February 28, 2017
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Botox

"The U.S. Food and Drug Administration today approved Botox injection (onabotulinumtoxinA) to prevent headaches in adult patients with chronic migraine. Chronic migraine is defined as having a history of migraine and experienci"...

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Botox




CLINICAL PHARMACOLOGY

Mechanism Of Action

BOTOX blocks neuromuscular transmission by binding to acceptor sites on motor or sympathetic nerve terminals, entering the nerve terminals, and inhibiting the release of acetylcholine. This inhibition occurs as the neurotoxin cleaves SNAP-25, a protein integral to the successful docking and release of acetylcholine from vesicles situated within nerve endings. When injected intramuscularly at therapeutic doses, BOTOX produces partial chemical denervation of the muscle resulting in a localized reduction in muscle activity. In addition, the muscle may atrophy, axonal sprouting may occur, and extrajunctional acetylcholine receptors may develop. There is evidence that reinnervation of the muscle may occur, thus slowly reversing muscle denervation produced by BOTOX.

When injected intradermally, BOTOX produces temporary chemical denervation of the sweat gland resulting in local reduction in sweating.

Following intradetrusor injection, BOTOX affects the efferent pathways of detrusor activity via inhibition of acetylcholine release.

Pharmacokinetics

Using currently available analytical technology, it is not possible to detect BOTOX in the peripheral blood following intramuscular injection at the recommended doses.

Animal Toxicology And/Or Pharmacology

In a study to evaluate inadvertent peribladder administration, bladder stones were observed in 1 of 4 male monkeys that were injected with a total of 6.8 Units/kg divided into the prostatic urethra and proximal rectum (single administration). No bladder stones were observed in male or female monkeys following injection of up to 36 Units/kg (~12X the highest human bladder dose) directly to the bladder as either single or 4 repeat dose injections or in female rats for single injections up to 100 Units/kg (~33X the highest human bladder dose).

Clinical Studies

Overactive Bladder (OAB)

Two double-blind, placebo-controlled, randomized, multi-center, 24-week clinical studies were conducted in patients with OAB with symptoms of urge urinary incontinence, urgency, and frequency (Studies OAB-1 and OAB-2). Patients needed to have at least 3 urinary urgency incontinence episodes and at least 24 micturitions in 3 days to enter the studies. A total of 1105 patients, whose symptoms had not been adequately managed with anticholinergic therapy (inadequate response or intolerable side effects), were randomized to receive either 100 Units of BOTOX (n=557), or placebo (n=548). Patients received 20 injections of study drug (5 units of BOTOX or placebo) spaced approximately 1 cm apart into the detrusor muscle.

In both studies, significant improvements compared to placebo in the primary efficacy variable of change from baseline in daily frequency of urinary incontinence episodes were observed for BOTOX 100 Units at the primary time point of week 12. Significant improvements compared to placebo were also observed for the secondary efficacy variables of daily frequency of micturition episodes and volume voided per micturition. These primary and secondary variables are shown in Tables 18 and 19, and Figures 5 and 6.

Table 18: Baseline and Change from Baseline in Urinary Incontinence Episode Frequency, Micturition Episode Frequency and Volume Voided Per Micturition, Study OAB-1

BOTOX 100 Units
(N=278)
Placebo
(N=272)
Treatment Difference p-value
Daily Frequency of Urinary Incontinence Episodesa
Mean Baseline 5.5 5.1
Mean Change* at Week 2 -2.6 -1.0 -1.6
Mean Change* at Week 6 -2.8 -1.0 -1.8
Mean Change* at Week 12** -2.5 -0.9 -1.6
(-2.1, -1.2)
< 0.001
Daily Frequency of Micturition Episodesb
Mean Baseline 12.0 11.2
Mean Change† at Week 12** -1.9 -0.9 -1.0
(-1.5, -0.6)
< 0.001
Volume Voided per Micturitionb (mL)
Mean Baseline 156 161
Mean Change† at Week 12** 38 8 30
(17, 43)
< 0.001
* Least squares (LS) mean change, treatment difference and p-value are based on an ANCOVA model with baseline value as covariate and treatment group and investigator as factors. Last observation carried forward (LOCF) values were used to analyze the primary efficacy variable.
† LS mean change, treatment difference and p-value are based on an ANCOVA model with baseline value as covariate and stratification factor, treatment group and investigator as factors.
**Primary timepoint
aPrimary variable
bSecondary variable

Table 19: Baseline and Change from Baseline in Urinary Incontinence Episode Frequency, Micturition Episode Frequency and Volume Voided Per Micturition, Study OAB-2

