Dysport in Hallux Abducto Valgus (HAV) Phase IIa (DYSTANCE)

• ClinicalTrials.gov Identifier: NCT03569098
• Recruitment Status: Completed
• First Posted: June 26, 2018
• Results First Posted: July 2, 2021
• Last Update Posted: July 2, 2021
• Sponsor: Ipsen
• Information provided by (Responsible Party): Ipsen

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Hallux Abducto Valgus
• Interventions: Biological: Botulinum toxin type A; Drug: Placebo
• Enrollment: 186

Participant Flow

Recruitment Details

This Phase II double-blind study was conducted at 27 sites in the United States between 19 June 2018 and 22 May 2020 in adult participants suffering from clinically significant hallux abducto valgus (HV) who have not undergone surgery for their condition.

Pre-assignment Details

The study consisted of a screening period (up to 3 weeks), followed by a double-blind treatment period (Cycle 1). From Week 12, retreatment criteria were evaluated every 4 weeks to determine eligibility to receive treatment in the open-label period (Cycles 2 and 3). Total study duration was a maximum of 36 weeks. A total of 186 participants were randomized in a 1:1:1 ratio to 1 of 3 treatment groups (placebo, Dysport 300 units (U) and Dysport 500 U) in the double-blind treatment period.

Arm/Group Title	Placebo	Dysport 300 U	Dysport 500 U
Arm/Group Description	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of placebo (matching with Dysport) intramuscular injection distributed between 4 injection points in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 300 U intramuscular injection distributed between 4 injection points (75 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 500 U intramuscular injection distributed between 4 injection points (125 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.
Period Title: Double-Blind Treatment Cycle 1
Started	63	63	60
Received Study Medication	61	63	56
Completed [1]	55	53	49
Not Completed	8	10	11
Reason Not Completed
Withdrawal by Subject	5	2	5
Study terminated by sponsor	0	6	3
Lost to Follow-up	1	1	0
Technical problems	0	0	2
Physician Decision	1	0	0
Protocol deviation	0	1	0
Other	1	0	1
[1] Completed the double-blind treatment cycle 1.
Period Title: Open-Label Treatment Cycle 2
Started	0 [1]	146 [2]	0 [3]
Completed [4]	0	111	0
Not Completed	0	35	0
Reason Not Completed
Study terminated by sponsor	0	21	0
Withdrawal by Subject	0	11	0
Lost to Follow-up	0	3	0
[1] No participants were treated with placebo during the open-label treatment cycle 2.; [2] All participants who met retreatment criteria were treated with Dysport 300 U during the open-label treatment cycle 2.; [3] No participants were treated with Dysport 500 U during the open-label treatment cycle 2.; [4] Completed the open-label treatment cycle 2.
Period Title: Open-Label Treatment Cycle 3
Started	0	8 [1]	56 [2]
Completed [3]	0	7	50
Not Completed	0	1	6
Reason Not Completed
Withdrawal by Subject	0	0	4
Study terminated by sponsor	0	1	1
Lost to Follow-up	0	0	1
[1] Participants were treated with Dysport 300 U during open-label treatment cycle 3 based on investigator judgment following clinical evaluation of the participant at the time of retreatment.; [2] Participants were treated with Dysport 500 U during open-label treatment cycle 3 based on investigator judgment following clinical evaluation of the participant at the time of retreatment.; [3] Completed the open-label treatment cycle 3.

Baseline Characteristics

Arm/Group Title		Placebo	Dysport 300 U	Dysport 500 U	Total
Arm/Group Description		On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of placebo (matching with Dysport) intramuscular injection distributed between 4 injection points in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 300 U intramuscular injection distributed between 4 injection points (75 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 500 U intramuscular injection distributed between 4 injection points (125 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	Total of all reporting groups
Overall Number of Baseline Participants		63	63	60	186
Baseline Analysis Population Description		The Intention-to-Treat (ITT) analysis set included all randomized participants.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	63 participants	63 participants	60 participants	186 participants
		48.3 (13.18)	48.4 (14.04)	48.0 (12.24)	48.2 (13.12)
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	63 participants	63 participants	60 participants	186 participants
	<65 years	56	58	57	171
	>=65 and <85 years	7	5	3	15
	>=85 years	0	0	0	0
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	63 participants	63 participants	60 participants	186 participants
	Female	55	60	56	171
	Male	8	3	4	15
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	63 participants	63 participants	60 participants	186 participants
American Indian or Alaska Native		0	0	0	0
Asian		1	5	6	12
Black or African American		10	4	9	23
Native Hawaiian or Other Pacific Islander		0	0	0	0
White		49	54	43	146
Other		3	0	2	5
Hispanic or Latino		16	10	16	42
Not Hispanic or Latino		47	53	44	144

