Cumulative Hours Of Headache Research Articles

Stopping Onabotulinum Treatment after the First Two Cycles Might Not Be Justified: Results of a Real-life Monocentric Prospective Study in Chronic Migraine.

Onabotulinum toxin A (OnabotA) cyclic treatment is approved for the prophylactic treatment of chronic migraine (CM), a highly disabling disorder. Although treatment response varies among patients, current guidelines suggest to stop treatment after cycle 2 if no response is achieved. This prospective study aimed to define, in real-life setting, the evolution of the response to OnabotA over five cycles of treatment among patients non-responding to cycle 1. The results of this study might help in decision-making, in particular whether prosecuting OnabotA further or not, when facing a patient not responding to cycle 1. Patients failing to respond at cycle 1 were recruited to complete five cycles. Key outcomes were: (i) a ≥50% reduction in headache days, (ii) a ≥50% reduction in total cumulative hours of headache on headache days and (iii) a ≥5-point improvement in Headache Impact Test-6 (HIT-6) scores. Overall, 56 patients were included. Mean age was 45.7 years (female 83.9%). Severe (≥60) HIT-6 score was reported at baseline by 95.8% of patients. Responders (headache days reduction of more than 50%) progressively increased cycle after cycle, doubling from cycle 2 to cycle 5 (from 27 to 48%). In addition, patients regressed from CM to episodic migraine moving on with each cycle, with 78% of them reaching less than nine migraine days/month after cycle 5. The headache days per month decreased significantly from cycle 1 to cycle 5 (overall from 23.3 ± 5.7 to 9.2 ± 3.6; p < 0.001). During 12 months (5 cycles), migraine days per month progressively abated (from 18.5 to 8.7; p < 0.001), days with symptomatic medications intake/month consistently decreased (from 17.4 to 8.1; p < 0.001), and mean HIT-6 score lowered (from 72.4 ± 5.7 to 50.2 ± 4.3; p < 0.001). The positive effect of OnabotA treatment spreads over the course of the treatment and might also manifest late in treatment course among patients with no benefit after the first two cycles. Thus, the results of this real-life study suggest to extend OnabotA treatment further, beyond cycle 2, to avoid premature withdrawal in patients who would have become responders at cycle 3, 4, or 5.

86. Onabotulinumtoxin-A treatment in chronic migraine with medication overuse: A two years Italian experience

Onabotulinumtoxin-A (BT-A) is an authorised prophylactic therapy in chronic migraine (CM). Its efficacy has been proved by both clinical trials and observational studies. Few data are still available on the efficacy of BT-A injection and the most adequate treatment interval after the first year of follow-up. This study aimed to verifyefficacy, safety and the most adequate timing of BT-A injections in CM patients during the second year of treatment. we evaluated 20 CM patients with medication overuse MO (17 females and 3 males) treated with BT-A for 24 months. After the fourth treatment, we decided to retreat responder patients based on their clinical result. Main efficacy variables were registered at each visit, including days of headache/migraine, total cumulative headache hours, MIDAS and HIT-6 scores, together with symptomatic drugs intake. All variables at week 24 maintained the improvement evidenced at week 12. Adverse events were rare and did not require treatment discontinuation. Most of the patients (n = 13) continued to perform trimestral injections, 5 patients every 4 months and 2 patients every 6 months. BT-A in CM patients is effective even after two years of treatment when administered with an individualised interval according to the clinical outcome.

Refractory chronic migraine: is drug withdrawal necessary before starting a therapy with onabotulinum toxin type A?

Onabotulinum toxin A (BT-A) is now one of the authorized prophylaxis treatments for chronic migraine (CM) thanks to previous clinical trials, which usually required a pharmacologic washout as a precondition for demonstrating its efficacy. Aim of our study was to assess the efficacy in daily clinical practice of BT-A injections in refractory CM patients, regardless of medication overuse without any standardized withdrawal protocol and without stopping the ongoing prophylaxis treatment as well. We treated 44 refractory CM patients (37 females and 7 males) trimonthly without any modification in symptomatic, or prophylactic drug therapy. Main efficacy variables included number of headache, or migraine days and episodes, total cumulative headache hours, MIDAS and HIT-6 scores; all items were assessed at baseline and at the 12-, 24-, and 36-week follow-up. All variables showed a statistically significant improvement at week 36. In general, more than 50% of patients had a good clinical outcome (including all improved patients, either partial or full responder) and that the percentage of drug abuser patients significantly decreased from 75 to 50%, thanks to a spontaneous reduction of the symptomatic drug intake. Adverse events were uncommon and did not require treatment discontinuation. Onabotulinum toxin A treatment in refractory CM patients with unsatisfactory prophylactic drug treatments and pharmacological abuse is effective in improving clinical outcome and quality of life. This result may be achieved through a flexible pharmacologic approach tailored to each patient's needs; moreover, the patient himself can be often expected to reduce drug consumption spontaneously.