BOTOX 100 Units
(N=275)
Placebo
(N=269)
Treatment Difference p-value
Daily Frequency of Urinary Incontinence Episodesa
Mean Baseline 5.5 5.7
Mean Change* at Week 2 -2.7 -1.1 -1.6
Mean Change* at Week 6 -3.1 -1.3 -1.8
Mean Change* at Week 12** -3.0 -1.1 -1.9
(-2.5, -1.4)
< 0.001
Daily Frequency of Micturition Episodesb
Mean Baseline 12.0 11.8
Mean Change† at Week 12** -2.3 -0.6 -1.7
(-2.2, -1.3)
< 0.001
Volume Voided per Micturitionb (mL)
Mean Baseline 144 153
Mean Change† at Week 12** 40 10 31
(20, 41)
< 0.001
*LS mean change, treatment difference and p-value are based on an ANCOVA model with baseline value as covariate and treatment group and investigator as factors. LOCF values were used to analyze the primary efficacy variable.
† LS mean change, treatment difference and p-value are based on an ANCOVA model with baseline value as covariate and stratification factor, treatment group and investigator as factors.
**Primary timepoint
aPrimary variable
bSecondary variable

Figure 5: Mean Change from Baseline in Daily Frequency of Urinary Incontinence Episodes following intradetrus or injection in Study OAB-1

Mean Change from Baseline in Daily Frequency of Urinary Incontinence Episodes following intradetrus or injection in Study OAB-1 - Illustration

Figure 6: Mean Change from Baseline in Daily Frequency of Urinary Incontinence Episodes following intradetrusor injection in Study OAB-2

Mean Change from Baseline in Daily Frequency of Urinary Incontinence Episodes following intradetrusor injection in Study OAB-2 - Illustration

The median duration of response in Study OAB-1 and OAB-2, based on patient qualification for retreatment, was 19-24 weeks for the BOTOX 100 Unit dose group compared to 13 weeks for placebo. To qualify for re-treatment, at least 12 weeks must have passed since the prior treatment, post-void residual urine volume must have been less than 200 mL and patients must have reported at least 2 urinary incontinence episodes over 3 days.

Detrusor Overactivity Associated With A Neurologic Condition

Two double-blind, placebo-controlled, randomized, multi-center clinical studies were conducted in patients with urinary incontinence due to detrusor overactivity associated with a neurologic condition who were either spontaneously voiding or using catheterization (Studies NDO-1 and NDO-2). A total of 691 spinal cord injury (T1 or below) or multiple sclerosis patients, who had an inadequate response to or were intolerant of at least one anticholinergic medication, were enrolled. These patients were randomized to receive either 200 Units of BOTOX (n=227), 300 Units of BOTOX (n=223), or placebo (n=241).

In both studies, significant improvements compared to placebo in the primary efficacy variable of change from baseline in weekly frequency of incontinence episodes were observed for BOTOX (200 Units) at the primary efficacy time point at week 6. Increases in maximum cystometric capacity and reductions in maximum detrusor pressure during the first involuntary detrusor contraction were also observed. These primary and secondary endpoints are shown in Tables 20 and 21, and Figures 7 and 8.

No additional benefit of BOTOX 300 Units over 200 Units was demonstrated.

Table 20: Baseline and Change from Baseline in Weekly Urinary Incontinence Episode Frequency, Maximum Cystometric Capacity and Maximum Detrusor Pressure during First Involuntary Detrusor Contraction (cmH20) Study NDO-1

BOTOX 200 Units Placebo Treatment Difference* p-value*
Weekly Frequency of Urinary Incontinence Episodesa
N 134 146
Mean Baseline 32.3 28.3
Mean Change* at Week 2 -15.3 -10.0 -5.3
Mean Change* at Week 6** -19.9 -10.6 -9.2
(-13.1, -5.3)
p < 0.001
Mean Change* at Week 12 -19.8 -8.8 -11.0
Maximum Cystometric Capacityb (mL)
N 123 129
Mean Baseline 253.8 259.1
Mean Change* at Week 6** 135.9 12.1 123.9
(89.1, 158.7)
p < 0.001
Maximum Detrusor Pressure during First Involuntary Detrusor Contractionb (cmH2O)
N 41 103
Mean Baseline 63.1 57.4
Mean Change* at Week 6** -28.1 -3.7 -24.4
*LS mean change, treatment difference and p-value are based on an analysis using an ANCOVA model with baseline weekly endpoint as covariate and treatment group, etiology at study entry (spinal cord injury or multiple sclerosis), concurrent anticholinergic therapy at screening, and investigator as factors. LOCF values were used to analyze the primary efficacy variable.
** Primary timepoint
aPrimary endpoint
bSecondary endpoint