Outcome Measures

1. Primary Outcome

Title	Least Square (LS) Mean Change From Baseline in the Daily Numeric Pain Rating Scale (NPRS) Score at Week 8
Description	The NPRS is a widely used and validated unidimensional measure of pain intensity in adults. Participants were asked to rate the intensity of their foot pain during physical activity (example, walking, standing or running) based on an 11-point scale ranging from 0 to 10, where 0 represents "no pain" and 10 represents "worst possible pain". Higher scores indicate a worse outcome. Daily pain intensities were recorded by the participant using an electronic diary (eDiary) for 7 consecutive days prior to each study visit. Baseline was defined as the daily NPRS score averaged over the 7 consecutive days prior to the Baseline visit (Day 1).
Time Frame	Baseline and Week 8 in the double-blind treatment period

Outcome Measure Data

Analysis Population Description

The ITT analysis set included all randomized participants. For participants without any available post-Baseline NPRS average scores, the Week 8 average pain score was imputed.

Arm/Group Title	Placebo	Dysport 300 U	Dysport 500 U
Arm/Group Description:	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of placebo (matching with Dysport) intramuscular injection distributed between 4 injection points in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 300 U intramuscular injection distributed between 4 injection points (75 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 500 U intramuscular injection distributed between 4 injection points (125 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.
Overall Number of Participants Analyzed	63	63	60
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
	-2.04; (-2.66 to -1.41)	-1.71; (-2.33 to -1.10)	-2.40; (-3.03 to -1.77)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dysport 300 U
	Comments	Dysport 300 U versus Placebo.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7669
	Comments	One-sided P-value. The model includes the fixed categorical effects of treatment group, visit, treatment group-by-visit interaction, and the stratification factor as fixed categorical covariates and the Baseline value as a fixed continuous covariate.
	Method	Mixed Model for Repeated Measures (MMRM)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in LS mean
	Estimated Value	0.32
	Confidence Interval	(2-Sided) 95%; -0.55 to 1.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.441
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dysport 500 U
	Comments	Dysport 500 U versus Placebo.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2085
	Comments	One-sided P-value. The model includes the fixed categorical effects of treatment group, visit, treatment group-by-visit interaction, and the stratification factor as fixed categorical covariates and the Baseline value as a fixed continuous covariate.
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in LS mean
	Estimated Value	-0.36
	Confidence Interval	(2-Sided) 95%; -1.24 to 0.51
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.444
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	LS Mean Change From Baseline in the Daily NPRS Score at Weeks 4 and 12
Description	The NPRS is a widely used and validated unidimensional measure of pain intensity in adults. Participants were asked to rate the intensity of their foot pain during physical activity (example, walking, standing or running) based on an 11-point scale ranging from 0 to 10, where 0 represents "no pain" and 10 represents "worst possible pain". Higher scores indicate a worse outcome. Daily pain intensities were recorded by the participant using an eDiary for 7 consecutive days prior to each study visit. Baseline was defined as the daily NPRS score averaged over the 7 consecutive days prior to the Baseline visit (Day 1).
Time Frame	Baseline and Weeks 4 and 12 in the double-blind treatment period

Outcome Measure Data

Analysis Population Description

The ITT analysis set included all randomized participants. For participants without any available post-Baseline NPRS average scores, the Weeks 4 and 12 average pain scores were imputed.

Arm/Group Title	Placebo	Dysport 300 U	Dysport 500 U
Arm/Group Description:	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of placebo (matching with Dysport) intramuscular injection distributed between 4 injection points in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 300 U intramuscular injection distributed between 4 injection points (75 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 500 U intramuscular injection distributed between 4 injection points (125 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.
Overall Number of Participants Analyzed	63	63	60
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
Week 4	-1.68; (-2.26 to -1.11)	-1.36; (-1.94 to -0.78)	-1.85; (-2.45 to -1.25)
Week 12	-1.72; (-2.35 to -1.09)	-1.61; (-2.23 to -1.00)	-2.42; (-3.06 to -1.78)

3. Secondary Outcome

Title	LS Mean Change From Baseline in the Daily Modified Foot Function Index (mFFI) Disability Subscale Score at Weeks 4, 8 and 12
Description	The foot function index (FFI) was developed to assess foot-related pain, disability and activity limitations and later revised to include foot-related health and quality of life. A modified version of FFI specific to this study was used. The mFFI consists of a total of 21 items grouped into 3 subscales: pain (7 questions), disability (9 questions) and activity limitation (5 questions). The mFFI disability subscale is rated using numeric rating scale ranging from 0 to 10, where 0 represents "no difficulty" and 10 represents "so difficult unable to do". For each item, the participant was asked to record the number value which best corresponded to effect of the foot complaints. To obtain a subscale score, the item scores for a given subscale (i.e., pain, disability or activity limitation subscales) were totaled and divided by maximum total possible and then multiplied by 100. Each subscale score, as well as the total score, ranged from 0 to 100. Higher scores indicate a worse outcome.
Time Frame	Baseline and Weeks 4, 8 and 12 in the double-blind treatment period

Outcome Measure Data

Analysis Population Description

The ITT analysis set included all randomized participants. The results are presented for the participants with data available at Baseline and specific time points.