44. Onabotulinumtoxin-a treatment in chronic migraine: A long-term prospective open label study

A large multicentre clinical trial (PREEMPT) demonstrated the efficacy and safety of onabotulinumtoxin A for prophylactic treatment of chronic migraine (CM) in prophylactic drug-free patients. This study aimed to verify the efficacy of repetitive injections of onabotulinumtoxin A in CM patients with ineffective chronic poly-therapy. Patients and methods: we studied 45 CM patients (36 females and 9 males) taking multiple prophylactic/symptomatic medications who were treated with onabotulinumtoxin-A for a follow up period of 9 months. The overall dose ranged between 155 and 180 U administered in 31–36 sites following PREEMPT protocol, repeated at 12 weeks intervals. The main evaluated variables to establish drug efficacy included number of headache/migraine days and episodes, total cumulative headache hours, MIDAS and HIT-6 scores; all items were assessed at baseline and after 12–24–36 weeks during follow-up. Results: all variables showed statistically significant changes after 36-weeks time-point. We observed a responder rate (partially responder plus completely responder patients) of about 40% after the first treatment; the rate reached 90% after the third treatment. Adverse events were uncommon and did not require treatment discontinuation. Conclusions: repeated treatments with onabotulinumtoxin A in CM patients with unsatisfactory prophylactic drug treatments, was very effective in improving all variables examined, determining a measurable positive impact on quality of life.

Per cent of patients with chronic migraine who responded per onabotulinumtoxinA treatment cycle: PREEMPT

ObjectiveThe approved use of onabotulinumtoxinA for prophylaxis of headaches in patients with chronic migraine (CM) involves treatment every 12 weeks. It is currently unknown whether patients who fail to respond...

88. Onabotulinumtoxin-A improves chronic migraine: An open label, single-center, post-marketing prospective study

Data from large multicenter clinical trials (PREEMPT) demonstrated efficacy and safety of onabotulinumtoxin A for prophylactic treatment of chronic migraine (CM), prophylactic drug-free patients. This study aimed to confirm the efficacy of onabotulinumtoxin A in CM patients with unsatisfactory chronic polytherapy. 26 CM patients (18 females) taking multiple prophylactic/symptomatic medications entered the study. The overall dose ranged between 155 and 170 U administered in 31–34 sites following PREEMPT protocol, repeated at 12 weeks intervals. Main efficacy variables included number of headache/migraine days and episodes, total cumulative headache hours, MIDAS and HIT-6 scores; all items were assessed at baseline and at the 12th-week and 24th-week follow-up. The following variables showed statistically significant changes at 12th-week time-point: headache/migraine days, moderate/severe headache days, migraine episodes, total cumulative hours of headache; slight, not significant MIDAS and HIT-6 scores’ improvement was observed. All the efficacy indicators further improved at the 24-week follow-up, even though only headache days and >4 h episodes number were significant. Adverse event were uncommon and did not require treatment discontinuation. Treatment with onabotulinumtoxin A reduced frequency and duration of headache, as well as need for drug consumption and was well tolerated in most cases.

Validation of the Headache Impact Test (HIT-6) in patients with chronic migraine.

BackgroundThe Headache Impact Test (HIT)-6 was developed and has been validated in patients with various types of headache. The objective of this study was to report the psychometric properties of the HIT-6 among patients with chronic migraine.MethodsData came from two international, multicenter, randomized, double-blind, placebo-controlled clinical trials of chronic migraine patients (N = 1,384) undergoing prophylaxis therapy. Confirmatory factor analysis and differential item functioning (DIF) analysis were used to test the latent structure and cross-cultural comparability of the HIT-6. Reliability, construct validity, and responsiveness were assessed. Two sets of criterion groups were used: (1) 28-day headache frequency: <10, 10–14, and ≥15 days; (2) sample quartiles of the total cumulative hours of headache: <140, 140 to <280, 280 to <420, and ≥420 hours. Two sets of responsiveness categories were defined as reduction of <30%, 30% to <50%, or ≥50% in (1) number of headache days and (2) cumulative hours of headache.ResultsMeasurement invariance tests supported the stability of the HIT-6 latent structure across studies. DIF analysis supported cross-cultural comparability. Good reliability was observed across studies (Cronbach’s α: 0.75–0.92; intraclass correlation coefficient: 0.76–0.80). HIT-6 scores correlated strongly (−0.86 to −0.59) with scores of the Migraine-Specific Quality-of-Life Questionnaire. Analysis of variance indicated that HIT-6 scores discriminated across both types of criterion groups (P<0.001), across studies and time points. HIT-6 change scores were significantly higher in magnitude in groups experiencing greater improvement (P<0.001).ConclusionAll measurement properties were consistently verified across the two studies, supporting the validity of the HIT-6 among chronic migraine patients.Trial registrationNCT00156910 and NCT00168428 on www.ClinicalTrials.gov.