Table 21: Baseline and Change from Baseline in Weekly Urinary Incontinence Episode Frequency, Maximum Cystometric Capacity and Maximum Detrusor Pressure during First Involuntary Detrusor Contraction (cmH20) in Study NDO-2

BOTOX 200 Units Placebo Treatment Difference* p-value*
Weekly Frequency of Urinary Incontinence Episodesa
N 91 91
Mean Baseline 32.7 36.8
Mean Change* at Week 2 -18.0 -7.9 -10.1
Mean Change* at Week 6** -19.6 -10.8 -8.8
(-14.5, -3.0)
p=0.003
Mean Change* at Week 12 -19.6 -10.7 -8.9
Maximum Cystometric Capacityb (mL)
N 88 85
Mean Baseline 239.6 253.8
Mean Change* at Week 6** 150.8 2.8 148.0
(101.8, 194.2)
p < 0.001
Maximum Detrusor Pressure during First Involuntary Detrusor Contractionb (cmH2O)
N 29 68
Mean Baseline 65.6 43.7
Mean Change* at Week 6** -28.7 2.1 -30.7
*LS mean change, treatment difference and p-value are based on an analysis using an ANCOVA model with baseline weekly endpoint as covariate and treatment group, etiology at study entry (spinal cord injury or multiple sclerosis), concurrent anticholinergic therapy at screening, and investigator as factors. LOCF values were used to analyze the primary efficacy variable.
** Primary timepoint
aPrimary endpoint
bSecondary endpoint

Figure 7: Mean Change from Baseline in Weekly Frequency of Urinary Incontinence Episodes During Treatment Cycle 1 in Study NDO-1

Mean Change from Baseline in Weekly Frequency of Urinary Incontinence Episodes During Treatment Cycle 1 in Study NDO-1 - Illustration

Figure 8: Mean Change from Baseline in Weekly Frequency of Urinary Incontinence Episodes During Treatment Cycle 1 in Study NDO-2

Mean Change from Baseline in Weekly Frequency of Urinary Incontinence Episodes During Treatment Cycle 1 in Study NDO-2 - Illustration

The median duration of response in study NDO-1 and NDO-2, based on patient qualification for retreatment was 295-337 days (42-48 weeks) for the 200 Units dose group compared to 96-127 days (13- 18 weeks) for placebo. Re-treatment was based on loss of effect on incontinence episode frequency (50% of effect in Study NDO-1; 70% of effect in Study NDO-2).

Chronic Migraine

BOTOX was evaluated in two randomized, multi-center, 24-week, 2 injection cycle, placebo-controlled double-blind studies. Study 1 and Study 2 included chronic migraine adults who were not using any concurrent headache prophylaxis, and during a 28-day baseline period had ≥ 15 headache days lasting 4 hours or more, with ≥ 50% being migraine/probable migraine. In both studies, patients were randomized to receive placebo or 155 Units to 195 Units BOTOX injections every 12 weeks for the 2-cycle, double-blind phase. Patients were allowed to use acute headache treatments during the study. BOTOX treatment demonstrated statistically significant and clinically meaningful improvements from baseline compared to placebo for key efficacy variables (see Table 22).

Table 22: Week 24 Key Efficacy Variables for Study 1 and Study 2

Efficacy per 28 days Study 1 Study 2
BOTOX
(N=341)
Placebo
(N=338)
BOTOX
(N=347)
Placebo
(N=358)
Change from baseline in frequency of headache days -7.8* -6.4 -9.2* -6.9
Change from baseline in total cumulative hours of headache on headache days -107* -70 -134* -95
* Significantly different from placebo (p ≤ 0.05)

Patients treated with BOTOX had a significantly greater mean decrease from baseline in the frequency of headache days at most timepoints from Week 4 to Week 24 in Study 1 (Figure 9), and all timepoints from Week 4 to Week 24 in Study 2 (Figure 10), compared to placebo-treated patients.

Figure 9: Mean Change from Baseline in Number of Headache Days for Study 1

Mean Change from Baseline in Number of Headache Days for Study 1 - Illustration

Figure 10: Mean Change from Baseline in Number of Headache Days for Study 2

Mean Change from Baseline in Number of Headache Days for Study 2 - Illustration

Spasticity

Upper Limb Spasticity

The efficacy of BOTOX for the treatment of upper limb spasticity was evaluated in three randomized, multi-center, double-blind, placebo-controlled studies (Studies 1, 2, and 3). Two additional randomized, multi-center, double-blind, placebo-controlled studies for upper limb spasticity in adults also included the evaluation of the efficacy of BOTOX for the treatment of thumb spasticity (Studies 4 and 5).

