14 CLINICAL STUDIES

14.1 Cervical Dystonia

The efficacy of DYSPORT was evaluated in two randomized, double-blind, placebo-controlled, single-dose, parallel-group studies in treatment-naive cervical dystonia patients. The principal analyses from these trials provide the primary demonstration of efficacy involving 252 patients (121 on DYSPORT, 131 on placebo) with 36% male and 64% female. Ninety-nine percent of the patients were Caucasian.

In both placebo-controlled studies (Study 1 and Study 2), a dose of 500 Units of DYSPORT was given by intramuscular injection divided among two to four affected muscles. These studies were followed by long-term open-label extensions that allowed titration in 250 Unit steps to doses in a range of 250 to 1000 Units, after the initial dose of 500 Units. In the extension studies, re-treatment was determined by clinical need after a minimum of 12 weeks. The median time to re-treatment was 14 weeks and 18 weeks for the 75 thpercentile.

The primary assessment of efficacy was based on the total Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) change from baseline at Week 4 for both studies. The scale evaluates the severity of dystonia, patient-perceived disability from dystonia, and pain. The adjusted mean change from baseline in the TWSTRS total score was statistically significantly greater for the DYSPORT group than the placebo group at Weeks 4 in both studies (see Table 14) .

Table 14: TWSTRS Total Score Efficacy Outcome from the Phase 3 Cervical Dystonia Studies Intent to Treat Population
* Change from baseline is expressed as adjusted least square mean (SE) † Significant at p-value < 0.05
	Study 1		Study 2
	DYSPORT 500 Units N=55	Placebo N=61	DYSPORT 500 Units N=37	Placebo N=43
Baseline (week 0) Mean (SD)	43.8 (8.0)	45.8 (8.9)	45.1 (8.7)	46.2 (9.4)
Week 4 Mean (SD) Change from Baseline *	30.0 (12.7) -15.6 (2.0)	40.2 (11.8) -6.7 (2.)	35.2 (13.8) -9.6 (2.0)	42.4 (12.2) -3.7 (1.8)
treatment difference 95% confidence interval	-8.9 † [-12.9 to -4.7]		-5.9 † [-10.6 to -1.3]
Week 8 Mean (SD) Change from Baseline *	29.2 (11.0) -14.7 (2.0)	39.6 (13.5) -5.9 (2.0)
treatment difference 95% confidence interval	-8.8 † [-12.9 to -4.7]

Analyses by gender, weight, geographic region, underlying pain, cervical dystonia severity at baseline and history of treatment with botulinum toxin did not show any meaningful differences between groups.

Table 15 indicates the average DYSPORT dose, and percentage of total dose, injected into specific muscles in the pivotal clinical trials.

Table 15: DYSPORT 500 Units starting dose (units and % of the total dose) by Unilateral Muscle Injected During Double-blind Pivotal Phase 3 studies 2 and 1 Combined

* Total number of patients in combined studies 2 and 1 who received initial treatment = 121.
Number of patients injected per muscle *		DYSPORT Dose Injected		Percentage of the total DYSPORT Dose Injected
		Median [DYSPORT Units] (min, max)	75th percentile [DYSPORT Units]	Median [%] (min, max)	75th percentile [%]
Sternocleidomastoid	90	125 Units (50, 350)	150 Units	26.5% (10, 70)	30.0%
Splenius capitis	85	200 Units (75, 450)	250 Units	40.0% (15, 90)	50.0%
Trapezius	50	102.6 Units (50, 300)	150 Units	20.6% (10, 60)	30.0%
Levator scapulae	35	105.3 Units (50, 200)	125 Units	21.1% (10, 40)	25.0%
Scalenus (medius and anterior)	26	115.5 Units (50, 300)	150 Units	23.1% (10,60)	30.0%
Semispinalis capitis	21	131.6 Units (50, 250)	175 Units	29.4% (10, 50)	35.0%
Longissimus	3	150 Units (100, 200)	200 Units	30.0% (20, 40)	40.0%

14.2 Glabellar Lines

Three double-blind, randomized, placebo-controlled, clinical studies evaluated the efficacy of DYSPORT for use in the temporary improvement of the appearance of moderate to severe glabellar lines. These three studies enrolled healthy adults (ages 19-75) with glabellar lines of at least moderate severity at maximum frown. Subjects were excluded if they had marked ptosis, deep dermal scarring, or a substantial inability to lessen glabellar lines, even by physically spreading them apart. The subjects in these studies received either DYSPORT or placebo. The total dose was delivered in equally divided aliquots to specified injection sites (see Figure 1 ).

