Study to Evaluate Effects of DYSPORT® Injected in Lower and Upper Limb Combined With Guided Self-Rehabilitation Contract (GSC)

Study Overview
=================
Brief Summary
-----------------
The purpose of this clinical study is to assess whether AbobotulinumtoxinA (Dysport®) injections in upper and lower limbs accompanied with a personal exercise plan called Guided Self-rehabilitation Contract (GSC) can improve voluntary movements in subjects with hemiparesis.

Official Title
-----------------
An International, Multicentre, Prospective, Single-Arm Study to Assess the Effect on Voluntary Movements of AbobotulinumtoxinA 1500 U Administered in Both Upper and Lower Limbs in Conjunction With a Guided Self-Rehabilitation Contract in Adult Subjects With Spastic Hemiparesis

Conditions
-----------------
Spastic Hemiparesis

Intervention / Treatment
-----------------
* Biological: Botulinum toxin type A
* Other: GSC


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects aged at least the national legal adult age. Subjects with hemiparesis due to acquired brain injury (ABI) presenting with muscle overactivity impeding motor function based on investigator's judgement including, but not limited to, at least one of the following requiring botulinum neurotoxin (BoNT) treatment: typical clenched fist; flexed wrist; flexed elbow; or plantar flexed foot pattern. At least 12 months since the ABI (i.e. stroke or traumatic brain injury (TBI)). Naïve or non-naïve to BoNT treatment; if non-naïve, at least 4 months after the last BoNT injection, of any serotype. Upper limb active function with an overall score between 2 and 7, as assessed by Modified Frenchay Scale (MFS), if the primary TT limb is the upper limb (UL). A 10-metre maximal WS barefoot between 0.2 and 1.4 m/s, if the primary TT limb is the lower limb (LL). Maximal WS barefoot will be performed without walking aids. However, a cane may be permitted if absolutely necessary (although this may prevent detection of treatment-induced improvements). In this case, the same aid will have to be used for all WS assessments during the study. Subjects must provide written informed consent to participate in the study prior to any study-related procedures. Female subjects of childbearing potential (not surgically sterile or 2 years postmenopausal) must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study until the last visit of the subjects and for at least 12 weeks post injection. Acceptable methods of contraception include total abstinence, male partner has had a vasectomy, double barrier method (e.g. male condom plus spermicide, or female diaphragm plus spermicide), intrauterine device, or hormonal contraceptive (oral, transdermal, implanted and injected). Subjects must be willing and able to comply with study restrictions and to remain at the clinic for the required duration during the study period and willing to return to the clinic for the follow-up evaluation as specified in the protocol Exclusion Criteria: Inability to understand protocol procedures and requirements, which, in the opinion of the investigator, could negatively impact on protocol compliance, in particularly inability to exercise according to the GSC. Previous surgery on the affected muscles and ligaments, tendons, nerve trunks, or bones of the treated upper or lower limb. Previous treatment with phenol and/or alcohol in any of the treated limbs any time before the study. Any medical condition (including severe dysphagia or breathing difficulties) that may increase, in the opinion of the investigator, the likelihood of adverse events (AEs) related to BoNT A treatment. Current, planned or received within the last 4 weeks prior to study treatment, treatment with any drug that interferes either directly or indirectly with neuromuscular function (for example, aminoglycosides). Major neurological impairment other than spastic paresis (including major proprioceptive ataxia or apraxia on the paretic side) that could negatively impact on the functional performance of the subject. Known disease of the neuromuscular junction (such as Lambert-Eaton myasthenic syndrome or myasthenia gravis). Known sensitivity to BoNT-A or any excipient of Dysport. Infection at the injection site(s). Current pregnancy or lactation. A pregnancy test will be performed at the start of the study for all female subjects of childbearing potential (i.e. not surgically sterile or 2 years postmenopausal). Mental condition rendering the subject unable to understand the nature, scope and possible consequences of the study and/or evidence of an uncooperative attitude. Abnormal baseline findings or any other medical condition(s) that, in the opinion of the investigator, might jeopardise the subject's safety. Subjects treated, or likely to be treated, with intrathecal baclofen during the course of the study or during the 4 weeks before study entry. Subjects who have participated in any therapeutic clinical study/received any investigational agent within 30 days of enrolment.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dysport<br>Each subject will undergo two intramuscular injection (treatment) cycles, receiving AbobotulinumtoxinA (Dysport®) 1500 U on Day 1 of each cycle; the two dosing occasions will be separated by at least 12 weeks (maximum 20 weeks). Subjects will also receive daily GSC therapy. The main focus of GSC will be on the primary treatment target (TT) limb (as determined at the Baseline Visit) and then the other limb. All muscle groups requiring active training and/or stretching should be trained. Subjects will be be given a diary to record each day whether they have performed the GSC therapy. | Biological: Botulinum toxin type A<br>* Dysport® administered in both upper and lower limbs (total dose of 1500 U per injection split between the 2 limbs).