Arm/Group Title		Placebo	Dysport 300 U	Dysport 500 U
Arm/Group Description:		On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of placebo (matching with Dysport) intramuscular injection distributed between 4 injection points in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 300 U intramuscular injection distributed between 4 injection points (75 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 500 U intramuscular injection distributed between 4 injection points (125 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.
Overall Number of Participants Analyzed		52	53	47
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
Week 4	Number Analyzed	52 participants	50 participants	46 participants
		-17.95; (-23.06 to -12.84)	-15.29; (-20.47 to -10.12)	-16.87; (-22.27 to -11.48)
Week 8	Number Analyzed	49 participants	52 participants	47 participants
		-22.44; (-28.00 to -16.87)	-18.68; (-24.19 to -13.17)	-21.26; (-27.05 to -15.48)
Week 12	Number Analyzed	48 participants	53 participants	46 participants
		-17.21; (-23.11 to -11.31)	-21.04; (-26.80 to -15.27)	-21.50; (-27.61 to -15.39)

4. Secondary Outcome

Title	LS Mean Change From Baseline in the Daily mFFI Pain Subscale Score at Weeks 4, 8 and 12
Description	The FFI was developed to assess foot-related pain, disability and activity limitations and later revised to include foot-related health and quality of life. A modified version of the FFI specific to this study was used. The mFFI consists of a total of 21 items grouped into 3 subscales: pain (7 questions), disability (9 questions) and activity limitation (5 questions). The mFFI pain subscale is rated using numeric rating scale ranging from 0 to 10, where 0 represents "no pain" and 10 represents "worst pain imaginable". For each item, the participant was asked to record the number value which best corresponded to the effect of the foot complaints. To obtain a subscale score, the item scores for a given subscale (i.e., pain, disability or activity limitation subscales) were totaled and divided by the maximum total possible and then multiplied by 100. Each subscale score, as well as the total score, ranged from 0 to 100. Higher scores indicate a worse outcome.
Time Frame	Baseline and Weeks 4, 8 and 12 in the double-blind treatment period

Outcome Measure Data

Analysis Population Description

The ITT analysis set included all randomized participants. The results are presented for the participants with data available at Baseline and specific time points.

Arm/Group Title		Placebo	Dysport 300 U	Dysport 500 U
Arm/Group Description:		On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of placebo (matching with Dysport) intramuscular injection distributed between 4 injection points in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 300 U intramuscular injection distributed between 4 injection points (75 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 500 U intramuscular injection distributed between 4 injection points (125 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.
Overall Number of Participants Analyzed		52	53	48
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
Week 4	Number Analyzed	52 participants	50 participants	46 participants
		-17.97; (-23.23 to -12.70)	-15.67; (-21.00 to -10.33)	-19.30; (-24.86 to -13.73)
Week 8	Number Analyzed	49 participants	52 participants	48 participants
		-22.30; (-28.15 to -16.45)	-20.69; (-26.50 to -14.88)	-24.58; (-30.67 to -18.49)
Week 12	Number Analyzed	48 participants	53 participants	46 participants
		-18.94; (-25.05 to -12.83)	-21.74; (-27.72 to -15.76)	-24.30; (-30.64 to -17.96)

5. Secondary Outcome

Title	LS Mean Change From Baseline in the Daily mFFI Total Score at Weeks 4, 8 and 12
Description	The FFI was developed to assess foot-related pain, disability and activity limitations and later revised to include foot-related health and quality of life. A modified version of the FFI specific to this study was used. The mFFI consists of a total of 21 items grouped into three subscales: pain (7 questions), disability (9 questions) and activity limitation (5 questions). The mFFI items are rated using numeric rating scales ranging from 0 to 10, where 0 represents "no pain/no difficulty/none of the time" and 10 represents "worst pain imaginable/so difficult unable to do/all of the time" for pain, disability and activity limitation subscales, respectively. For each item, the participant was asked to record the number value which best corresponded to the effect of the foot complaints. To obtain a total score, the scores of all 3 subscales were totaled and divided by 3. Each subscale score, as well as the total score, ranged from 0 to 100. Higher scores indicate a worse outcome.
Time Frame	Baseline and Weeks 4, 8 and 12 in the double-blind treatment period

Outcome Measure Data

Analysis Population Description

The ITT analysis set included all randomized participants. The results are presented for the participants with data available at Baseline and specific time points.

