14 CLINICAL STUDIES

14.1 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 Table 25 and Table 26, and Figure 7 and Figure 8.

Table 25: 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

a Primary variable

b Secondary variable

Table 26: 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

a Primary variable

b Secondary variable

Figure 7: Mean Change from Baseline in Daily Frequency of Urinary Incontinence Episodes Following Intradetrusor Injection in Study OAB-1

Figure 7: Mean Change from Baseline in Daily Frequency of Urinary Incontinence Episodes following intradetrusor injection in Study OAB-1

Figure 8: Mean Change from Baseline in Daily Frequency of Urinary Incontinence Episodes Following Intradetrusor Injection in Study OAB-2

Figure 8: Mean Change from Baseline in Daily Frequency of Urinary Incontinence Episodes following intradetrusor injection in Study OAB-2

The median duration of response in Study OAB-1 and OAB-2, based on patient qualification for re-treatment, 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.

14.2 Adult 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 Table 27 and Table 28, and Figure 9 and Figure 10.

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

Table 27: Baseline and Change from Baseline in Weekly Urinary Incontinence Episode Frequency, Maximum Cystometric Capacity and Maximum Detrusor Pressure during First Involuntary Detrusor Contraction (cmH2O) 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	p<0.001
			(-13.1, -5.3)
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	p<0.001
			(89.1, 158.7)
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

a Primary endpoint

b Secondary endpoint

Table 28: Baseline and Change from Baseline in Weekly Urinary Incontinence Episode Frequency, Maximum Cystometric Capacity and Maximum Detrusor Pressure during First Involuntary Detrusor Contraction (cmH2O) 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	p=0.003
			(-14.5, -3.0)
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	p<0.001
			(101.8, 194.2)
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

a Primary endpoint

b Secondary endpoint

Figure 9: Mean Change from Baseline in Weekly Frequency of Urinary Incontinence Episodes During Treatment Cycle 1 in Study NDO-1

Figure 9: Mean Change from Baseline in Weekly Frequency of Urinary Incontinence Episodes During Treatment Cycle 1 in Study NDO-1

Figure 10: Mean Change from Baseline in Weekly Frequency of Urinary Incontinence Episodes During Treatment Cycle 1 in Study NDO-2

Figure 10: Mean Change from Baseline in Weekly Frequency of Urinary Incontinence Episodes During Treatment Cycle 1 in Study NDO-2

The median duration of response in study NDO-1 and NDO-2, based on patient qualification for re-treatment 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).

A placebo-controlled, double-blind randomized post-approval 52 week study (Study NDO-3) was conducted in MS patients with urinary incontinence due to neurogenic detrusor overactivity who were not adequately managed with at least one anticholinergic agent and not catheterizing at baseline. These patients were randomized to receive either 100 Units of BOTOX (n=66) or placebo (n=78).

Significant improvements compared to placebo in the primary efficacy variable of change from baseline in daily frequency of incontinence episodes were observed for BOTOX (100 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 Table 29.

Table 29: Baseline and Change from Baseline in Daily Urinary Incontinence Episode Frequency, Maximum Cystometric Capacity and Maximum Detrusor Pressure during First Involuntary Detrusor Contraction (cmH2O) in Study NDO-3
	BOTOX 100 Units	Placebo	Treatment Difference*	p-value*
Daily Frequency of Urinary Incontinence Episodesa
N	66	78
Mean Baseline	4.2	4.3
Mean Change* at Week 2	-2.9	-1.2	-1.7	─
Mean Change* at Week 6**	-3.4	-1.1	-2.3	p<0.001
			(-3.0, -1.7)
Mean Change* at Week 12	-2.7	-1.0	-1.8	─
Maximum Cystometric Capacityb (mL)
N	62	72
Mean Baseline	248.9	245.5
Mean Change* at Week 6**	134.4	3.5	130.9	p<0.001
			(94.8, 167.0)
Maximum Detrusor Pressure during First Involuntary Detrusor Contractionb (cmH2O)
N	25	51
Mean Baseline	42.4	39.0
Mean Change* at Week 6**	-19.2	2.7	-21.9
			(-37.5, -6.3)

* LS mean change, treatment difference and p-value are based on an analysis using an ANCOVA model with baseline daily endpoint as covariate and treatment group and propensity score stratification as factors. LOCF values were used to analyze the primary efficacy variable.