Investigators and subjects assessed efficacy at maximum frown by using a 4-point scale (none, mild, moderate, severe).

Overall treatment success was defined as post-treatment glabellar line severity of none or mild with at least 2 grade improvement from Baseline for the combined investigator and subject assessments (composite assessment) on Day 30 (see Table 16). Additional endpoints for each of the studies were post-treatment glabellar line severity of none or mild with at least a 1 grade improvement from Baseline for the separate investigator and subject assessments on Day 30.

After completion of the randomized studies, subjects were offered participation in a two-year, open-label re-treatment study to assess the safety of multiple treatments.

Table 16: Treatment Success at Day 30 (None or Mild with at least a 2 Grade Improvement from Baseline at Maximum Frown for the combined Investigator and Subject Assessments (Composite))
	2 Grade Improvement
Study	DYSPORT n/N (%)	Placebo n/N (%)
GL-1	58/105 (55%)	0/53 (0%)
GL-2	37/71 (52%)	0/71 (0%)
GL-3	120/200 (60%)	0/100 (0%)

Treatment with DYSPORT reduced the severity of glabellar lines for up to four months.

Study GL-1

Study GL-1 was a single-dose, double-blind, multicenter, randomized, placebo-controlled study in which 158 previously untreated subjects received either placebo or 50 Units of DYSPORT, administered in five aliquots of 10 Units (see Figure 1 ). Subjects were followed for 180 days. The mean age was 43 years; most of the subjects were women (85%), and predominantly Caucasian (49%) or Hispanic (47%). At Day 30, 55% of DYSPORT-treated subjects achieved treatment success: a composite 2 grade improvement of glabellar line severity at maximum frown (Table 16).

In study GL-1, the reduction of glabellar line severity at maximum frown was greater at Day 30 in the DYSPORT group compared to the placebo group as assessed by both Investigators and subjects (Table 17).

Table 17: GL-1: Investigators' and Subjects' Assessment of Glabellar Line Severity at Maximum Frown Using a 4-point Scale (% and Number of Subjects with Severity of None or Mild)
	Investigators' Assessment		Subjects' Assessment
Day	DYSPORT N=105	Placebo N=53	DYSPORT N=105	Placebo N=53
14	90% 95	17% 9	77% 81	9% 5
30	88% 92	4% 2	74% 78	9% 5
60	64% 67	2% 1	60% 63	6% 3
90	43% 45	6% 3	36% 38	6% 3
120	23% 24	4% 2	19% 20	6% 3
150	9% 9	2% 1	8% 8	4% 2
180	6% 6	0% 0	7% 7	8% 4

Study GL-2

Study GL-2 was a repeat-dose, double-blind, multicenter, placebo-controlled, randomized study. The study was initiated with two or three open-label treatment cycles of 50 Units of DYSPORT administered in five aliquots of 10 Units DYSPORT (see Figure 1 ). After the open-label treatments, subjects were randomized to receive either placebo or 50 Units of DYSPORT. Subjects could have received up to four treatments through the course of the study. Efficacy was assessed in the final randomized treatment cycle. The study enrolled 311 subjects into the first treatment cycle and 142 subjects were randomized into the final treatment cycle. Overall, the mean age was 47 years; most of the subjects were women (86%) and predominantly Caucasian (80%).

At Day 30, 52% of DYSPORT -treated subjects achieved treatment success: a composite 2 grade improvement of glabellar line severity at maximum frown (see Table 16).

The proportion of responders in the final treatment cycle was comparable to the proportion of responders in all prior treatment cycles.

After the final repeat treatment with DYSPORT, the reduction of glabellar line severity at maximum frown was greater at Day 30 in the DYSPORT group compared to the placebo group as assessed by both Investigators and subjects (see Table 18).

Table 18: GL-2 Investigators' and Subjects' Assessments of Glabellar Line Severity at Maximum Frown Using a 4-point Scale (% and Number of Subjects with Severity of None or Mild)
	Investigators' Assessment		Subjects' Assessment
Day	DYSPORT N=71	Placebo N=71	DYSPORT N=71	Placebo N=71
30	85% 60	4% 3	79% 56	1% 1

Study GL-3

Study GL-3 was a single-dose, double-blind, multicenter, randomized, placebo-controlled study in which 300 previously untreated subjects received either placebo or 50 Units of DYSPORT, administered in five aliquots of 10 Units (see Figure 1 ). Subjects were followed for 150 days. The mean age was 44 years; most of the subjects were women (87%), and predominantly Caucasian (75%) or Hispanic (18%).