Arm/Group Title		Placebo	Dysport 300 U	Dysport 500 U
Arm/Group Description:		On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of placebo (matching with Dysport) intramuscular injection distributed between 4 injection points in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 300 U intramuscular injection distributed between 4 injection points (75 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 500 U intramuscular injection distributed between 4 injection points (125 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.
Overall Number of Participants Analyzed		52	53	47
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
Week 4	Number Analyzed	52 participants	50 participants	46 participants
		-14.87; (-18.98 to -10.75)	-12.80; (-16.96 to -8.64)	-15.10; (-19.45 to -10.76)
Week 8	Number Analyzed	49 participants	52 participants	47 participants
		-18.82; (-23.32 to -14.32)	-16.16; (-20.62 to -11.69)	-18.79; (-23.48 to -14.11)
Week 12	Number Analyzed	48 participants	53 participants	46 participants
		-15.65; (-20.48 to -10.82)	-17.45; (-22.18 to -12.72)	-18.89; (-23.90 to -13.88)

6. Secondary Outcome

Title	LS Mean Change From Baseline in the Daily mFFI Activity Limitation Subscale Score at Weeks 4, 8 and 12
Description	The FFI was developed to assess foot-related pain, disability and activity limitations and later revised to include foot-related health and quality of life. A modified version of the FFI specific to this study was used. The mFFI consists of a total of 21 items grouped into 3 subscales: pain (7 questions), disability (9 questions) and activity limitation (5 questions). The mFFI activity limitation subscale is rated using numeric rating scale ranging from 0 to 10, where 0 represents "none of the time" and 10 represents "all of the time". For each item, the participant was asked to record the number value which best corresponded to the effect of the foot complaints. To obtain a subscale score, the item scores for a given subscale (i.e., pain, disability or activity limitation subscales) were totaled and divided by the maximum total possible and then multiplied by 100. Each subscale score, as well as the total score, ranged from 0 to 100. Higher scores indicate a worse outcome.
Time Frame	Baseline and Weeks 4, 8 and 12 in the double-blind treatment period

Outcome Measure Data

Analysis Population Description

The ITT analysis set included all randomized participants. The results are presented for the participants with data available at Baseline and specific time points.

Arm/Group Title		Placebo	Dysport 300 U	Dysport 500 U
Arm/Group Description:		On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of placebo (matching with Dysport) intramuscular injection distributed between 4 injection points in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 300 U intramuscular injection distributed between 4 injection points (75 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 500 U intramuscular injection distributed between 4 injection points (125 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.
Overall Number of Participants Analyzed		52	53	48
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
Week 4	Number Analyzed	52 participants	50 participants	46 participants
		-9.02; (-12.08 to -5.96)	-7.00; (-10.08 to -3.91)	-9.03; (-12.28 to -5.79)
Week 8	Number Analyzed	49 participants	52 participants	48 participants
		-12.12; (-15.52 to -8.71)	-8.81; (-12.17 to -5.45)	-10.62; (-14.17 to -7.07)
Week 12	Number Analyzed	48 participants	53 participants	46 participants
		-11.09; (-14.79 to -7.40)	-9.25; (-12.87 to -5.63)	-10.84; (-14.69 to -6.99)

7. Secondary Outcome

Title	LS Mean Change From Baseline in HV Angle at Weeks 4, 8 and 12
Description	The HV angle was measured directly on weight-bearing anteriorposterior radiographs, in which the X-ray beam was angled 15° towards the heel centered on the second tarsometatarsal joint with a source to image-receptor distance of 100 centimeters (cm).
Time Frame	Baseline and Weeks 4, 8 and 12 in the double-blind treatment period

Outcome Measure Data

Analysis Population Description

The ITT analysis set included all randomized participants. The results are presented for the participants with data available at Baseline and specific time points.

Arm/Group Title		Placebo	Dysport 300 U	Dysport 500 U
Arm/Group Description:		On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of placebo (matching with Dysport) intramuscular injection distributed between 4 injection points in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 300 U intramuscular injection distributed between 4 injection points (75 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 500 U intramuscular injection distributed between 4 injection points (125 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.
Overall Number of Participants Analyzed		59	62	54
Least Squares Mean (95% Confidence Interval); Unit of Measure: degrees
Week 4	Number Analyzed	59 participants	62 participants	54 participants
		-0.31; (-1.06 to 0.45)	-0.25; (-0.99 to 0.49)	-0.92; (-1.71 to -0.13)
Week 8	Number Analyzed	57 participants	59 participants	54 participants
		-0.43; (-1.17 to 0.30)	-0.67; (-1.40 to 0.05)	-0.80; (-1.57 to -0.04)
Week 12	Number Analyzed	56 participants	59 participants	51 participants
		0.30; (-0.44 to 1.05)	-0.68; (-1.41 to 0.04)	-0.45; (-1.22 to 0.33)

8. Secondary Outcome

Title	LS Mean Change From Baseline in Intermetatarsal Angle at Weeks 4, 8 and 12
Description	The intermetatarsal angle was measured directly on weight-bearing anteriorposterior radiographs, in which the X-ray beam was angled 15° towards the heel centered on the second tarsometatarsal joint with a source to image-receptor distance of 100 cm.
Time Frame	Baseline and Weeks 4, 8 and 12 in the double-blind treatment period

Outcome Measure Data

Analysis Population Description

The ITT analysis set included all randomized participants. The results are presented for the participants with data available at Baseline and specific time points.