<br>* Other names: AbobotulinumtoxinA (Dysport®);Other: GSC<br>* The GSC is a motivational tool. The physiotherapist will teach each subject the stretching postures and exercises to perform on a daily basis throughout the study. These will be tailored to the individual subject's needs and will form the GSC therapy.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Responder Participants at Week 6 After the Second Injection, According to Composite Active Range of Motion (AROM) in the Primary TT Limb | Percentage of responder participants according to AROM was measured by goniometer in the primary TT limb, using zero as the theoretical position of minimal stretch for the muscle assessed. Participants were asked to perform the active movement as far as possible against that muscle and the angle was measured. A participant was considered a responder if he/she achieved at least the predefined improvement threshold - larger or equal to 35 degrees in UL or 5 degrees in LL - in the primary TT limb (based on the composite AROM individual change from baseline to Week 6 after the second injection). | At Week 6, Cycle 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Responder Participants at Week 6 After the First Injection, According to Composite AROM in the Primary TT Limb | Percentage of responder participants according to composite AROM was measured by goniometer in the primary TT limb, using zero as the theoretical position of minimal stretch for the muscle assessed. Participants were asked to perform the active movement as far as possible against that muscle and the angle was measured. A participant was considered a responder if he/she achieved at least the predefined improvement threshold - larger or equal to 35 degrees in UL or 5 degrees in LL - in the primary TT limb (based on the composite AROM individual change from baseline to Week 6 after the first injection). | At Week 6, Cycle 1 | 
| Mean Change From Baseline in AROM Against 10 Prespecified Muscle Groups at Week 6 and Week 12 of Each Treatment Cycle, Reinjection Cycle Visit and Last Study Visit | The AROM was measured by goniometer in the primary TT limb, using zero as the theoretical position of minimal stretch for the muscle assessed. Participants were asked to perform the active movement as far as possible against that muscle and the angle was measured. The angle of joint movement was measured in 10 prespecified muscle groups (injected or noninjected); UL: shoulder extensors (SE), elbow flexors (EF), wrist flexors (WF), extrinsic finger flexors (FF) and pronator teres (PT), LL: soleus (Sol), gastrocnemius (GN), gluteus maximus (GM), hamstrings (HS) and rectus femoris (RF). The reinjection cycle visit corresponds to Week 12, 16 or 20 of injection Cycle 1. The last study visit corresponds to the last post-baseline visit performed by the participant (including the early withdrawal visit). | Week 6 and Week 12 of each treatment cycle, reinjection cycle visit and last study visit | 
| Mean Change From Baseline in Composite AROM Against Injected Muscle Groups (Any of the 10 Prespecified Muscles) at Week 6 and Week 12 of Each Treatment Cycle, Reinjection Cycle Visit and Last Study Visit | Composite AROM (XA) was measured by goniometer in the primary TT limb (either UL or LL, depending on which one has been selected as the primary TT limb), composite AROM in the UL injected muscle groups was calculated as the sum of the AROM in the EF, WF and FF. Composite AROM in the LL injected muscle groups was calculated as the sum of the AROM in Sol and GN. | Week 6 and Week 12 of each treatment cycle, reinjection cycle visit and last study visit | 
| Mean Change From Baseline in Full Composite AROM Against 5 UL or 5 LL Muscle Groups, Regardless of Whether the Muscle Groups Were Injected or Not at Week 6 and Week 12 of Each Treatment Cycle, Reinjection Cycle Visit and Last Study Visit | Full composite AROM, regardless of whether the muscle groups was injected or not was measured by goniometer in the primary TT limb. Full Composite AROM in the UL was calculated as the sum of the AROM in the 5 UL muscle groups (SE+EF+WF+FF+PT). Full Composite AROM in the LL was calculated as the sum of the AROM in the 5 LL muscle groups (Sol+GN+GM+HS+RF). | Week 6 and Week 12 of each treatment cycle, reinjection cycle visit and last study visit | 
| Mean Change From Baseline in Modified Frenchay Scale (MFS) Overall Score Evaluated Locally and Centrally at Week 12 of Each Treatment Cycle and Last Study Visit | The MFS was used to measure active function in the UL. The MFS consists of 10 tasks, each of which was evaluated locally by the site investigator and centrally by a blinded central reviewer at the coordinating investigators' site, on a 10-point visual analogue scale (VAS) ranging from No movement to Normal. Higher score indicates a better outcome. The MFS overall scores were obtained by averaging all individual task scores, provided that at least 8 out of the 10 were not missing. The mean change from baseline was calculated for the local and central assessments and a positive change from baseline indicates an improvement in active function. | Week 12 of each treatment cycle and last study visit | 
| Mean Change From Baseline in Maximal Walking Speed Barefoot at Week 12 of Each Treatment Cycle and at Last Study Visit | The 10-meter walking speed test (WST) was used to measure active function in the LL. The participant performed the WST barefoot without a walking aid. If it was absolutely necessary that the participant used a cane, this may have been permitted provided that the same cane was used at baseline and all other walking speed assessments for that participant. The participant was given instructions to walk at his/her maximum speed. The time taken for the participant to walk from the start to the end of the 10 meters was recorded. | Week 12 of each treatment cycle and last study visit | 
