatments, and disallow concomitant prophylactic medications.

Botulinum toxin type a prophylactic treatment of episodic migraine: a randomized, double-blind, placebo-controlled exploratory study.

OBJECTIVE: This exploratory trial evaluated the safety and efficacy of multiple treatments of botulinum toxin type A (BoNTA; BOTOX, Allergan, Inc., Irvine, CA, USA) as prophylactic treatment of episodic migraine headaches. DESIGN AND METHODS: This was an 11-month randomized, double-blind, placebo-controlled, exploratory study. Patients were screened during a 30-day baseline period, and eligible patients with 4 or more migraine episodes and < or =15 headache days entered a single-blind 30-day placebo run-in period. Patients were classified as placebo nonresponders (PNR) if they had at least 4 moderate-to-severe migraine episodes and did not experience at least a 50% decrease from baseline in the frequency of migraine episodes following their placebo treatment. All other subjects were classified as placebo responders (PR). Patients were randomized within each stratum (PNR, PR) to 3 treatments with BoNTA (110 to 260 U of BoNTA per treatment cycle) or placebo at 90-day intervals using a modified follow-the-pain treatment paradigm. The primary efficacy outcome measure was the mean change from baseline in the frequency of migraine episodes for the 30 days prior to day 180 in the PNR group. Secondary efficacy measures included the proportion of patients with a decrease from baseline of 50% or more migraine episodes per 30-day period. Patients were allowed to take concomitant acute and prophylactic headache medications. Adverse events were reported. RESULTS: A total of 809 patients were screened and 369 patients (89.2% female; mean age, 45 years; range, 20 to 65 years) entered the placebo run-in period and were subsequently randomized to BoNTA or placebo. The mean total dose of BoNTA was 190.5 units (U) (range, 110 U to 260 U). The predetermined primary efficacy endpoint was not met. Substantial mean improvements of 2.4 and 2.2 fewer migraine episodes per month at day 180 in the PNR stratum treated with BoNTA and placebo, respectively, were observed (P > .999). From day 180 through the end of the study (day 270) at least 50% of all patients in each treatment group had a decrease from baseline of 50% or more migraine episodes per 30-day period. However, in the group of patients with > or =12 headache days at baseline (and < or =15 headache days), BoNTA patients experienced a mean change from baseline of -4.0 headache episodes at day 180 compared with -1.9 headache episodes in the placebo group (P= .048). The majority of treatment-related adverse events were transient and mild to moderate in severity. Only 7 patients (1.9%) discontinued the study due to adverse events (6 BoNTA, 1 placebo). CONCLUSION: There were no statistically significant between-group differences in the mean change from baseline in the frequency of migraine episodes per 30-day period. There were substantial, sustained improvements during the course of the study in all groups. Multiple treatments with BoNTA were shown to be safe and well tolerated over an active treatment period lasting 9 months.