Arm/Group Title		Placebo	Dysport 300 U	Dysport 500 U
Arm/Group Description:		On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of placebo (matching with Dysport) intramuscular injection distributed between 4 injection points in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 300 U intramuscular injection distributed between 4 injection points (75 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 500 U intramuscular injection distributed between 4 injection points (125 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.
Overall Number of Participants Analyzed		59	62	54
Least Squares Mean (95% Confidence Interval); Unit of Measure: degrees
Week 4	Number Analyzed	59 participants	62 participants	54 participants
		0.06; (-0.34 to 0.46)	0.40; (0.01 to 0.79)	0.16; (-0.25 to 0.58)
Week 8	Number Analyzed	57 participants	59 participants	54 participants
		-0.02; (-0.41 to 0.36)	0.49; (0.11 to 0.87)	0.45; (0.05 to 0.85)
Week 12	Number Analyzed	56 participants	59 participants	51 participants
		0.42; (0.01 to 0.83)	0.19; (-0.21 to 0.59)	0.04; (-0.38 to 0.47)

9. Secondary Outcome

Title	Median Time to Retreatment
Description	Time to retreatment was calculated as ([Date of retreatment - previous injection date] + 1) / 7 (week). Time to retreatment was calculated for each cycle and the data presented here for the double-blind treatment period.
Time Frame	Up to 24 weeks in the double-blind treatment period

Outcome Measure Data

Analysis Population Description

The safety population included all participants who received at least one dose of study drug administration (including only partial administration). Participants who were not retreated were considered censored at the date of their last visit and not included in the summary but included in the analysis.

Arm/Group Title	Placebo	Dysport 300 U	Dysport 500 U
Arm/Group Description:	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of placebo (matching with Dysport) intramuscular injection distributed between 4 injection points in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 300 U intramuscular injection distributed between 4 injection points (75 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 500 U intramuscular injection distributed between 4 injection points (125 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.
Overall Number of Participants Analyzed	61	63	56
Median (95% Confidence Interval); Unit of Measure: weeks
	12.6; (12 to 13)	13.1; (13 to 16)	13.1; (13 to 15)

10. Secondary Outcome

Title	LS Mean Change From Baseline in Patient Global Impression of Severity (PGI-S) of Foot Pain Score at Weeks 4, 8 and 12
Description	An assessment of PGI-S of foot pain was conducted by the participant using a 4-point Likert scale ranging from 0= no pain to 3= severe pain. Higher scores indicate a worse outcome. The PGI-S was assessed by the participant by answering the following question: "How severe was your foot pain while performing physical activities (example, standing, walking or running) over the past week?" (0=no pain; 1=mild pain; 2=moderate pain; 3=severe pain).
Time Frame	Baseline and Weeks 4, 8 and 12 in the double-blind treatment period

Outcome Measure Data

Analysis Population Description

The ITT analysis set included all randomized participants. The results are presented for the participants with data available at Baseline and specific time points.

Arm/Group Title		Placebo	Dysport 300 U	Dysport 500 U
Arm/Group Description:		On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of placebo (matching with Dysport) intramuscular injection distributed between 4 injection points in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 300 U intramuscular injection distributed between 4 injection points (75 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 500 U intramuscular injection distributed between 4 injection points (125 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.
Overall Number of Participants Analyzed		50	53	46
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
Week 4	Number Analyzed	50 participants	49 participants	42 participants
		-0.76; (-0.99 to -0.54)	-0.56; (-0.80 to -0.32)	-0.46; (-0.71 to -0.22)
Week 8	Number Analyzed	45 participants	47 participants	46 participants
		-0.74; (-0.97 to -0.51)	-0.64; (-0.88 to -0.39)	-0.79; (-1.03 to -0.56)
Week 12	Number Analyzed	47 participants	53 participants	41 participants
		-0.58; (-0.82 to -0.35)	-0.59; (-0.82 to -0.36)	-0.60; (-0.85 to -0.35)

11. Secondary Outcome

Title	LS Mean Change From Baseline in PGI-S of Disability Score at Weeks 4, 8 and 12
Description	An assessment of PGI-S of disability was conducted by the participant using a 4-point Likert scale ranging from 0= no disability to 3= severe disability. Higher scores indicate a worse outcome. The PGI-S was assessed by the participant by answering the following question: "How severe was your disability while performing physical activities (example, standing, walking or running) over the past week?" (0=no disability; 1=mild disability; 2=moderate disability; 3=severe disability).
Time Frame	Baseline and Weeks 4, 8 and 12 in the double-blind treatment period

Outcome Measure Data

Analysis Population Description

The ITT analysis set included all randomized participants. The results are presented for the participants with data available at Baseline and specific time points.