** Primary timepoint

a Primary endpoint

b Secondary endpoint

The median duration of response in study NDO-3, based on patient qualification for re-treatment was 362 days (52 weeks) for the BOTOX 100 Units dose group compared to 88 days (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 with no more than 1 incontinence-free day.

14.3 Pediatric Detrusor Overactivity Associated with a Neurologic Condition

Study 191622-120 (NCT01852045) was a multicenter, randomized, double-blind, parallel-group clinical study conducted in patients 5 to 17 years of age with urinary incontinence due to detrusor overactivity associated with a neurologic condition and using clean intermittent catheterization. A total of 113 patients (including 99 with spinal dysraphism such as spina bifida, 13 with spinal cord injury and 1 with transverse myelitis) who had an inadequate response to or were intolerant of at least one anticholinergic medication were enrolled. The median age was 11 years (range: 5 to 17 years), 49% were female; 75% were White, 10% were Black. These patients were randomized to 50 Units, 100 Units or 200 Units, not to exceed 6 Units/kg body weight. Patients receiving less than the randomized dose due to the 6 Units/kg maximum, were assigned to the nearest dose group for analysis. The sample size for BOTOX 50 Units, 100 Units, and 200 Units were 38, 45 and 30, respectively. Prior to treatment administration, patients received anesthesia based on age and local site practice. One hundred and nine patients (97.3%) received general anesthesia or conscious sedation and 3 patients (2.7%) received local anesthesia.

The study results demonstrated within group improvements in the primary efficacy variable of change from baseline in daytime urinary incontinence episodes (normalized to 12 hours) at the primary efficacy time point (Week 6) for all 3 BOTOX treatment groups. Additional benefits were seen with BOTOX 200 Units for measures related to reducing maximum bladder pressure when compared to 50 Units. The decrease in maximum detrusor pressure (MDP) during the storage phase (MDP defined as the highest value in the Pdet channel during the storage phase [e.g., the greater of the following: the maximum Pdet during the highest amplitude IDC, the maximum Pdet during a terminal detrusor contraction, the Pdet at the end of filling, or the highest Pdet at any other time during the storage phase]) for BOTOX 200 Units at Week 6 was greater than the decrease observed for 50 Units. Within group improvements for the primary and secondary endpoints for the 200 Units dose group are shown in Table 30.

The efficacy of BOTOX 6 U/kg for pediatric patients with NDO weighing less than 34 kg was comparable to that of BOTOX 200 U.

Table 30: Baseline and Change from Baseline in Daily Daytime Frequency of Urinary Incontinence Episodes, Urine Volume at First Morning Catheterization, Maximum Detrusor Pressure during the Storage Phase (cmH2O), and Maximum Cystometric Capacity (mL) in Study191622-120
	BOTOX 200 U N=30
Daily average frequency of daytime urinary incontinence episodesa
Mean Baseline	3.7
Mean Change* at Week 2 (95% CI)	-1.1 (-1.7, -0.6)
Mean Change* at Week 6** (95% CI)	-1.3 (-1.8, -0.9)
Mean Change* at Week 12 (95% CI)	-0.9 (-1.5, -0.4)
Urine Volume at First Morning Catheterization (mL)ᵇ
Mean Baseline	187.7
Mean Change* at Week 2 (95% CI)	63.2 (27.9, 98.6)
Mean Change* at Week 6** (95% CI)	87.5 (52.1, 122.8)
Mean Change* at Week 12 (95% CI)	45.2 (10.0, 80.5)
Maximum Detrusor Pressure (PdetMax) During the Storage Phase (cm H2O)ᵇ
Mean Baseline	56.7
Mean Change* at Week 6** (95% CI)	-27.3 (-36.4, -18.2)
Maximum Cystometric Capacity (mL) (MCC)ᵇ
Mean Baseline	202.3
Mean Change* at Week 6** (95% CI)	63.6 (29.0, 98.1)

CI = Confidence Interval

* LSmean change and 95% CI are based on an ANCOVA model with baseline value as covariate and treatment group, age (< 12 years or >= 12 years), baseline daytime urinary incontinence episodes (<= 6 or > 6) and anticholinergic therapy (yes/no) at baseline as factors.

** Primary timepoint

a Primary endpoint

b Secondary endpoint

The median duration of response in this study, based on patient qualification for re-treatment was 207 days (30 weeks) for BOTOX 200 Units dose group. To qualify for re-treatment, patients must have reported at least 2 urinary incontinence episodes over 2 days and at least 12 weeks have passed from the prior bladder injection.

