This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Headache is a common neurological symptom in clinical practice. In 1 year most of the US population will have a headache and over 5% will seek medical aid (Silberstein Silberstein, 1990). Headaches are either episodic (less than 15 headache days/month) or chronic (greater than or equal to 15 headache days/month) (Headache Classification Subcommittee of the International Headache Society, revised 2004 [ICHD-II]). Recurrent headaches (HA) can be symptoms of a chronic primary headache disorder.Primary chronic daily headache (CDH) is a syndrome characterized by HA not attributable to a secondary disorder, which last more than 4 hours/day and occur 16 or more days/month (Bigal et al, 2004; Silberstein and Lipton, 2001). Chronic daily headache is a heterogeneous disorder, affecting approximately 4% to 5% of the general population (based on global epidemiological studies; Castillo et al, 1999; Scher et al, 1998; Wang et al, 2000) and is the most common headache seen in headache specialty clinics. More than 90% of CDH patients initially report episodic HA (Silberstein and Lipton, 2000). Patients in whom episodic migraines have progressed into CDH are described as having 'transformed migraine' (Silberstein it al, 1994). Most patients with CDH report their role functioning and well-being as frequently and severely impaired (Holroyd et al, 2000), highlighting the importance of this group of headaches on quality of life (Monzon and Lainez, 1998; Wang et al, 2001).Very few studies have evaluated HA prophylactic treatment in patients with CDH. To date, no drug has received regulatory authority approval for the prophylaxis of headaches in migraine patients with transformed migraine. There appears to be a large unmet medical need in this debilitated patient population.Botulinum Toxin Type A Purified Neurotoxin Complex (BOTOX) therapy has been reported to alleviate pain associated with various conditions with or without concomitant excess muscle contractions (Aoki, 2001). This includes cervical dystonia, spasticity, tension-associated HA, chronic whiplash-associated neck pain, myofascial pain, migraine prophylaxis, and back pain. The toxin is known to inhibit the release of the neurotransmitter, acetylcholine, at the neuromuscular junction, thereby inhibiting striated muscle contractions. In the majority of pain syndromes where Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) has been studied inhibiting muscle spasms has been identified to be an important component of its activity. However, the reduction of pain often occurs before the decrease in muscle contractions suggesting that Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) has a more complex mechanism of action that initially hypothesized (Aoki, 2003). Current data suggests an antinociceptive effect of Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) that is separate from its neuromuscular activity. Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) appears to act both peripherally and centrally on sensory nerves. The hypothesis that Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) medicates an antinociceptive activity peripherally is supported by its inhibition of neurotransmitters such as glutamate (CUI et al, 2004), calcitonin gene-related peptide (CGRP) (Purkiss et al, 2000; Welch et al, 2000), and substance P (Durham et al, 2004). An indirect reduction of central sensitization is supported by studies investigating the stimulation of the immediate early gene, c-fos, using the formalin-challenged rat model. In these studies activation of the c-fos gene and expression of its protein product, Fos, indicate rapid neuronal firing in response to stimuli. Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) treatment reduced Fos expression after formalin challenge in a dose-dependent manner indicating an indirect central effect in reducing pain (Cui et al, 2002). Early phase 2 Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) studies evaluated 2 distinct patient populations: episodic migraine and chronic tension type headache (CTTH). Concurrent with the early phase 2 trials was growing clinical experience with Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) has a HA preventative treatment in those patients who had failed, or who were intolerant to, other conventional preventative HA medications (Blumenfeld, 2003; Brin et al, 2000; Mathew it al, 2003). As a result, Allergan imitated and completed a comprehensive exploratory phase 2 development program that included 2 studies in migraine patients with > 16 headache days during a 4 week baseline period (Study Reports 191622-038 & 191622-039). The actual number of units and injection sites investigators' used in the phase 2 studies, as well as the efficacy and safety profiles were reviewed to determine the dosing for this study. The exploratory phase 2 studies have identified a specific patient population, dose, treatment regimen and efficacy endpoint that await confirmation in pivotal phase 3 trials. The total dose, muscles to be injected, dose and number of injection sites per muscle specified in this study are based on an evaluation of the exploratory phase 2 studies. Dose range studied for 191622-038 and 105-260 U and the range studied for 191622-039 was 75U, 150U and 225U. This protocol is therefore designed to confirm the efficacy and safety of Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) in migraine patients with 15 or more headache days during a 28 day baseline period.The purpose of this study is to investigate whether injections of Botulinum Toxin Type A Purified Neurotoxin Complex (BOTOX) into specific muscle areas in the head and neck are effective and safe for preventing headaches in migraine patients with 15 or more headache days per 4-week period. This study will further test the safety and effectiveness of Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) as a headache prevention treatment in migraine patients. The study data will be used to develop a better understanding of diseases capable of being treated with Botulinum Toxin Type A Purified Neurotoxin Complex (Botox). The clinical hypothesis is that Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) is more effective than placebo as measured by the difference between treatment groups in the change form baseline in the frequency of headaches. And that Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) has an acceptable safety profile.The objectives of the Double-blind Phase is to evaluate the efficacy and safety of Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) compared with placebo as a HA prophylaxis in migraine subjects with 15 or more headache days per 4 week period. The objective of the Open-Label Phase is to evaluate the long-term safety of Botulinum Toxin Type A Purified Neurotoxin Complex (Botox) as headache prophylaxis in migraine subjects with 15 or more headache days per 4-week period.
Showing the most recent 10 out of 1825 publications