Arm/Group Title		Placebo	Dysport 300 U	Dysport 500 U
Arm/Group Description:		On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of placebo (matching with Dysport) intramuscular injection distributed between 4 injection points in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 300 U intramuscular injection distributed between 4 injection points (75 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 500 U intramuscular injection distributed between 4 injection points (125 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.
Overall Number of Participants Analyzed		50	53	46
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
Week 4	Number Analyzed	50 participants	49 participants	41 participants
		-0.47; (-0.70 to -0.25)	-0.57; (-0.82 to -0.32)	-0.42; (-0.68 to -0.16)
Week 8	Number Analyzed	45 participants	47 participants	46 participants
		-0.54; (-0.80 to -0.28)	-0.66; (-0.93 to -0.38)	-0.68; (-0.94 to -0.42)
Week 12	Number Analyzed	47 participants	53 participants	41 participants
		-0.55; (-0.80 to -0.31)	-0.63; (-0.87 to -0.38)	-0.67; (-0.93 to -0.40)

12. Secondary Outcome

Title	LS Mean Patient Global Impression of Improvement (PGI-I) of Foot Pain Score at Weeks 4, 8 and 12
Description	An assessment of PGI-I of foot pain was conducted by the participant using a 7-point Likert scale ranging from -3= very much worse to +3= very much improved. Higher scores indicate a better outcome. The PGI-I was assessed by the participant answering the following question: "Compared to your foot pain prior to the study treatment initiation, your foot pain while performing physical activities (example, standing, walking or running) now is: +3=very much improved; +2=much improved; +1=minimally improved; 0=no change; -1=minimally worse; -2=much worse; -3=very much worse".
Time Frame	Weeks 4, 8 and 12 in the double-blind treatment period

Outcome Measure Data

Analysis Population Description

The ITT analysis set included all randomized participants. The results are presented for the participants with data available at specific time points.

Arm/Group Title		Placebo	Dysport 300 U	Dysport 500 U
Arm/Group Description:		On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of placebo (matching with Dysport) intramuscular injection distributed between 4 injection points in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 300 U intramuscular injection distributed between 4 injection points (75 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 500 U intramuscular injection distributed between 4 injection points (125 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.
Overall Number of Participants Analyzed		51	53	46
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
Week 4	Number Analyzed	51 participants	50 participants	42 participants
		1.32; (0.98 to 1.65)	1.32; (0.98 to 1.66)	1.53; (1.17 to 1.90)
Week 8	Number Analyzed	45 participants	47 participants	46 participants
		1.30; (0.94 to 1.67)	1.36; (1.00 to 1.73)	1.32; (0.96 to 1.69)
Week 12	Number Analyzed	47 participants	53 participants	41 participants
		1.28; (0.93 to 1.63)	1.40; (1.07 to 1.74)	1.21; (0.83 to 1.59)

13. Secondary Outcome

Title	LS Mean PGI-I of Disability Score at Weeks 4, 8 and 12
Description	An assessment of PGI-I of the participant's disability was conducted by the participant using a 7-point Likert scale ranging from -3= very much worse to +3= very much improved. Higher scores indicate a better outcome. The PGI-I was assessed by the participant answering the following question: "Compared to your disability prior to the study treatment initiation, your disability while performing physical activities (example, standing, walking or running) now is: +3=very much improved; +2=much improved; +1=minimally improved; 0=no change; -1=minimally worse; -2=much worse; -3=very much worse".
Time Frame	Weeks 4, 8 and 12 in the double-blind treatment period

Outcome Measure Data

Analysis Population Description

The ITT analysis set included all randomized participants. The results are presented for the participants with data available at specific time points.

Arm/Group Title		Placebo	Dysport 300 U	Dysport 500 U
Arm/Group Description:		On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of placebo (matching with Dysport) intramuscular injection distributed between 4 injection points in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 300 U intramuscular injection distributed between 4 injection points (75 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 500 U intramuscular injection distributed between 4 injection points (125 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.
Overall Number of Participants Analyzed		51	53	46
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
Week 4	Number Analyzed	51 participants	49 participants	42 participants
		1.15; (0.83 to 1.47)	1.16; (0.83 to 1.48)	1.31; (0.95 to 1.66)
Week 8	Number Analyzed	45 participants	47 participants	46 participants
		1.19; (0.85 to 1.53)	1.23; (0.88 to 1.57)	1.41; (1.06 to 1.75)
Week 12	Number Analyzed	47 participants	53 participants	41 participants
		1.15; (0.81 to 1.48)	1.21; (0.89 to 1.52)	1.28; (0.92 to 1.64)