OnabotulinumtoxinA for chronic migraine: efficacy, safety, and tolerability in patients who received all five treatment cycles in the PREEMPT clinical program

ObjectiveChronic migraine (CM) is a prevalent and disabling neurological disorder. Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program assessed efficacy and safety of onabotulinumtoxinA (BOTOX®) for prophylaxis of headaches in adults with CM. This secondary analysis assessed patients who received all five treatment cycles and completed the study.Materials and methodsPREEMPT (two phase III studies: 24-week double-blind, placebo-controlled [DBPC], parallel-group phase, followed by 32-week open-label [OL] phase) evaluated the efficacy and safety of onabotulinumtoxinA in CM (≥15 days/month with headache lasting ≥4 h a day). Patients were randomized (1:1) to onabotulinumtoxinA or placebo every 12 weeks for two cycles, followed by onabotulinumtoxinA for three cycles. Multiple headache symptom measures were evaluated. Results for the completer (five cycles) subgroup of patients are reported.ResultsOf 1384 total PREEMPT patients, 1005 received all five treatment cycles (513 received onabotulinumtoxinA only [onabotulinumtoxinA/onabotulinumtoxinA (O/O)] and 492 received two cycles of placebo then three cycles of onabotulinumtoxinA [placebo/onabotulinumtoxinA (P/O)]). Demographics were similar between treatment groups. At Week 56, after all patients were treated with onabotulinumtoxinA, there continued to be significant between-group differences favoring the O/O vs P/O group for the following headache symptom measures: LS mean change from baseline in frequencies of headache days (−12.0 O/O, −11.1 P/O; P = 0.035), migraine days (−11.6 O/O, −10.7 P/O; P = 0.038), and moderate/severe headache days (−11.0 O/O, −10.1 P/O; P = 0.042). For other measures (cumulative hours of headache on headache days, frequency of headache episodes, and percentage with severe Headache Impact Test (HIT)-6 score, and total HIT-6 and Migraine-Specific Quality of Life Questionnaire scores), there were also large mean improvements from baseline. The percent of patients with a ≥50% reduction from baseline in frequency of headache days was significantly greater for the onabotulinumtoxinA-only group at Week 56 (69.6% O/O, 62.8% P/O; P = 0.023). The treatment-related adverse event rate was 28.5% for onabotulinumtoxinA vs 12.4% for placebo in the DBPC phase and 34.8% for patients treated with onabotulinumtoxinA for all five cycles throughout the 56-week trials.ConclusionsThis subgroup analysis demonstrated improvements with onabotulinumtoxinA treatment (five cycles) vs placebo (two cycles)/onabotulinumtoxinA (three cycles) for multiple headache symptom measures and suggests that at Week 56, patients treated earlier with onabotulinumtoxinA had better outcomes. These findings demonstrate the continued need and cumulative benefit over time with continued prophylaxis, an important and clinically pragmatic observation for clinicians and patients.

OnabotulinumtoxinA for treatment of chronic migraine: PREEMPT 24-week pooled subgroup analysis of patients who had acute headache medication overuse at baseline