Study 1 included 126 patients (64 BOTOX and 62 placebo) with upper limb spasticity (Ashworth score of at least 3 for wrist flexor tone and at least 2 for finger flexor tone) who were at least 6 months poststroke. BOTOX (a total dose of 200 Units to 240 Units) and placebo were injected intramuscularly (IM) into the flexor digitorum profundus, flexor digitorum sublimis, flexor carpi radialis, flexor carpi ulnaris, and if necessary into the adductor pollicis and flexor pollicis longus (see Table 23). Use of an EMG/nerve stimulator was recommended to assist in proper muscle localization for injection. Patients were followed for 12 weeks.

Table 23: Study Medication Dose and Injection Sites in Study 1

Muscles Injected Volume (mL) BOTOX (Units) Number of Injection Sites
Wrist
Flexor Carpi Radialis 1 50 1
Flexor Carpi Ulnaris 1 50 1
Finger
Flexor Digitorum Profundus 1 50 1
Flexor Digitorum Sublimis 1 50 1
Thumb
Adductor Pollicisa 0.4 20 1
Flexor Pollicis Longusa 0.4 20 1
ainjected only if spasticity is present in this muscle

The primary efficacy variable was wrist flexors muscle tone at week 6, as measured by the Ashworth score. The Ashworth Scale is a 5-point scale with grades of 0 [no increase in muscle tone] to 4 [limb rigid in flexion or extension]. It is a clinical measure of the force required to move an extremity around a joint, with a reduction in score clinically representing a reduction in the force needed to move a joint (i.e., improvement in spasticity).

Key secondary endpoints included Physician Global Assessment, finger flexors muscle tone, and thumb flexors tone at Week 6. The Physician Global Assessment evaluated the response to treatment in terms of how the patient was doing in his/her life using a scale from -4 = very marked worsening to +4 = very marked improvement. Study 1 results on the primary endpoint and the key secondary endpoints are shown in Table 24.

Table 24: Primary and Key Secondary Endpoints by Muscle Group at Week 6 in Study 1

BOTOX
(N=64)
Placebo
(N=62)
Median Change from Baseline in Wrist Flexor Muscle Tone on the Ashworth Scale†a -2.0* 0.0
Median Change from Baseline in Finger Flexor Muscle Tone on the Ashworth Scale ††b -1.0* 0.0
Median Change from Baseline in Thumb Flexor Muscle Tone on the Ashworth Scale ††c -1.0 -1.0
Median Physician Global Assessment of Response to Treatment†† 2.0* 0.0
† Primary endpoint at Week 6
† † Secondary endpoints at Week 6
*Significantly different from placebo (p ≤ 0.05)
aBOTOX injected into both the flexor carpi radialis and ulnaris muscles
bBOTOX injected into the flexor digitorum profundus and flexor digitorum sublimis muscles
cBOTOX injected into the adductor pollicis and flexor pollicis longus muscles

Study 2 compared 3 doses of BOTOX with placebo and included 91 patients [BOTOX 360 Units (N=21), BOTOX 180 Units (N=23), BOTOX 90 Units (N=21), and placebo (N=26)] with upper limb spasticity (expanded Ashworth score of at least 2 for elbow flexor tone and at least 3 for wrist flexor tone) who were at least 6 weeks post-stroke. BOTOX and placebo were injected with EMG guidance into the flexor digitorum profundus, flexor digitorum sublimis, flexor carpi radialis, flexor carpi ulnaris, and biceps brachii (see Table 25).

Table 25: Study Medication Dose and Injection Sites in Study 2 and Study 3

Muscles Injected Total Dose
BOTOX low dose (90 Units) BOTOX mid dose (180 Units) BOTOX high dose (360 Units) Volume (mL) per site Injection Sites (n)
Wrist
Flexor Carpi Ulnaris 10 Units 20 Units 40 Units 0.4 1
Flexor Carpi Radialis 15 Units 30 Units 60 Units 0.6 1
Finger
Flexor Digitorum Profundus 7.5 Units 15 Units 30 Units 0.3 1
Flexor Digitorum Sublimis 7.5 Units 15 Units 30 Units 0.3 1
Elbow
Biceps Brachii 50 Units 100 Units 200 Units 0.5 4

The primary efficacy variable in Study 2 was the wrist flexor tone at Week 6 as measured by the expanded Ashworth Scale. The expanded Ashworth Scale uses the same scoring system as the Ashworth Scale, but allows for half-point increments.

Key secondary endpoints in Study 2 included Physician Global Assessment, finger flexors muscle tone, and elbow flexors muscle tone at Week 6. Study 2 results on the primary endpoint and the key secondary endpoints at Week 6 are shown in Table 26.

