Using Botox for Migraine and Headache Treatment

Allergan Inc has completed several exploratory Phase II clinical trials investigating the potential use of BOTOX® (botulinum toxin type A) to treat various forms of headache and levels of headache severity, in an effort to identify a responsive patient population, dose and efficacy endpoints to guide its Phase III program.

– In studies of patients with chronic headache conditions (i.e., chronic daily headache [CDH], a disabling headache disorder characterized by headaches and/or migraines that occur on 16 or more days each month), no statistically significant between-group differences (BOTOX® vs. placebo) on predetermined primary outcome measures were observed. However, significant differences in favor of BOTOX® were demonstrated on other key, clinically meaningful efficacy measures such as decrease in the frequency of headache episodes; decrease of at least 50% in headache days; and decrease in acute medication use.

– Furthermore, a priori planned subgroup analyses of patients in the CDH trials revealed that the predetermined primary outcome measure (i.e., mean change from baseline in the number of headache-free days at day 180) was met in several subsets of patients receiving BOTOX®.

– In studies of patients with episodic migraine, no significant between-group differences were observed on predetermined outcome measures. Additional studies are needed to further examine the possible role of BOTOX® in the treatment of patients with episodic migraine.

– While the primary endpoints in the chronic and episodic studies were not met, results may have been confounded by several factors including a high proportion of patients taking concomitant prophylactic and acute headache pain medications during the studies, increasing the difficulty of differentiating study treatment from placebo.

– Across all Phase II studies, BOTOX® was found to be generally well-tolerated with less than 5% of patients discontinuing the studies due to adverse events.

Based on the Phase II findings specific to patients with CDH, Allergan has reached an agreement with the U.S. Food and Drug Administration (FDA) to move forward with a large Phase III clinical trial program, currently scheduled to begin in late 2005, to investigate the safety and efficacy of BOTOX® as a prophylactic therapy in a subset of migraine patients with CDH. Patients with CDH are at the more severe end of the headache/migraine spectrum, and currently available therapies typically provide inadequate relief to these patients due to intolerable side effects or other limitations. BOTOX® is not currently approved by the FDA for the treatment of any headache disorder.

Investigators will present all new as well as previously reported data from Allergan’s Phase II clinical trial program exploring the use of BOTOX® as a treatment for various forms of migraine and headache at the American Headache Society (AHS) 2005 Annual Meeting, as follows:

Where:
Philadelphia Marriott Downtown
Philadelphia, Pennsylvania

When:
June 23 – 26, 2005

What:
Data from Allergan’s Exploratory Phase II Clinical Trial Program Investigating BOTOX® as a Treatment for Various Forms of Migraine and Headache

Chronic Daily Headache (CDH)

“Botulinum Toxin Type A for the Prophylaxis of Chronic Daily Headache in Migraineurs: A Randomized, Double-Blind, Placebo Controlled Trial,” Benjamin M. Frishberg, MD, et al.

[PLATFORM SESSION III: SATURDAY JUNE 25TH, 3:00-4:30 PM]

(Please see summary below.)

“Botulinum Toxin Type A for the Prophylaxis of Chronic Daily Headache in Migraineurs: Subgroup Analysis of Patients Not Receiving Other Prophylactic Medications (A Randomized, Double-blind, Placebo-Controlled Study),” David W. Dodick, MD, et al.

[PLATFORM SESSION III: SATURDAY JUNE 25TH, 3:00-4:30 PM]

(Please see summary below.)

“Efficacy of Prophylactic Treatment with Botulinum Toxin Type A in Migraineurs with Chronic Daily Headache Overusing Acute Headache Pain Medications,” Joel R. Saper, MD, FACP, FAAN, et al.

[PLATFORM SESSION II, #ABH0163: SATURDAY JUNE 25TH, 12:00-2:00 PM]

Summary:

Between-group differences (BOTOX® vs. placebo) on the primary efficacy measure (i.e., mean change from baseline in the number of headache-free days at day 180) did not reach statistical significance. However, significant differences compared to placebo were demonstrated on other key, clinically meaningful efficacy measures, including a decrease in the frequency of headache episodes, a decrease of at least 50% in headache days, and a decrease in acute medication use (Frishberg et al).

– Differences on key efficacy measures in favor of BOTOX® were even more evident in a subgroup analysis of patients who were not taking other prophylactic medication to treat their headache (Dodick et al), and were more robust still in a further subanalysis of these patients who were overusing acute pain medications (Saper et al). These latter results are especially meaningful since the overuse of pain medication for headache is associated with maintenance of chronic headache and considerable disability.

– Treatment with BOTOX® was well-tolerated.

“Botulinum Toxin Type A for the Prophylaxis of Chronic Daily Headache in Migraineurs: Effect on Acute Headache Pain Medication Use,” Frederick G. Freitag, DO, et al.

[PLATFORM SESSION II, #ABH0161: SATURDAY JUNE 25TH, 12:00-2:00 PM]

– This was a subanalysis of Frishberg et al, in which between-group differences (BOTOX® vs. placebo) on the primary efficacy measure (i.e., mean change from baseline in the number of headache-free days at day 180) did not reach statistical significance.

– However, significant differences in favor of BOTOX® were demonstrated on other key, clinically meaningful efficacy measures such as decrease in the frequency of headache episodes; decrease of at least 50% in headache days; and decrease in acute medication use.

