E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10048970 |
E.1.2 | Term | Arm spasticity |
E.1.2 | System Organ Class | 100000004852 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary study objective is to assess the long term safety of Dysport in hemiparetic subjects with upper limb spasticity due to stroke or traumatic brain injury over repeated treatment cycles. |
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E.2.2 | Secondary objectives of the trial |
The secondary study objective is to assess the long term efficacy of repeated treatment with Dysport |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects who have completed the double blind study (Study 145) up to the Week 12, Week 16, Week 20 or Week 24 follow up visit will be eligible for this open label extension study.
De novo subjects must satisfy all of the following inclusion criteria to be eligible for the study :
(1) Provision of written informed consent prior to any study related procedures.
(2) Subjects with hemiparesis and aged between 18 and 80 years, inclusive.
(3) Subjects who had one clinically defined stroke episode, as defined by the World Health Organisation (WHO) criteria or who have had one brain trauma, or subjects who had a nonevolutive lesion diagnosed prior to the stroke and in the same hemisphere as shown by brain imaging (i.e. scan or MRI).
(4) At least 6 months post-stroke or traumatic brain injury.
(5) Modified Ashworth Scale (MAS) score ≥2 in the primary targeted muscle group for toxin naïve subjects or MAS score ≥3 in the primary targeted muscle group for toxin non-naïve subjects at least 4 months after the last BTX injection, of any serotype. Please note that for the purpose of this protocol, a naïve subject is defined as a subject who has never received any BTX in the affected upper limb.
(6) Disability Assessment Scale (DAS) score ≥2 on the PTT.
(7) Spasticity angle ≥10° in the primary targeted muscle group.
(8) Modified Frenchay Scale (MFS) overall score (average of all task scores) between 1 and 8 (including limit values).
(9) Subjects able to receive 1000 U in their upper limb at Treatment Cycle 1.
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E.4 | Principal exclusion criteria |
Subjects (both rollover and de novo) are not be excluded if any of the following apply:
• Major limitation in the passive ROM at the affected wrist, fingers and elbow, as defined by:
o Maximum passive elbow extension <150º (0º corresponding to the minimal stretch of the elbow flexors, which corresponds to a fully flexed elbow position).
o Maximum passive wrist extension <70º (0º corresponding to the minimal stretch of the wrist flexors, which corresponds to a fully flexed wrist position).
o Maximum passive finger extension <70º (0º corresponding to the minimal stretch of the extrinsic finger flexors, which corresponds to a formed fist with the second phalanx parallel to the metacarpal).
• Previous surgery to treat spasticity of the affected upper limb.
• Previous treatment with phenol and/or alcohol in the treated upper limb anytime before the study.
• Any medical condition (including severe dysphagia or airway disease) that may increase, in the opinion of the Investigator, the likelihood of AEs related to botulinum toxin (BTX) treatment.
• 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).
• Inability to understand protocol procedures and requirements which, in the opinion of the Investigator, could negatively impact on protocol compliance.
• Known sensitivity to BTX or any excipients of Dysport.
• Infection at the injection site(s).
• Unwillingness or inability to comply with the protocol.
• Current or planned treatment with any drug that interferes either directly or indirectly with neuromuscular function (e.g. aminoglycosides) within the last 4 weeks prior to study treatment.
• Pregnant women, or premenopausal women not willing to use contraceptive measures throughout the duration of the study.
• Treatment with a new investigational drug in the 4 weeks prior to enrolment into the study or scheduled to receive such a drug during the study period.
• Any underlying disease (not associated with the stroke or brain trauma) likely to affect upper limb function and/or muscle tone and/or spasticity.
• Any medical condition (or laboratory finding), which in the opinion of the Investigator may compromise compliance with the objectives and/or procedures of this protocol or preclude the administration of BTX.
• Subjects treated or likely to be treated with intrathecal baclofen during the course of the study
De novo subjects are to be excluded if any of the following additional criteria apply:
(1) Physiotherapy initiated less than 4 weeks before entry or expected to be initiated during the study.
(2) Previous treatment with BTX of any type within 4 months prior to study entry for any condition.
(3) Previous primary or secondary non response to any BTXs for the targeted condition.
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety Endpoints:
•Adverse events (AEs)
•Vital signs (systolic and diastolic BP and HR)
•Clinical laboratory parameters (haematology and clinical chemistry)
•Presence of BTX A Abs
•A 12 lead ECG |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Adverse events (AEs) at each study visit.
• Vital signs (systolic and diastolic BP and HR) at Day 1 of Treatment Cycle 1 and at each study visit.
• Clinical laboratory parameters (haematology and clinical chemistry) at Day 1 of Treatment Cycle 1, Week 4 of each treatment cycle and at the end of study or early withdrawal.
• Presence of BTX A Abs at Day 1 of Treatment Cycle 1, Week 4 of each treatment cycle and at the end of study or early withdrawal.
• A 12 lead ECG at Day 1 of Treatment Cycle 1, Week 4 of each treatment cycle and at the end of study or early withdrawal.
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E.5.2 | Secondary end point(s) |
In all of the following endpoints, the baseline is defined as the baseline in the double blind study for rollover subjects and baseline visit (Cycle 1, Day 1) of this open label study for de novo subjects .
• Mean change from baseline in the MAS in the primary targeted muscle group.
• Mean change from baseline in the MAS in the following muscle groups: shoulder extensors, elbow flexors and pronators, wrist flexors and extrinsic finger flexors in subjects injected in these muscle groups and having a baseline MAS score ≥2.
• Proportion of subjects with at least one grade decrease from baseline on the MAS in the primary targeted muscle group.
• Mean PGA score.
• Mean change from baseline in the Principal Target of Treatment (PTT) of the DAS.
• Mean change from baseline in the MFS overall score (i.e. mean score over the 10 tasks).
• Proportion of subjects with a decrease from baseline of at least one grade in the PTT and in each domain of disability of the DAS for subjects having a baseline score ≥2 in the considered domain.
• Mean change from baseline in the TS in the primary targeted muscle group (spasticity grade, angle of catch and spasticity angle).
• Mean change from baseline in the TS in the shoulder extensors, elbow flexors and pronators, wrist flexors and extrinsic finger flexors in subjects injected in these muscle groups and with a baseline spasticity angle >10º (spasticity grade, angle of catch and spasticity angle).
• Mean change from baseline in the active ROM against the primary targeted muscle group.
• Mean change from baseline in the ease of applying splints.
• Mean change from baseline in QoL measured on the Short Form (36) Health Survey and European QoL 5 Dimensions scales.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The study visits considered for the analysis of the efficacy endpoints (with the exception of QoL) will be Week 4, Week 12 and potentially Week 16, Week 20 and Week 24 of each treatment cycle. The study visit considered for the analyses of the QoL will be the end of the study or early withdrawal. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Russian Federation |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 40 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 40 |