Table 26: Primary and Key Secondary Endpoints by Muscle Group and BOTOX Dose at Week 6 in Study 2

BOTOX low dose (90 Units)
(N=21)
BOTOX mid dose (180 Units)
(N=23)
BOTOX high dose (360 Units)
(N=21)
Placebo
(N=26)
Median Change from Baseline in Wrist Flexor Muscle Tone on the Ashworth Scale †b -1.5* -1.0* -1.5* -1.0
Median Change from Baseline in Finger Flexor Muscle Tone on the Ashworth Scale††c -0.5 -0.5 -1.0 -0.5
Median Change from Baseline in Elbow Flexor Muscle Tone on the Ashworth Scale††d -0.5 -1.0* -0.5a -0.5
Median Physician Global Assessment of Response to Treatment 1.0* 1.0* 1.0* 0.0
† Primary endpoint at Week 6
† † Secondary endpoints at Week 6
*Significantly different from placebo (p ≤ 0.05)
ap=0.053
bTotal dose of BOTOX injected into both the flexor carpi radialis and ulnaris muscles
cTotal dose of BOTOX injected into the flexor digitorum profundus and flexor digitorum sublimis muscles
dDose of BOTOX injected into biceps brachii muscle

Study 3 compared 3 doses of BOTOX with placebo and enrolled 88 patients [BOTOX 360 Units (N=23), BOTOX 180 Units (N=23), BOTOX 90 Units (N=23), and placebo (N=19)] with upper limb spasticity (expanded Ashworth score of at least 2 for elbow flexor tone and at least 3 for wrist flexor tone and/or finger flexor tone) who were at least 6 weeks post-stroke. BOTOX and placebo were injected with EMG guidance into the flexor digitorum profundus, flexor digitorum sublimis, flexor carpi radialis, flexor carpi ulnaris, and biceps brachii (see Table 25).

The primary efficacy variable in Study 3 was wrist and elbow flexor tone as measured by the expanded Ashworth score. A key secondary endpoint was assessment of finger flexors muscle tone. Study 3 results on the primary endpoint at Week 4 are shown in Table 27.

Table 27: Primary and Key Secondary Endpoints by Muscle Group and BOTOX Dose at Week 4 in Study 3

BOTOX low dose (90 Units)
(N=23)
BOTOX mid dose (180 Units)
(N=21)
BOTOX high dose (360 Units)
(N=22)
Placebo
(N=19)
Median Change from Baseline in Wrist Flexor Muscle Tone on the Ashworth Scale †b -1.0 -1.0 -1.5* -0.5
Median Change from Baseline in Finger Flexor Muscle Tone on the Ashworth Scale††c -1.0 -1.0 -1.0* -0.5
Median Change from Baseline in Elbow Flexor Muscle Tone on the Ashworth Scale †d -0.5 -0.5 -1.0* -0.5
† Primary endpoint at Week 4
† † Secondary endpoints at Week 4
*Significantly different from placebo (p ≤ 0.05)
bTotal dose of BOTOX injected into both the flexor carpi radialis and ulnaris muscles
cTotal dose of BOTOX injected into the flexor digitorum profundus and flexor digitorum sublimis muscles
dDose of BOTOX injected into biceps brachii muscle

Study 4 included 170 patients (87 BOTOX and 83 placebo) with upper limb spasticity who were at least 6 months post-stroke. In Study 4, patients received 20 Units of BOTOX into the adductor pollicis and flexor pollicis longus (total BOTOX dose =40 Units in thumb muscles) or placebo (see Table 28). Study 5 included 109 patients with upper limb spasticity who were at least 6 months post-stroke. In Study 5, patients received 15 Units (low dose) or 20 Units (high dose) of BOTOX into the adductor pollicis and flexor pollicis longus under EMG guidance (total BOTOX low dose =30 Units, total BOTOX high dose =40 Units), or placebo (see Table 28). The duration of follow-up in Study 4 and Study 5 was 12 weeks.

Table 28: Study Medication Dose and Injection Sites in Studies 4 and 5

Muscles Injected Study 4 Study 5 Number of Injection Sites for Studies 4 and 5
BOTOX (Units ) Volume (mL) BOTOX low dose (Units) BOTOX high dose (Units) Volume low dose (mL) Volume high dose (mL)
Thumb Adductor Pollicis 20 0.4 15 20 0.3 0.4 1
Flexor Pollicis Longus 20 0.4 15 20 0.3 0.4 1

The results of Study 4 for the change from Baseline to Week 6 in thumb flexor tone measured by modified Ashworth Scale (MAS) and overall treatment response by Physician Global Assessment at week 6 are presented in Table 29. The MAS uses a similar scoring system as the Ashworth Scale.