14.4 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 31).

Table 31: 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 11), and all timepoints from Week 4 to Week 24 in Study 2 (Figure 12), compared to placebo-treated patients.

Figure 11: Mean Change from Baseline in Number of Headache Days for Study 1

Figure 11: Mean Change from Baseline in Number of Headache Days for Study 1

Figure 12: Mean Change from Baseline in Number of Headache Days for Study 2

Figure 12: Mean Change from Baseline in Number of Headache Days for Study 2

14.5 Adult Spasticity

Adult Upper Limb Spasticity

The efficacy of BOTOX for the treatment of adult upper limb spasticity was evaluated in several randomized, multi-center, double-blind, placebo-controlled studies (Studies 1 through 6).

Study 1 included 126 adult 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 post-stroke. 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 32). Use of an EMG/nerve stimulator was recommended to assist in proper muscle localization for injection. Patients were followed for 12 weeks.

Table 32: BOTOX 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

a Injected 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 33.

Table 33: 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)

a BOTOX injected into both the flexor carpi radialis and ulnaris muscles

b BOTOX injected into the flexor digitorum profundus and flexor digitorum sublimis muscles

c BOTOX injected into the adductor pollicis and flexor pollicis longus muscles

Study 2 compared 3 doses of BOTOX with placebo and included 91 adult 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 34).

Table 34: BOTOX Dose and Injection Sites in Study 2 and Study 3
	Total Dose
Muscles Injected	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 35.

Table 35: 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)

a p=0.053

b Total dose of BOTOX injected into both the flexor carpi radialis and ulnaris muscles

c Total dose of BOTOX injected into the flexor digitorum profundus and flexor digitorum sublimis muscles

d Dose of BOTOX injected into biceps brachii muscle

Study 3 compared 3 doses of BOTOX with placebo and enrolled 88 adult 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 34).

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 36.

Table 36: 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)

b Total dose of BOTOX injected into both the flexor carpi radialis and ulnaris muscles

c Total dose of BOTOX injected into the flexor digitorum profundus and flexor digitorum sublimis muscles

d Dose of BOTOX injected into biceps brachii muscle

Study 4 (NCT01153815) included 170 adult 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 37). Study 5 (NCT00460564) included 109 patients with upper limb spasticity who were at least 6 months post-stroke. In Study 5, adult 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 37). The duration of follow-up in Study 4 and Study 5 was 12 weeks.

Table 37: BOTOX Dose and Injection Sites in Studies 4 and 5
	Study 4		Study 5
Muscles Injected	BOTOX (Units)	Volume (mL)	BOTOX low dose (Units)	BOTOX high dose (Units)	Volume low dose (mL)	Volume high dose (mL)	Number of Injection Sites for Studies 4 and 5
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 38. The MAS uses a similar scoring system as the Ashworth Scale.

Table 38: 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)

a BOTOX 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 39.

Table 39: 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)

a BOTOX injected into the adductor pollicis and flexor pollicis longus muscles

Study 6 (NCT03261167) enrolled 124 post-stroke adult patients with upper limb spasticity. In Study 6, 61 patients received 160 Units BOTOX divided among 3 elbow flexors (biceps brachii, brachioradialis, and brachialis) and 63 patients received placebo (see Table 40). EMG, nerve stimulation, or ultrasound techniques were recommended to assist in proper muscle localization for injections. The duration of follow-up was 12 weeks.

Table 40: BOTOX Dose and Injection Sites in Study 6
Muscles Injected	BOTOX 160 U (Units)	Volume (mL)	Number of Injection Sites
Elbow Biceps Brachii	70	1.4	2
Brachioradialis	45	0.9	1
Brachialis	45	0.9	1

The change from baseline in elbow flexor tone measured by modified Ashworth Scale at Week 6 is presented in Table 41.

Table 41: Primary Efficacy Endpoint Results for Elbow Flexors at Week 6 in Study 6
	BOTOX 160 U (N=61)	Placebo (N=63)
Mean Change from Baseline in Elbow Flexor Muscle Tone on the modified Ashworth Scale at Week 6	-1.09*	-0.71

*nominal p value <0.05

Adult Lower Limb Spasticity

The efficacy and safety of BOTOX for the treatment of adult lower limb spasticity was evaluated in Study 7, a randomized, multi-center, double-blind, placebo-controlled study. Study 7 included 468 post-stroke adult 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 42) 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 42: BOTOX Dose and Injection Sites in Study 7
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 how the 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 43).