– Furthermore, decreases in acute headache pain medication use were consistently greater for BOTOX®-treated patients vs. placebo throughout the study period, with statistically significant between-group differences at four time points (p≤0.05).

– Between-group differences in mean change from baseline were greater after repeated treatments.

– Treatment with BOTOX® was well-tolerated.

“Botulinum Toxin Type A for the Prophylaxis of Chronic Daily Headache in Migraineurs: Effect on the Frequency of Headaches of > 4 Hours Duration (A Randomized, Double-blind, Placebo-Controlled Study),” Sheena K. Aurora, MD, et al. [PLATFORM SESSION II, #ABH0162: SATURDAY JUNE 25TH, 12:00-2:00 PM]

– This was a subanalysis of Frishberg et al, in which between-group differences (BOTOX® vs. placebo) on the primary efficacy measure (i.e., mean change from baseline in the number of headache-free days at day 180) did not reach statistical significance.

– However, significant differences in favor of BOTOX® were demonstrated on other key, clinically meaningful efficacy measures such as decrease in the frequency of headache episodes; decrease of at least 50% in headache days; and decrease in acute medication use.

– Furthermore, the decrease from baseline in the number of headaches of long duration (≥ 4 hours) was significantly greater for BOTOX®-treated patients vs. placebo at each assessment (p≤0.05).

– Treatment with BOTOX® was well-tolerated.

“Botulinum Toxin Type A (BOTOX®) for the Prophylaxis of Chronic Daily Headache in Migraineurs Using a Fixed-Site, Fixed-Dose Treatment Paradigm: A Randomized, Double-Blind, Placebo Controlled Trial,” Stephen D. Silberstein, MD, et al.

[PLATFORM SESSION II, #ABH0166: SATURDAY JUNE 25TH, 12:00-2:00 PM]

– Between-group differences (BOTOX® vs. placebo) on the primary efficacy measure (i.e., mean change from baseline in the number of headache-free days at day 180) did not reach statistical significance.

– However, following three treatment sessions, the 225 U and 150 U BOTOX® treatment groups had a significantly greater reduction from baseline in the frequency of headache episodes vs. placebo at day 240.

– Statistically significant between-group differences were observed for the mean change from baseline in the number of migrainous headaches vs. placebo at days 30, 90, and 150.

– Treatment with BOTOX® was well-tolerated.

“Burden of Disease Among Patients with Transformed Migraine Participating in a Clinical Trial,”
Richard B. Lipton, MD, et al.

[PLATFORM SESSION I, #ABH0168: FRIDAY JUNE 24TH, 12:30-2:30 PM]

– This was a clinical trial designed to assess the burden of disease among migraine patients with CDH (also known as transformed migraine). During the 90-day period prior to their enrollment in Allergan’s primary Phase II clinical trial (Frishberg et al), migraine patients with CDH experienced an average of 62.9 days of headache (±22.6) and an average of 57.6 days (±55) of activity limitation (e.g., missed days or reduced productivity at work, school or home, or missed social activities).

– Based on the overall mean Migraine Disability Assessment Questionnaire (MIDAS) score (57.6), most subjects were severely disabled (score > 21).

– All outcome measures showed these patients experience a substantial burden of disease (e.g., economic, quality of life, satisfaction and health-related costs).

Chronic Tension-Type Headache (CTTH)

“The Safety and Efficacy of a Single Treatment of Botulinum Toxin Type A in the Prophylactic Treatment of Chronic Tension-Type Headache (CTTH): A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group Study,” Stephen D. Silberstein, MD, et al.

[PLATFORM SESSION II, #ABH0165: SATURDAY JUNE 25TH, 12:00-2:00 PM]

– Between-group differences (BOTOX® vs. placebo) on the primary efficacy measure (i.e., mean change from baseline in the number of tension headache-free days at day 60 post-injection) did not reach statistical significance. Nor were there any significant between-group differences on other key efficacy measures (e.g., headache severity, concurrent headache medication usage, Beck Depression Inventory score, etc.).

– However, at day 90, significantly more patients in three BOTOX® treatment groups had a ≥ 50% decrease in tension headache days vs. placebo (p≤0.024).

– Treatment with BOTOX® was well tolerated.

– The results of the study may have been confounded by several factors including a high proportion of patients taking concomitant prophylactic and acute headache pain medications.

Episodic Migraine

“Botulinum Toxin Type A Prophylactic Treatment for Episodic Migraine Using a Modified Follow-the-Pain Treatment Paradigm: A Randomized, Double-Blind, Placebo Controlled, Phase II Study,” Sheena K. Aurora, MD, et al. [PLATFORM SESSION II, #ABH0164: SATURDAY JUNE 25TH, 12:00-2:00 PM]

– Between-group differences (BOTOX® vs. placebo) on the primary efficacy measure (i.e., mean change from baseline in the number of migraines for 30 days prior to day 180) did not reach statistical significance.

– Treatment with BOTOX® was well-tolerated.

– The results of the study may have been confounded by several factors including a high proportion of patients taking concomitant prophylactic and acute headache pain medications. — Additional studies are needed to further examine the possible role of BOTOX® in the treatment of patients with episodic migraine.