Table 29: Efficacy Endpoints for Thumb Flexors at Week 6 in Study 4

BOTOX
(N=66)
Placebo
(N=57)
Median Change from Baseline in Thumb Flexor Muscle Tone on the modified Ashworth Scale† †a -1.0* 0.0
Median Physician Global Assessment of Response to Treatment† † 2.0* 0.0
†† Secondary endpoints at Week 6
*Significantly different from placebo (p ≤ 0.001)
aBOTOX injected into the adductor pollicis and flexor pollicis longus muscles

In Study 5, the results of the change from Baseline to Week 6 in thumb flexor tone measured by modified Ashworth Scale and Clinical Global Impression (CGI) of functional assessment scale assessed by the physician using an 11-point Numeric Rating Scale [-5 worst possible function to +5 best possible function]) are presented in Table 30.

Table 30: Efficacy Endpoints for Thumb Flexors at Week 6 in Study 5

BOTOX low dose (30 Units)
(N=14)
Placebo low dose
(N=9)
BOTOX high dose (40 Units)
(N=43)
Placebo high dose
(N=23)
Median Change from Baseline in Thumb Flexor Muscle Tone on the modified Ashworth Scale† † †a -1.0 -1.0 -0.5* 0.0
Median Change from Baseline in Clinical Global Impression Score by Physician † † 1.0 0.0 2.0* 0.0
† † Secondary endpoint at Week 6
† † † Other endpoint at Week 6
*Significantly different from placebo (p ≤ 0.010)
aBOTOX injected into the adductor pollicis and flexor pollicis longus muscles

Lower Limb Spasticity

The efficacy and safety of BOTOX for the treatment of lower limb spasticity was evaluated in Study 6, a randomized, multi-center, double-blind, placebo-controlled study. Study 6 included 468 post-stroke patients (233 BOTOX and 235 placebo) with ankle spasticity (modified Ashworth Scale ankle score of at least 3) who were at least 3 months post-stroke. A total dose of 300 Units of BOTOX or placebo were injected intramuscularly and divided between the gastrocnemius, soleus, and tibialis posterior, with optional injection into the flexor hallucis longus, flexor digitorum longus, flexor digitorum brevis, extensor hallucis, and rectus femoris (see Table 31) with up to an additional 100 Units (400 Units total dose). The use of electromyographic guidance or nerve stimulation was required to assist in proper muscle localization for injections. Patients were followed for 12 weeks.

Table 31: Study Medication Dose and Injection Sites in Study 6

Muscles Injected BOTOX (Units) Number of Injection Sites
Mandatory Ankle Muscles
Gastrocnemius (medial head) 75 3
Gastrocnemius (lateral head) 75 3
Soleus 75 3
Tibialis Posterior 75 3
Optional Muscles
Flexor Hallucis Longus 50 2
Flexor Digitorum Longus 50 2
Flexor Digitorum Brevis 25 1
Extensor Hallucis 25 1
Rectus Femoris 100 4

The co-primary endpoints were the average of the change from baseline in modified Ashworth Scale (MAS) ankle score at Week 4 and Week 6, and the average of the Physician Global Assessment of Response (CGI) at Week 4 and Week 6. The CGI evaluated the response to treatment in terms of howthe patient was doing in his/her life using a 9-point scale from -4=very marked worsening to +4=very marked improvement).

Statistically significant between-group differences for BOTOX over placebo were demonstrated for the co-primary efficacy measures of MAS and CGI (see Table 32).

Table 32: Co-Primary Efficacy Endpoints Results in Study 6 (Intent-to-treat Population)

BOTOX 300 to 400 Units
(N=233)
Placebo
(N=235)
Mean Change from Baseline in Ankle Plantar Flexors on the modified Ashworth Scale
Week 4 and 6 Average -0.8* -0.6
Mean Clinical Global Impression Score by Investigator
Week 4 and 6 Average 0.9* 0.7
* Significantly different from placebo (p < 0.05)

Compared to placebo, significant improvements in MAS change from baseline for ankle plantar flexors (see Figure 11) and CGI (see Figure 12) were observed at Week 2, Week 4, and Week 6 for patients treated with BOTOX.

Figure 11: Modified Ashworth Scale Ankle Score for Study 6 – Mean Change from Baseline by Visit

Modified Ashworth Scale Ankle Score for Study 6 - Illustration

Figure 12: Clinical Global Impression by Physician for Study 6 – Mean Scores by Visit

Clinical Global Impression by Physician for Study 6 - Illustration

Cervical Dystonia

A randomized, multi-center, double-blind, placebo-controlled study of the treatment of cervical dystonia was conducted. This study enrolled adult patients with cervical dystonia and a history of having received BOTOX in an open label manner with perceived good response and tolerable side effects. Patients were excluded if they had previously received surgical or other denervation treatment for their symptoms or had a known history of neuromuscular disorder. Subjects participated in an open label enrichment period where they received their previously employed dose of BOTOX. Only patients who were again perceived as showing a response were advanced to the randomized evaluation period. The muscles in which the blinded study agent injections were to be administered were determined on an individual patient basis.