Acute headache medication overuse (MO) is common in patients with chronic migraine (CM). We evaluated safety and efficacy of onabotulinumtoxinA as preventive treatment of headache in CM patients with baseline MO (CM+MO) in a planned secondary analysis from two similarly designed, randomized, placebo-controlled, parallel, Phase III trials. Patients were randomized to treatment groups (155–195U of onabotulinumtoxinA or placebo) using MO (patient-reported and diary-captured frequency of intake) as a stratifying variable. Of 1384 patients, 65.3% (n=904) met MO criteria (onabotulinumtoxinA: n=445, placebo: n=459). For the CM+MO subgroup at Week 24, statistically significant between-treatment group mean changes from baseline favoring onabotulinumtoxinA versus placebo were observed for headache days (primary endpoint: −8.2 vs. −6.2; p<0.001) and other secondary endpoints: frequencies of migraine days (p<0.001), moderate/severe headache days (p<0.001), cumulative headache hours on headache days (p<0.001), headache episodes (p=0.028), and migraine episodes (p=0.018) and the percentage of patients with severe Headache Impact Test-6 category (p<0.001). At Week 24, change from baseline in frequency of acute headache medication intakes (secondary endpoint) was not statistically significant (p=0.210) between groups, except for triptan intakes (p<0.001), where the onabotulinumtoxinA-treated group was favored. OnabotulinumtoxinA was effective and well tolerated as headache prophylaxis in CM+MO patients.

The percent of chronic migraine patients who responded to onabotulinumtoxinA treatment per treatment cycle in the PREEMPT clinical program

Results Pooled analyses demonstrated high responder rates among onabotulinumtoxinA-treated patients (n=688) after Treatment Cycle 1 in frequency of headache days (49.3% of patients), moderate/severe headache days (53.0%), and cumulative hours of headache on headache days (54.2%) and a 21;5-point improvement in HIT-6 (56.3%). After Treatment Cycle 2, an additional 11.314.5% of patients who did not respond to Treatment Cycle 1 became responders. With a third treatment, an additional 7.4-10.3% of patients became responders.

The psychometric properties of the Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ) in chronic migraine patients.

ObjectiveThe Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ) has been shown to have good psychometric performance in measuring headache impact in migraine patients, but its properties specifically in chronic migraine (CM) patients are unknown. The objective of this study was to evaluate the psychometric properties of the MSQ in a group of CM patients undergoing prophylactic treatment.MethodsMeasurement properties of the MSQ were examined using two international, multicenter, randomized clinical trials evaluating onabotulinumtoxinA as headache prophylaxis in CM patients (N = 1,376). Confirmatory factor analysis (CFA) was used to test the latent structure of the MSQ in CM patients. The reliability, convergent and discriminant validity, and responsiveness of the MSQ were assessed.ResultsCFA confirmed the currently proposed three-factor MSQ latent structure across the two studies. Good reliability was observed for all three MSQ scales, across studies and time points. MSQ scale scores strongly correlated with the scores of the Headache Impact Test-6 (HIT-6). Analysis of known-groups validity indicated that MSQ scale scores discriminated between groups of patients differing in their 28-day headache frequency were as follows <10, 10–14, and ≥15 days, and the sample-derived quartiles of the total cumulative hours of headache were as follows <140, 140 to <280, 280 to <420, and ≥420 h (p < 0.0001), across both studies and time points. MSQ change scores were higher in magnitude in groups experiencing greater decline in headache frequency (p < 0.001).ConclusionThe MSQ is a psychometrically valid tool that can be used to reliably measure the impact of migraine among CM patients.

OnabotulinumtoxinA (BOTOX®)

This article reviews the pharmacology, therapeutic efficacy and tolerability profile of intramuscularly injected onabotulinumtoxinA (onaBoNTA; BOTOX®) for headache prophylaxis in adults with chronic migraine, with a focus on UK labelling for the drug. The pharmacological actions of onaBoNTA include a direct antinociceptive (analgesic) effect; while not fully understood, the mechanism of action underlying its headache prophylaxis effect in chronic migraine is presumed to involve inhibition of peripheral and central sensitization in trigeminovascular neurones. Pooled findings from two large phase III studies of virtually identical design (PREEMPT [Phase III REsearch Evaluating Migraine Prophylaxis Therapy] 1 and 2) showed that treatment with up to five cycles of onaBoNTA (155-195 units/cycle) at 12-week intervals was effective in reducing headache symptoms, decreasing headache-related disability, and improving health-related quality of life (HR-QOL) in patients with chronic migraine, approximately two-thirds of whom were overusing acute headache medications at baseline. During the double-blind phase of both trials, significantly more patients treated with onaBoNTA (two cycles) than placebo experienced clinically meaningful improvements in the monthly frequencies of headache days, moderate to severe headache days and migraine days, and in the cumulative hours of headache on headache days/month. OnaBoNTA therapy also resulted in statistically significant and clinically meaningful improvements in functioning and HR-QOL compared with placebo. Notably, improvements in headache symptoms, functioning and HR-QOL favouring onaBoNTA over placebo were seen regardless of whether or not patients were medication overusers and irrespective of whether or not they were naive to (oral) prophylactic therapy. Further improvements relative to baseline in headache symptoms, functioning and HR-QOL were observed during the open-label extension phase of both trials (all patients received three cycles of onaBoNTA). Treatment with up to five cycles of onaBoNTA was generally well tolerated in the PREEMPT trials. Treatment-related adverse events reported by onaBoNTA recipients (e.g. neck pain, facial paresis and eyelid ptosis) were consistent with the well established tolerability profile of the neurotoxin when injected into head and neck muscles; no new safety events were observed. Debate surrounding the PREEMPT studies has centred on the small treatment effect of onaBoNTA relative to placebo, the possibility that blinding was inadequate and the relevance of the evaluated population. Nonetheless, the totality of the data showed that onaBoNTA therapy produced clinically meaningful improvements in headache symptoms, functioning and HR-QOL; on the basis of these trials, it has become the first (and so far only) headache prophylactic therapy to be specifically approved for chronic migraine in the UK and US. Overall, onaBoNTA offers a beneficial, acceptably tolerated and potentially convenient option for the management of this highly disabling condition, for example in patients who are refractory to oral medications used for prophylaxis.