Table 43: Co-Primary Efficacy Endpoints Results in Study 7 (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 13) and CGI (see Figure 14) were observed at Week 2, Week 4, and Week 6 for patients treated with BOTOX.

Figure 13: Modified Ashworth Scale Ankle Score for Study 7 – Mean Change from Baseline by Visit

Figure 13: Modified Ashworth Scale Ankle Score for Study 6 – Mean Change from Baseline by Visit

Figure 14: Clinical Global Impression by Physician for Study 7 – Mean Scores by Visit

Figure 14: Clinical Global Impression by Physician for Study 6 – Mean Scores by Visit

14.6 Pediatric Spasticity

Pediatric Upper Limb Spasticity

The efficacy and safety of BOTOX for the treatment of upper limb spasticity in pediatric patients 2 to 17 years of age was evaluated in Study 1 (NCT01603602), a randomized, multi-center, double-blind, placebo-controlled study. Study 1 included 234 pediatric patients (78 BOTOX 3 Units/kg, 77 BOTOX 6 Units/kg, and 79 placebo) with upper limb spasticity (modified Ashworth Scale elbow or wrist score of at least 2) because of cerebral palsy or stroke. A total dose of 3 Units/kg BOTOX (maximum 100 Units), 6 Units/kg BOTOX (maximum 200 Units), or placebo was injected intramuscularly and divided between the elbow or wrist and finger muscles (see Table 44). Electromyographic guidance, nerve stimulation, or ultrasound techniques were used to assist in muscle localization for injections. Patients were followed for 12 weeks after injection.

Table 44: BOTOX Dose and Injection Sites in Study 1
Muscles Injected	BOTOX 3 Units/kg* (maximum Units per muscle)	BOTOX 6 Units/kg** (maximum Units per muscle)	Number of Injection Sites
Elbow Flexor Muscles
Biceps	1.5 Units/kg (50 Units)	3 Units/kg (100 Units)	4
Brachialis	1 Unit/kg (30 Units)	2 Units/kg (60 Units)	2
Brachioradialis	0.5 Units/kg (20 Units)	1 Unit/kg (40 Units)	2
Wrist and Finger Muscles
Flexor carpi radialis	1 Unit/kg (25 Units)	2 Units/kg (50 Units)	2
Flexor carpi ulnaris	1 Unit/kg (25 Units)	2 Units/kg (50 Units)	2
Flexor digitorum profundus	0.5 Units/kg (25 Units)	1 Unit/kg (50 Units)	2
Flexor digitorum sublimis	0.5 Units/kg (25 Units)	1 Unit/kg (50 Units)	2

* Did not exceed a total dose of 100 Units

** Did not exceed a total dose of 200 Units

The co-primary endpoints were the average of the change from baseline in modified Ashworth Scale (MAS) principal muscle group score (elbow or wrist) at Week 4 and Week 6, and the average of the Clinical Global Impression of Overall Change by Physician (CGI) at Week 4 and Week 6. The CGI evaluated the response to treatment in terms of how the patient was doing in his/her life using a 9-point scale (-4=very marked worsening to +4=very marked improvement).

Compared to placebo, significant improvements in MAS change from baseline were observed at all timepoints for BOTOX-treated patients (see Table 45, Figure 15 and Figure 16). Although CGI scores numerically favored BOTOX over placebo, the difference was not statistically significant.

Table 45: Co-Primary Efficacy Endpoints Results in Study 1 (Pediatric Upper Limb Spasticity, Modified Intent-To-Treat Population)
	BOTOX 3 Units/kg (N=78)	BOTOX 6 Units/kg (N=77)	Placebo (N=79)
Mean Change from Baseline in Principal Muscle Group (Elbow or Wrist) on the modified Ashworth Scale
Week 4 and 6 Average	-1.92*	-1.87*	-1.21
Mean Clinical Global Impression Score
Week 4 and 6 Average	1.88	1.87	1.66

*Nominal p value <0.05

Figure 15: Modified Ashworth Scale Score for Study 1 (Pediatric Upper Limb Spasticity, Modified Intent-To-Treat Population) – Mean Change from Baseline by Visit

Figure 15: Modified Ashworth Scale Score for Study 1 (Pediatric Upper Limb Spasticity, Modified Intent-To-Treat Population) – Mean Change from Baseline by Visit