There were 214 subjects evaluated for the open label period, of which 170 progressed into the randomized, blinded treatment period (88 in the BOTOX group, 82 in the placebo group). Patient evaluations continued for at least 10 weeks post-injection. The primary outcome for the study was a dual endpoint, requiring evidence of both a change in the Cervical Dystonia Severity Scale (CDSS) and an increase in the percentage of patients showing any improvement on the Physician Global Assessment Scale at 6 weeks after the injection session. The CDSS quantifies the severity of abnormal head positioning and was newly devised for this study. CDSS allots 1 point for each 5 degrees (or part thereof) of head deviation in each of the three planes of head movement (range of scores up to theoretical maximum of 54). The Physician Global Assessment Scale is a 9 category scale scoring the physician's evaluation of the patients' status compared to baseline, ranging from –4 to +4 (very marked worsening to complete improvement), with 0 indicating no change from baseline and +1 slight improvement. Pain is also an important symptom of cervical dystonia and was evaluated by separate assessments of pain frequency and severity on scales of 0 (no pain) to 4 (constant in frequency or extremely severe in intensity). Study results on the primary endpoints and the pain-related secondary endpoints are shown in Table 33.

Table 33: Efficacy Outcomes of the Phase 3 Cervical Dystonia Study (Group Means )

Placebo
(N=82)
BOTOX
(N=88)
95% CI on Difference
Baseline CDSS 9.3 9.2
Change in CDSS at Week 6 -0.3 -1.3 (-2.3, 0.3) [a,b]
% Patients with Any Improvement on Physician Global Assessment 31% 51% (5%, 34%) [a]
Pain Intensity Baseline 1.8 1.8
Change in Pain Intensity at Week 6 -0.1 -0.4 (-0.7, -0.2) [c]
Pain Frequency Baseline 1.9 1.8
Change in Pain Frequency at Week 6 -0.0 -0.3 (-0.5, -0.0) [c]
aConfidence intervals are constructed from the analysis of covariance table with treatment and investigational site as main effects, and baseline CDSS as a covariate.
bThese values represent the prospectively planned method for missing data imputation and statistical test. Sensitivity analyses indicated that the 95% confidence interval excluded the value of no difference between groups and the p-value was less than 0.05. These analyses included several alternative missing data imputation methods and non-parametric statistical tests.
cConfidence intervals are based on the t-distribution.

Exploratory analyses of this study suggested that the majority of patients who had shown a beneficial response by week 6 had returned to their baseline status by 3 months after treatment. Exploratory analyses of subsets by patient sex and age suggest that both sexes receive benefit, although female patients may receive somewhat greater amounts than male patients. There is a consistent treatmentassociated effect between subsets greater than and less than age 65. There were too few non-Caucasian patients enrolled to draw any conclusions regarding relative efficacy in racial subsets.

In this study the median total BOTOX dose in patients randomized to receive BOTOX (N=88) was 236 Units, with 25th to 75th percentile ranges of 198 Units to 300 Units. Of these 88 patients, most received injections to 3 or 4 muscles; 38 received injections to 3 muscles, 28 to 4 muscles, 5 to 5 muscles, and 5 to 2 muscles. The dose was divided amongst the affected muscles in quantities shown in Table 34. The total dose and muscles selected were tailored to meet individual patient needs.

Table 34: Number of Patients Treated per Muscle and Fraction of Total Dose Injected into Involved Muscles

Muscle Number of Patients Treated in this Muscle
(N=88)
Mean % Dose per Muscle Mid-Range of % Dose per Muscle*
Splenius capitis/cervicis 83 38 25-50
Sternocleidomastoid 77 25 17-31
Levator scapulae 52 20 16-25
Trapezius 49 29 18-33
Semis pinalis 16 21 13-25
Scalene 15 15 6-21
Longissimus 8 29 17-41
* The mid-range of dose is calculated as the 25th to 75th percentiles.

There were several randomized studies conducted prior to the double-blind, placebo-controlled study, which were supportive but not adequately designed to assess or quantitatively estimate the efficacy of BOTOX.