OnabotulinumtoxinA for Treatment of Chronic Migraine: Pooled Analyses of the 56‐Week PREEMPT Clinical Program

To evaluate safety and efficacy of onabotulinumtoxinA (BOTOX(®) ) as headache prophylaxis in adults with chronic migraine. Chronic migraine is a prevalent, disabling, and undertreated neurological disorder. OnabotulinumtoxinA is the only approved prophylactic therapy in this highly disabled patient population. 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. 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. Repeated treatment with ≤ 5 cycles of onabotulinumtoxinA was effective, safe, and well tolerated in adults with chronic migraine.

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

To assess the efficacy, safety, and tolerability of onabotulinumtoxinA (BOTOX) as headache prophylaxis in adults with chronic migraine. Chronic migraine is a prevalent, disabling, and undertreated neurological disorder. Few preventive treatments have been investigated and none is specifically indicated for chronic migraine. The 2 multicenter, pivotal trials in the PREEMPT: Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy clinical program each included a 24-week randomized, double-blind phase followed by a 32-week open-label phase (ClinicalTrials.gov identifiers NCT00156910, NCT00168428). Qualified patients were randomized (1:1) to onabotulinumtoxinA (155-195 U) or placebo injections every 12 weeks. Study visits occurred every 4 weeks. These studies were identical in design (eg, inclusion/exclusion criteria, randomization, visits, double-blind phase, open-label phase, safety assessments, treatment), with the only exception being the designation of the primary and secondary endpoints. Therefore, the predefined pooling of the results was justified and performed to provide a complete overview of between-group differences in efficacy, safety, and tolerability that may not have been evident in individual studies. The primary endpoint for the pooled analysis was mean change from baseline in frequency of headache days at 24 weeks. Secondary endpoints were mean change from baseline to week 24 in frequency of migraine/probable migraine days, frequency of moderate/severe headache days, total cumulative hours of headache on headache days, frequency of headache episodes, frequency of migraine/probable migraine episodes, frequency of acute headache pain medication intakes, and the proportion of patients with severe (> or =60) Headache Impact Test-6 score at week 24. Results of the pooled analyses of the 2 PREEMPT double-blind phases are presented. A total of 1384 adults were randomized to onabotulinumtoxinA (n = 688) or placebo (n = 696). Pooled analyses demonstrated a large mean decrease from baseline in frequency of headache days, with statistically significant between-group differences favoring onabotulinumtoxinA over placebo at week 24 (-8.4 vs -6.6; P < .001) and at all other time points. Significant differences favoring onabotulinumtoxinA were also observed for all secondary efficacy variables at all time points, with the exception of frequency of acute headache pain medication intakes. Adverse events occurred in 62.4% of onabotulinumtoxinA patients and 51.7% of placebo patients. Most patients reported adverse events that were mild to moderate in severity and few discontinued (onabotulinumtoxinA, 3.8%; placebo, 1.2%) due to adverse events. No unexpected treatment-related adverse events were identified. The pooled PREEMPT results demonstrate that onabotulinumtoxinA is an effective prophylactic treatment for chronic migraine. OnabotulinumtoxinA resulted in significant improvements compared with placebo in multiple headache symptom measures, and significantly reduced headache-related disability and improved functioning, vitality, and overall health-related quality of life. Repeat treatments with onabotulinumtoxinA were safe and well tolerated.

OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial

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. 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. 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. 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.