14. Secondary Outcome

Title	Mean Change From Baseline in 36-Item Short Form Health Survey (SF-36) Score at Weeks 8 and 12
Description	The SF-36 is a 36-item questionnaire which measures the extent to which physical health impacts an individual's functional ability and perceived wellbeing in mental, social, and physical aspects of life. The SF-36 has 8 subscales: physical function, role physical, bodily pain, global health, vitality, social function, role emotional and mental health. Each scale ranges from 0-100, where 0= lowest level of health and 100= highest level of health. Scores on these subscales can be aggregated into the physical component summary (physical function, role physical, bodily pain and global health) and mental component summary (mental health, vitality, social function and role emotional). Physical component summary score ranges from 0.65 to 80.73 and mental component summary score ranges from -8.81 to 81.65, where low score indicates lowest level of health and high score indicates highest level of health. Positive change from Baseline indicates an improvement in quality of life.
Time Frame	Baseline and Weeks 8 and 12 in the double-blind treatment period

Outcome Measure Data

Analysis Population Description

The ITT analysis set included all randomized participants. The results are presented for the participants with data available at Baseline and specific time points.

Arm/Group Title		Placebo	Dysport 300 U	Dysport 500 U
Arm/Group Description:		On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of placebo (matching with Dysport) intramuscular injection distributed between 4 injection points in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 300 U intramuscular injection distributed between 4 injection points (75 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.	On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 500 U intramuscular injection distributed between 4 injection points (125 U each) in the 4 targeted muscles of the study foot. Following the double-blind treatment period, all participants who met retreatment criteria were treated during the open-label period with Dysport 300 U on Cycle 2 Day 1 and either Dysport 300 U or 500 U on Cycle 3 Day 1. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.
Overall Number of Participants Analyzed		58	59	53
Mean (Standard Deviation); Unit of Measure: units on a scale
Week 8: SF-36 - Physical component summary score	Number Analyzed	58 participants	59 participants	53 participants
		3.08 (7.815)	3.19 (6.013)	3.30 (7.127)
Week 12: SF-36 - Physical component summary score	Number Analyzed	56 participants	58 participants	53 participants
		3.19 (7.776)	5.04 (7.430)	2.51 (7.133)
Week 8: SF-36 - Mental component summary score	Number Analyzed	58 participants	59 participants	53 participants
		-0.66 (7.299)	-0.30 (6.419)	-0.84 (6.022)
Week 12: SF-36 - Mental component summary score	Number Analyzed	56 participants	58 participants	53 participants
		-0.43 (5.587)	-0.28 (7.821)	-0.22 (6.970)

Adverse Events

Time Frame

From first administration of study drug (Cycle 1 Day 1) up to end of the study, approximately 36 weeks.

Adverse Event Reporting Description

The safety population included all participants who received at least one dose of study drug administration (including only partial administration).

Arm/Group Title

Double-Blind Treatment Period (Cycle 1): Placebo

Double-Blind Treatment Period (Cycle 1): Dysport 300 U

Double-Blind Treatment Period (Cycle 1): Dysport 500 U

Open-Label Treatment Period (Cycle 2): Dysport 300 U

Open-Label Treatment Period (Cycle 3): Dysport 300 U

Open-Label Treatment Period (Cycle 3): Dysport 500 U

Arm/Group Description

On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of placebo (matching with Dysport) intramuscular injection distributed between 4 injection points in the 4 targeted muscles of the study foot. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.

On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 300 U intramuscular injection distributed between 4 injection points (75 U each) in the 4 targeted muscles of the study foot. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.

On Cycle 1 Day 1 in the double-blind treatment period, participants received a single dose of Dysport 500 U intramuscular injection distributed between 4 injection points (125 U each) in the 4 targeted muscles of the study foot. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.

On Cycle 2 Day 1 in the open-label treatment period, all participants who met retreatment criteria received a single dose of Dysport 300 U intramuscular injection distributed between 4 injection points (75 U each) in the 4 targeted muscles of the study foot. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.

On Cycle 3 Day 1 in the open-label treatment period, all participants who met retreatment criteria received a single dose of Dysport 300 U intramuscular injection distributed between 4 injection points (75 U each) in the 4 targeted muscles of the study foot. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.

On Cycle 3 Day 1 in the open-label treatment period, all participants who met retreatment criteria received a single dose of Dysport 500 U intramuscular injection distributed between 4 injection points (125 U each) in the 4 targeted muscles of the study foot. The 4 targeted muscles of the study foot were the oblique head of the adductor hallucis muscle, the transverse head of the adductor hallucis muscle, the flexor hallucis brevis muscle and the extensor hallucis brevis muscle.