Primary Axillary Hyperhidrosis

The efficacy and safety of BOTOX for the treatment of primary axillary hyperhidrosis were evaluated in two randomized, multi-center, double-blind, placebo-controlled studies. Study 1 included adultpatients with persistent primary axillary hyperhidrosis who scored 3 or 4 on a Hyperhidrosis Disease Severity Scale (HDSS) and who produced at least 50 mg of sweat in each axilla at rest over 5 minutes. HDSS is a 4-point scale with 1 = “underarm sweating is never noticeable and never interferes with my daily activities”; to 4 = “underarm sweating is intolerable and always interferes with my daily activities”. A total of 322 patients were randomized in a 1:1:1 ratio to treatment in both axillae with either 50 Units of BOTOX, 75 Units of BOTOX, or placebo. Patients were evaluated at 4-week intervals. Patients who responded to the first injection were re-injected when they reported a reincrease in HDSS score to 3 or 4 and produced at least 50 mg sweat in each axilla by gravimetric measurement, but no sooner than 8 weeks after the initial injection.

Study responders were defined as patients who showed at least a 2-grade improvement from baseline value on the HDSS 4 weeks after both of the first two treatment sessions or had a sustained response after their first treatment session and did not receive re-treatment during the study. Spontaneous resting axillary sweat production was assessed by weighing a filter paper held in the axilla over a period of 5 minutes (gravimetric measurement). Sweat production responders were those patients who demonstrated a reduction in axillary sweating from baseline of at least 50% at week 4.

In the three study groups the percentage of patients with baseline HDSS score of 3 ranged from 50% to 54% and from 46% to 50% for a score of 4. The median amount of sweat production (averaged for each axilla) was 102 mg, 123 mg, and 114 mg for the placebo, 50 Units and 75 Units groups respectively.

The percentage of responders based on at least a 2-grade decrease from baseline in HDSS or based on a > 50% decrease from baseline in axillary sweat production was greater in both BOTOX groups than in the placebo group (p < 0.001), but was not significantly different between the two BOTOX doses (see Table 35).

Duration of response was calculated as the number of days between injection and the date of the first visit at which patients returned to 3 or 4 on the HDSS scale. The median duration of response following the first treatment in BOTOX treated patients with either dose was 201 days. Among those who received a second BOTOX injection, the median duration of response was similar to that observed after the first treatment.

In study 2, 320 adults with bilateral axillary primary hyperhidrosis were randomized to receive either 50 Units of BOTOX (n=242) or placebo (n=78). Treatment responders were defined as subjects showing at least a 50% reduction from baseline in axillary sweating measured by gravimetric measurement at 4 weeks. At week 4 post-injection, the percentages of responders were 91% (219/242) in the BOTOX group and 36% (28/78) in the placebo group, p < 0.001. The difference in percentage of responders between BOTOX and placebo was 55% (95% CI=43.3, 65.9).

Table 35: Study 1 - Study Outcomes

Treatment Response BOTOX 50 Units
(N=104)
BOTOX 75 Units
(N=110)
Placebo
(N=108)
BOTOX 50-placebo (95% CI) BOTOX 75-placebo (95% CI)
HDSS Score change > 2 (n)a 55% (57) 49% (54) 6% (6) 49.3% (38.8, 59.7) 43% (33.2, 53.8)
> 50% decrease in axillary sweat production % (n) 81% (84) 86% (94) 41% (44) 40% (28.1, 52.0) 45% (33.3, 56.1)
a Patients who showed at least a 2-grade improvement from baseline value on the HDSS 4 weeks after both of the first two treatment sessions or had a sustained response after their first treatment session and did not receive retreatment during the study.

Blepharospasm

Botulinum toxin has been investigated for use in patients with blepharospasm in several studies. In an open label, historically controlled study, 27 patients with essential blepharospasm were injected with 2 Units of BOTOX at each of six sites on each side. Twenty-five of the 27 patients treated with botulinum toxin reported improvement within 48 hours. One patient was controlled with a higher dosage at 13 weeks post initial injection and one patient reported mild improvement but remained functionally impaired.

In another study, 12 patients with blepharospasm were evaluated in a double-blind, placebo-controlled study. Patients receiving botulinum toxin (n=8) improved compared with the placebo group (n=4). The effects of the treatment lasted a mean of 12 weeks.

One thousand six hundred eighty-four patients with blepharospasm who were evaluated in an open label trial showed clinical improvement as evaluated by measured eyelid force and clinically observed intensity of lid spasm, lasting an average of 12 weeks prior to the need for re-treatment.

Strabismus

Six hundred seventy-seven patients with strabismus treated with one or more injections of BOTOX were evaluated in an open label trial. Fifty-five percent of these patients improved to an alignment of 10 prism diopters or less when evaluated six months or more following injection.

Last reviewed on RxList: 9/9/2016
This monograph has been modified to include the generic and brand name in many instances.

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