Dysport in Hallux Abducto Valgus (HAV) Phase IIa

Study Overview
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Brief Summary
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The purpose of this study is to investigate the efficacy and safety of treatment with multiple doses of Dysport in adults suffering from clinically significant pain associated with HAV who have not undergone surgery for their condition.

Official Title
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A Multiple-dose, Double-blind, Randomised, Placebo-controlled Study to Evaluate the Efficacy and Safety of Dysport for the Treatment of Pain Associated With Hallux Abducto Valgus

Conditions
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Hallux Abducto Valgus

Intervention / Treatment
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* Biological: Botulinum toxin type A
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of HAV Painful HAV in the study foot at Baseline Exclusion Criteria: Flat or square metatarsal head, metatarsus primus elevates, or severe cavus/planus in the study foot Other podiatric or orthopedic condition which would interfere with the evaluation of pain and/or function Medical history or clinical evidence of any vascular disease and/or diabetic condition

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dysport Dose 1<br>Intramuscular injection of Dysport on day 1 of double-blind period, followed by up to 2 open-label injections during open-label cycles, during approximately 36 weeks. | Biological: Botulinum toxin type A<br>* Investigators will inject the reconstituted solution into foot muscles.<br>* Other names: Clostridium botulinum toxin type A haemagglutinin complex (BTX-A-HAC);|
| Experimental: Dysport Dose 2<br>Intramuscular injection of Dysport on day 1 of double-blind period, followed by up to 2 open-label injections during open-label cycles, during approximately 36 weeks. | Biological: Botulinum toxin type A<br>* Investigators will inject the reconstituted solution into foot muscles.<br>* Other names: Clostridium botulinum toxin type A haemagglutinin complex (BTX-A-HAC);|
| Placebo Comparator: Placebo<br>Intramuscular injection of Placebo on day 1 of cycle 1 (double-blind period) | Drug: Placebo<br>* Investigators will inject the reconstituted solution into foot muscles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Least Square (LS) Mean Change From Baseline in the Daily Numeric Pain Rating Scale (NPRS) Score at Week 8 | 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). | Baseline and Week 8 in the double-blind treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LS Mean Change From Baseline in the Daily NPRS Score at Weeks 4 and 12 | 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). | Baseline and Weeks 4 and 12 in the double-blind treatment period | 
| LS Mean Change From Baseline in the Daily Modified Foot Function Index (mFFI) Disability Subscale Score at Weeks 4, 8 and 12 | 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. | Baseline and Weeks 4, 8 and 12 in the double-blind treatment period | 
| LS Mean Change From Baseline in the Daily mFFI Pain Subscale Score at Weeks 4, 8 and 12 | 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. | Baseline and Weeks 4, 8 and 12 in the double-blind treatment period | 
| LS Mean Change From Baseline in the Daily mFFI Total Score at Weeks 4, 8 and 12 | 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. | Baseline and Weeks 4, 8 and 12 in the double-blind treatment period | 
| LS Mean Change From Baseline in the Daily mFFI Activity Limitation Subscale Score at Weeks 4, 8 and 12 | 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. | Baseline and Weeks 4, 8 and 12 in the double-blind treatment period | 
| LS Mean Change From Baseline in HV Angle at Weeks 4, 8 and 12 | 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). | Baseline and Weeks 4, 8 and 12 in the double-blind treatment period | 
| LS Mean Change From Baseline in Intermetatarsal Angle at Weeks 4, 8 and 12 | 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. | Baseline and Weeks 4, 8 and 12 in the double-blind treatment period | 
| Median Time to Retreatment | 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. | Up to 24 weeks in the double-blind treatment period | 
| LS Mean Change From Baseline in Patient Global Impression of Severity (PGI-S) of Foot Pain Score at Weeks 4, 8 and 12 | 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). | Baseline and Weeks 4, 8 and 12 in the double-blind treatment period | 
| LS Mean Change From Baseline in PGI-S of Disability Score at Weeks 4, 8 and 12 | 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). | Baseline and Weeks 4, 8 and 12 in the double-blind treatment period | 
| LS Mean Patient Global Impression of Improvement (PGI-I) of Foot Pain Score at Weeks 4, 8 and 12 | 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. | Weeks 4, 8 and 12 in the double-blind treatment period | 
| LS Mean PGI-I of Disability Score at Weeks 4, 8 and 12 | 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. | Weeks 4, 8 and 12 in the double-blind treatment period | 
| Mean Change From Baseline in 36-Item Short Form Health Survey (SF-36) Score at Weeks 8 and 12 | 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. | Baseline and Weeks 8 and 12 in the double-blind treatment period |