At Day 30, 60% of DYSPORT-treated subjects achieved treatment success: a composite 2 grade improvement of glabellar line severity at maximum frown (see Table 16).

In study GL-3, the reduction of glabellar line severity at maximum frown was greater at Day 30 in the DYSPORT group compared to the placebo group as assessed by both Investigators and subjects (see Table 19).

Table 19: GL-3 Investigators' and Subjects' Assessment of Glabellar Line Severity at Maximum Frown Using a 4-point Scale (% and Number of Subjects with Severity of None or Mild)
	Investigators' Assessment		Subjects' Assessment
Day	DYSPORT N=200	Placebo N=100	DYSPORT N=200	Placebo N=100
14	83% 166	5% 5	83% 165	2% 2
30	86% 171	0% 0	82% 163	2% 2
60	75% 150	1% 1	65% 130	4% 4
90	51% 102	1% 1	46% 91	2% 2
120	29% 58	1% 1	31% 61	3% 3
150	16% 32	1% 1	16% 31	3% 3

Geriatric Subjects

In GL1, GL2, and GL3, there were 8 subjects aged 65 and older who were randomized to DYSPORT 50 Units in 5 equal aliquots of 10 Units (4) or placebo (4). None of the geriatric DYSPORT subjects were a treatment success at maximum frown at Day 30.

14.3 Spasticity in Adults

Upper Limb Spasticity

The efficacy and safety of DYSPORT for the treatment of upper limb spasticity in adults was evaluated in a randomized, multicenter, double-blind, placebo-controlled study that included 238 patients (159 DYSPORT and 79 placebo) with upper limb spasticity (Modified Ashworth Scale (MAS) score ≥2 in the primary targeted muscle group for toxin-naive patients or MAS score ≥3 in the primary targeted muscle group for toxin non-naive patients at least 4 months after the last botulinum toxin injection, of any serotype) who were at least 6 months post-stroke or post-traumatic brain injury. The median age of the patients in this study was 55 years (range 18 to 78 years), 64% were male, and 86% were Caucasian.

DYSPORT 500 Units (N=80), DYSPORT 1000 Units (N=79), or placebo (N=79) was injected intramuscularly into the affected upper limb muscles. After injection of the primary targeted muscle groups (PTMG), the remainder of the dose was injected into at least two additional upper limb muscles determined by the patient's individual presentation. Table 20 provides the mean and range of DYSPORT doses injected and the number of injections into specific muscles of the upper limb.

Table 20: DYSPORT Dose Injected and Number of Injections per Muscle in Adults with Upper Limb Spasticity
Muscle	DYSPORT Treatment Group	Number of Patients	Mean DYSPORT Units injected (Min, Max)	Number of Injection Sites Median [Q1 ; Q3]
Flexor digitorum profundus (FDP)*	500 U 1000 U	54 65	93.5 Units (50 to 100) 195.5 Units (100 to 300)	1, [1 ; 2] 2, [1 ; 2]
Flexor digitorum superficialis (FDS)*	500 U 1000 U	63 73	95.4 Units (50 to 100) 196.8 Units (100 to 300)	2, [1 ; 2] 2, [1 ; 2]
Flexor carpi radialis (FCR)*	500 U 1000 U	57 57	92.2 Units (25 to 100) 178.1 Units (80 to 300)	1, [1 ; 2] 1, [1 ; 2]
Flexor carpi ulnaris (FCU)*	500 U 1000 U	47 49	89.9 Units (25 to 180) 171.2 Units (80 to 200)	1, [1 ; 2] 1, [1 ; 2]
Brachialis*	500 U 1000 U	60 43	148.5 Units (50 to 200) 321.4 Units (100 to 300)	2, [1 ; 2] 2, [1 ; 2]
Brachioradialis*	500 U 1000 U	42 28	88.3 Units (50 to 200) 172.1Units (50 to 200)	1, [1 ; 2] 1, [1 ; 2]
Biceps Brachii (BB)	500 U 1000 U	28 19	106.4 Units (50 to 200) 207.4 Units (100 to 400)	2, [1 ; 2] 2, [1 ; 2]
Pronator Teres	500 U 1000 U	14 30	81.8 Units (45 to 200) 157.3 Units (80 to 200)	1, [1 ; 2] 1, [1 ; 2]
*Primary Targeted Muscle Group

The co-primary efficacy variables were muscle tone assessed by the MAS at the primary targeted muscle group at week 4 and the Physician Global Assessment (PGA; ranges from -4 = marked worse to +4 = marked improved) at week 4 (see Table 21).