Figure 16: Clinical Global Impression of Overall Change for Study 1 (Pediatric Upper Limb Spasticity, Modified Intent-To-Treat Population) – Mean Scores by Visit

Figure 16: Clinical Global Impression of Overall Change for Study 1 (Pediatric Upper Limb Spasticity, Modified Intent-To-Treat Population) – Mean Scores by Visit

Pediatric Lower Limb Spasticity

The efficacy and safety of BOTOX for the treatment of lower limb spasticity in pediatric patients 2 to 17 years of age was evaluated in Study 2 (NCT01603628), a randomized, multi-center, double-blind, placebo-controlled study. Study 2 included 381 pediatric patients (125 BOTOX 4 Units/kg, 127 BOTOX 8 Units/kg, and 129 placebo) with lower limb spasticity (modified Ashworth Scale ankle score of at least 2) because of cerebral palsy. A total dose of 4 Units/kg BOTOX (maximum 150 Units), 8 Units/kg BOTOX (maximum 300 Units), or placebo was injected intramuscularly and divided between the gastrocnemius, soleus, and tibialis posterior (see Table 46). Electromyographic guidance, nerve stimulation, or ultrasound techniques were used to assist in muscle localization for injections. Patients were followed for 12 weeks after injection.

Table 46: BOTOX Dose and Injection Sites in Study 2
Muscles Injected	BOTOX 4 Units/kg* (maximum Units per muscle)	BOTOX 8 Units/kg** (maximum Units per muscle)	Number of Injection Sites
Mandatory Ankle Muscles Gastrocnemius medial head	1 Unit/kg (37.5 Units)	2 Units/kg (75 Units)	2
Gastrocnemius lateral head	1 Unit/kg (37.5 Units)	2 Units/kg (75 Units)	2
Soleus	1 Unit/kg (37.5 Units)	2 Units/kg (75 Units)	2
Tibialis Posterior	1 Unit/kg (37.5 Units)	2 Units/kg (75 Units)	2

* did not exceed a total dose of 150 Units

** did not exceed a total dose of 300 Units

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 Clinical Global Impression of Overall Change by Physician (CGI) at Week 4 and Week 6. The CGI evaluated the response to treatment in terms of how the patient was doing in his/her life using a 9-point scale (-4=very marked worsening to +4=very marked improvement).

Statistically significant differences between BOTOX and placebo were demonstrated for the MAS and CGI for the 8 Units/kg dose only (see Table 47).

Table 47: Co-Primary Efficacy Endpoints Results in Study 2 (Pediatric Lower Limb Spasticity, Modified Intent-To-Treat Population)
	BOTOX 4 Units/kg (N = 125)	BOTOX 8 Units/kg (N=127)	Placebo (N=129)
Mean Change from Baseline in Plantar Flexors on the modified Ashworth Scale
Week 4 and 6 Average	-1.01**	-1.06*	-0.80
Mean Clinical Global Impression Score
Week 4 and 6 Average	1.49	1.65*	1.36

* Significantly different from placebo (p<0.05)

** Nominal p value <0.05

Compared to placebo, improvements in mean change from baseline for the MAS, and mean CGI score for lower limb spasticity were observed at timepoints up to Week 12 for BOTOX-treated patients (see Figure 17 and Figure 18).

Figure 17: Modified Ashworth Scale Ankle Score for Study 2 (Pediatric Lower Limb Spasticity, Modified Intent-To-Treat Population) – Mean Change from Baseline by Visit

Figure 17: Modified Ashworth Scale Ankle Score for Study 2 (Pediatric Lower Limb Spasticity, Modified Intent-To-Treat Population) – Mean Change from Baseline by Visit

Figure 18: Clinical Global Impression of Overall Change for Study 2 (Pediatric Lower Limb Spasticity, Modified Intent-To-Treat Population) – Mean Scores by Visit

Figure 18: Clinical Global Impression of Overall Change for Study 2 (Pediatric Lower Limb Spasticity, Modified Intent-To-Treat Population) – Mean Scores by Visit

14.7 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 48.

Table 48: 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]

[a] Confidence intervals are constructed from the analysis of covariance table with treatment and investigational site as main effects, and baseline CDSS as a covariate.

[b] These 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.

[c] Confidence 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 treatment-associated 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 49. The total dose and muscles selected were tailored to meet individual patient needs.

Table 49: 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
Semispinalis	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.

14.8 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 adult patients 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 re-increase 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 50).

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 50: 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 re-treatment during the study.

14.9 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.

14.10 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.