All-Cause Mortality

Double-Blind Treatment Period (Cycle 1): Placebo

Double-Blind Treatment Period (Cycle 1): Dysport 300 U

Double-Blind Treatment Period (Cycle 1): Dysport 500 U

Open-Label Treatment Period (Cycle 2): Dysport 300 U

Open-Label Treatment Period (Cycle 3): Dysport 300 U

Open-Label Treatment Period (Cycle 3): Dysport 500 U

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Affected / at Risk (%)

Total

0/61 (0.00%)

0/63 (0.00%)

0/56 (0.00%)

0/146 (0.00%)

0/8 (0.00%)

0/56 (0.00%)

Serious Adverse Events

Double-Blind Treatment Period (Cycle 1): Placebo

Double-Blind Treatment Period (Cycle 1): Dysport 300 U

Double-Blind Treatment Period (Cycle 1): Dysport 500 U

Open-Label Treatment Period (Cycle 2): Dysport 300 U

Open-Label Treatment Period (Cycle 3): Dysport 300 U

Open-Label Treatment Period (Cycle 3): Dysport 500 U

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Total

0/61 (0.00%)

0/63 (0.00%)

1/56 (1.79%)

1/146 (0.68%)

0/8 (0.00%)

1/56 (1.79%)

Gastrointestinal disorders

Abdominal pain † 1

0/61 (0.00%)

0

0/63 (0.00%)

0

0/56 (0.00%)

0

1/146 (0.68%)

1

0/8 (0.00%)

0

0/56 (0.00%)

0

Constipation † 1

0/61 (0.00%)

0

0/63 (0.00%)

0

0/56 (0.00%)

0

1/146 (0.68%)

1

0/8 (0.00%)

0

0/56 (0.00%)

0

Colitis ischaemic † 1

0/61 (0.00%)

0

0/63 (0.00%)

0

0/56 (0.00%)

0

1/146 (0.68%)

1

0/8 (0.00%)

0

0/56 (0.00%)

0

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Chronic myeloid leukaemia † 1

0/61 (0.00%)

0

0/63 (0.00%)

0

1/56 (1.79%)

1

0/146 (0.00%)

0

0/8 (0.00%)

0

0/56 (0.00%)

0

Nervous system disorders

Aphasia † 1

0/61 (0.00%)

0

0/63 (0.00%)

0

0/56 (0.00%)

0

0/146 (0.00%)

0

0/8 (0.00%)

0

1/56 (1.79%)

1

1 Term from vocabulary, MedDRA 23.0; † Indicates events were collected by systematic assessment

Other (Not Including Serious) Adverse Events

Frequency Threshold for Reporting Other Adverse Events

5%

Double-Blind Treatment Period (Cycle 1): Placebo

Double-Blind Treatment Period (Cycle 1): Dysport 300 U

Double-Blind Treatment Period (Cycle 1): Dysport 500 U

Open-Label Treatment Period (Cycle 2): Dysport 300 U

Open-Label Treatment Period (Cycle 3): Dysport 300 U

Open-Label Treatment Period (Cycle 3): Dysport 500 U

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Affected / at Risk (%)

# Events

Total

6/61 (9.84%)

9/63 (14.29%)

6/56 (10.71%)

11/146 (7.53%)

0/8 (0.00%)

4/56 (7.14%)

General disorders

Injection site pain † 1

1/61 (1.64%)

1

2/63 (3.17%)

2

3/56 (5.36%)

3

3/146 (2.05%)

4

0/8 (0.00%)

0

3/56 (5.36%)

3

Musculoskeletal and connective tissue disorders

Pain in extremity † 1

3/61 (4.92%)

3

2/63 (3.17%)

3

3/56 (5.36%)

5

6/146 (4.11%)

6

0/8 (0.00%)

0

1/56 (1.79%)

1

Skin and subcutaneous tissue disorders

Hyperkeratosis † 1

2/61 (3.28%)

2

5/63 (7.94%)

5

1/56 (1.79%)

1

3/146 (2.05%)

3

0/8 (0.00%)

0

0/56 (0.00%)

0

1 Term from vocabulary, MedDRA 23.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

Based on the results of the primary analysis the sponsor terminated the study early due to lack of efficacy of the tested doses at the primary endpoint. The decision by the sponsor to terminate the study early was not related to any safety or tolerability concerns with Dysport.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Medical Director
• Organization: Ipsen Pharma
• Phone: see email
• EMail: clinical.trials@ipsen.com

• Responsible Party: Ipsen
• ClinicalTrials.gov Identifier: NCT03569098
• Other Study ID Numbers: D-FR-52120-237
• First Submitted: June 14, 2018
• First Posted: June 26, 2018
• Results First Submitted: May 7, 2021
• Results First Posted: July 2, 2021
• Last Update Posted: July 2, 2021