| Participant Satisfaction With the GSC at Week 6 and Week 12 of Each Treatment Cycle, Reinjection Cycle Visit and Last Study Visit | Each participant received a personalised rehabilitation programme. The physiotherapist taught each participant the stretching postures and exercises to perform on a daily basis throughout the study. These were tailored to the individual participant's needs and formed the GSC therapy. The main focus was on the primary TT limb and then the other limb. Participant satisfaction was determined by asking the question How satisfied are you TODAY regarding the GSC? Responses were recorded using a 5-level Likert scale, as follows: completely satisfied (+2), rather satisfied (+1), neither satisfied nor dissatisfied (0), rather dissatisfied (-1), and completely dissatisfied (-2). | At baseline (for participants who had GSC previously only), Week 6 and Week 12 of each treatment cycle, reinjection cycle visit and last study visit | 
| Change From Baseline in Participant's Beliefs That the GSC Will Help to Improve Functional Capacity at Week 6 and Week 12 of Each Treatment Cycle, Reinjection Cycle Visit and Last Study Visit | Participants were asked the following question: Do you believe that GSC will help to improve your arm and leg function? Responses were recorded on a 5-level Likert scale, as follows: very true of what I believe (+2), somewhat true of what I believe (+1), no opinion/don't know (0), somewhat untrue of what I believe (-1), and very untrue of what I believe (-2). | Week 6 and Week 12 of each treatment cycle, reinjection cycle visit and last study visit | 
| Change From Baseline in Physiotherapist's Beliefs That the GSC Will Help to Improve Functional Capacity at Week 6 and Week 12 of Each Treatment Cycle, Reinjection Cycle Visit and Last Study Visit | Physiotherapists were asked the following question: Do you believe that GSC will help to improve your patient's arm and leg function? Responses were recorded on a 5-level Likert scale, as follows: very true of what I believe (+2), somewhat true of what I believe (+1), no opinion/don't know (0), somewhat untrue of what I believe (-1), and very untrue of what I believe (-2). | Week 6 and Week 12 of each treatment cycle, reinjection cycle visit and last study visit | 
| Percentage of Days Over Study Period When GSC Therapy Was Performed | The investigator counted the number of days when GSC therapy was not performed since the last visit. Using the total number of study days and the total number of days when GSC therapy was not performed, the number of days when GSC was performed was calculated. | From baseline to end of the study, up to 280 days | 
| Global Assessment of Benefits of the Study Therapy | A global assessment of the benefits of the study therapy was made by the investigator and the participant (or the caregiver). The participant's caregiver performed the global assessment only in those cases when the participant was not capable to do this. Participants were asked the following question: How would you rate the overall response to study therapy since baseline? Responses on the global assessment were recorded on a 5-level Likert scale, as follows: much better (+2), a bit better (+1), the same (0), a bit worse (-1), and much worse (-2). | At reinjection cycle visit (Week 12, 16 or 20) and last study visit (Week 24 or 40) | 
| Number of Participants Satisfied With a Longer Interval Between 2 Treatment Cycles | Participants who were not reinjected at Week 12 of a given cycle, recorded their satisfaction with a longer interval between 2 injections collected at the corresponding reinjection visit or the last cycle visit (Week 16 or Week 20 for each cycle). To assess this, the participants were asked the following question: Are you satisfied with a longer interval between 2 injections?. The possible answers were: Yes, No or No opinion. | At reinjection cycle visit (Week 16 or 20) and last study visit (Week 24 or 40) | 
| Change From Baseline in European Quality of Life 5 Dimensions (EQ-5D-5L) Scores at Last Study Visit | Participants were asked to complete EQ-5D-5L questionnaire to assess their current health status. The EQ-5D-5L was a generic, preference-based measure of health-related quality of life (QoL). Questions were answered based on how the participant was feeling Today. The EQ-5D-5L consists of 2 parts: EQ-5D descriptive system and EQ VAS. The EQ-5D descriptive system included questions for each of the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The VAS recorded participant's self-rated health on a vertical 20-centimeter VAS where the endpoints were labelled The best health you can imagine and The worst health you can imagine. The EQ-5D-5L questionnaire scores range from 0-100, where 0= worst self-perceived health and 100= best self-perceived health. Positive change from baseline indicates an improvement in QoL. | At last study visit (Week 24 or 40) | 
| Change From Baseline in Short Form 12 (SF-12) Scales at Last Study Visit | The SF-12 was a short form questionnaire survey consisting of 12 questions, which were a subset of the SF-36 health survey. Most of the questions were answered based on how the participant had felt over the previous 4 weeks. The SF-12 covers 8 domains, including physical functioning, role-physical, body pain, general health, vitality, social functioning, role-emotional and mental health. The SF-12 questionnaire survey scale ranges from 0-100, where 0= lowest level of health and 100= highest level of health. Positive change from baseline indicates an improvement in QoL. | At last study visit (Week 24 or 40) |