Table 21: Primary Endpoints (PTMG MAS and PGA) and MAS by Muscle Group at Week 4 in Adults with Upper Limb Spasticity
	Placebo (N=79)	DYSPORT
	Placebo (N=79)	(500 units) (N=80)	(1000 units) (N=79)
LS Mean Change from Baseline in PTMG Muscle Tone on the MAS	-0.3	-1.2*	-1.4*
LS Mean PGA of Response to Treatment	0.7	1.4*	1.8*
LS Mean Change from Baseline in Wrist Flexor Muscle Tone on the MAS	-0.3 (n=54)	-1.4 (n=57)	-1.6 (n-58)
LS Mean Change from Baseline in Finger Flexor Muscle Tone on the MAS	-0.3 (n=70)	-0.9 (n=66)	-1.2 (n=73)
LS Mean Change from Baseline in Elbow Flexor Muscle Tone on the MAS	-0.3 (n=56)	-1.0 (n=61)	-1.2 (n=48)
LS= Least Square *p≤0.05

Lower Limb Spasticity
The efficacy of DYSPORT for the treatment of lower limb spasticity was evaluated in a randomized, multicenter, double-blind, placebo-controlled study that included 381 patients (253 DYSPORT and 128 placebo). Patients had lower limb spasticity (Modified Ashworth Scale (MAS) score ≥2 in the affected ankle joint for toxin-naive patients, or MAS score ≥3 in the affected ankle joint for toxin non-naive patients) and were at least 6 months post-stroke or post-traumatic brain injury.

Table 22 provides the median DYSPORT doses injected and the number of injections into specific muscles of the lower limb as reported in the double-blind study. In the study, the gastrocnemius and soleus muscles, and at least one additional lower limb muscle were injected, according to the clinical presentation.

Table 22: DYSPORT Dose Injected and Number of Injections per Muscle in the Lower Limb - Median for the 1000 Unit and 1500 Unit Dose Groups
Injected Muscle	DYSPORT Units Injected	Number of Injection Sites
Gastrocnemius Lateral Medial	100 Units to 150 Units	1
Gastrocnemius Lateral Medial	100 Units to 150 Units	1
Soleus	333 Units to 500 Units	3
Tibialis posterior	200 Units to 300 Units	2
Flexor digitorum longus	133 Units to 200 Units	1 to 2
Flexor hallucis longus	67 Units to 200 Units	1

The primary efficacy variable was muscle tone assessed by the MAS at the ankle joint at week 4. The first secondary endpoint was the Physician Global Assessment at week 4 (see Table 23).

Table 23: Primary Endpoint Change in MAS and the First Secondary Endpoint PGA at Week 4 in Adults with Lower Limb Spasticity
* P‹0.05
LS Mean Change from Baseline on the Modified Ashworth Scale	DYSPORT 1000 Units (N=125)	DYSPORT 1500 Units (N=128)	Placebo (N=128)
Week 4	-0.6	-0.8 *	-0.5
LS Mean Physician Global Assessment Score Investigator
Week 4	0.9	0.9	0.7

14.4 Spasticity in Pediatric Patients

Upper Limb Spasticity in Pediatric Patients
The efficacy of DYSPORT for the treatment of upper limb spasticity in pediatric patients 2 to 17 years of age was evaluated in a double-blind, low-dose controlled, multicenter study (NCT02106351). A total of 208 patients with spasticity because of cerebral palsy who were toxin naïve or non-naïve (66% had prior treatment with botulinum toxin), weighed at least 10 kgs, and had a baseline Modified Ashworth Score (MAS) of grade 2 or greater (99% patients) at the primary targeted muscle groups (PTMG), were enrolled in the modified Intention to Treat population (mITT). Patients received DYSPORT 16 Units/kg (n=70), DYSPORT 8 Units/kg (n=69), or DYSPORT 2 Units/kg (n=69) injected into the upper limb. The elbow flexors and wrist flexors respectively were the PTMG in 57% and in 43% of patients. The median age of the patients in this study was 9 years (range 2 to 17 years; 57% were between 2 and 9 years of age); 60% of patients were male, and 75% were White.

The primary efficacy endpoint was the mean change from baseline in MAS in the PTMG at Week 6 (see Table 24). The secondary efficacy endpoint was the mean Physician Global Assessment (PGA) score assessed at Week 6 (Table 25). Although PGA scores numerically favored DYSPORT treatment over the low-dose control, the difference was not statistically significant.

Table 24: Modified Ashworth Scale Score in the PTMG Change from Baseline at Week 6 in Pediatric Patients with Upper LImb Spasticity (mITT Population)
	Control Group	Treatment Groups
	DYSPORT 2 U/kg (N=69)	DYSPORT 8 U/kg (N=69)	DYSPORT 16 U/kg (N=70)
Baseline
Mean (SD)	3.1 (0.3)	3.1 (0.3)	3.1 (0.5)
Week 6
LS amean change from baseline in PTMG bon MAS	-1.6	-2.0	-2.3
Difference from control in LS ameans		-0.4	-0.7
p-value c		0.0118 d	<0.0001
Week 16
LS amean change from baseline in PGMG bon MAS	-0.9	-1.2	-1.5
Difference from control in LS ameans		-0.3 d	-0.6 d

aLS = Least Square
bPTMG=Primary Targeted Muscle Group
cp-value is derived from ANCOVA on ranked MAS score change from baseline with treatment, baseline score, age range at baseline, prior botulinum toxin treatment status at baseline, and center as explanatory variables
dNominal p-value <0.05

Table 25: Physician Global Assessment of Treatment Response at Week 6 in Pediatric Patients with Upper Limb Spasticity (mITT Population)
	Control Group	Treatment Group
	DYSPORT 2 U/kg (N=68)	DYSPORT 8 U/kg (N=69)	DYSPORT 16 U/kg (N=70)
Week 6
Mean score (SD)	1.7 (0.9)	2.0 (0.9)	2.0 (0.9)
LS amean in PGA	1.8	2.0	2.0
Difference from control in LS amean		0.2	0.2
p-value b		0.2043	0.1880
Week 16
Mean score (SD)	1.7 (1.0)	1.6 (1.1)	1.9 (1.2)
LS amean in PGA	1.8	1.7	1.9
Difference from contron in LS amean		-0.1	0.1
p-value b		0.7001	0.4041

aLS=Least Square
bp-value is derived from ANOVA on ranked PGA score with treatment, age range at baseline, prior botulinum toxin treatment status at baseline, and center as explanatory variables

Lower Limb Spasticity in Pediatric Patients
The efficacy of DYSPORT for the treatment of lower limb spasticity in patients 2 to 17 years of age was evaluated in a double-blind, placebo-controlled, multicenter study. A total of 235 patients with cerebral palsy causing dynamic equinus foot deformity who were toxin-naïve or non-naïve and had a Modified Ashworth Score (MAS) of grade 2 or greater at the ankle plantar flexors were enrolled. Patients received DYSPORT 10 Units/kg/leg (n=79), DYSPORT 15 Units/kg/leg (n=79) or placebo (n=77) injected into the gastrocnemius and soleus muscles (see Table 27). Forty-one percent of patients (n=66) were treated bilaterally and received a total lower limb DYSPORT dose of either 20 Units/kg (n=37) or 30 Units/kg (n=29). The median age of the patients in this study was 5 years (range 2 to 17 years); 60% of patients were male, and 73% were Caucasian.

The primary efficacy endpoint was the mean change from baseline in MAS in ankle plantar flexor at Week 4; a co-primary endpoint was the mean Physician’s Global Assessment (PGA) score at Week 4 (see Table 26).

Table 26: MAS and PGA Change from Baseline at Week 4 in Pediatric Patient with Lower Limb Spasticity (ITT Population)
		Placebo (N=77)	DYSPORT 10 Units/kg/leg (N=79)	DYSPORT 15 Units/kg/leg (N=79)
LS Mean Change from Baseline in Ankle plantar flexor Muscle Tone on the MAS	Week 4	-0.5	-0.9*	-1.0*
	Week 12	-0.5	-0.8*	-1.0*
LS Mean PGA of Response to Treatment	Week 4	0.7	1.5*	1.5*
LS Mean PGA of Response to Treatment	Week 12	0.4	0.8*	1.0*
LS=Least Square *p‹0.05