E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Upper limb spasticity after stroke or traumatic brain injury |
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E.1.1.1 | Medical condition in easily understood language |
Medical condition where Upper limb muscles are tight or in spasm after stroke or traumatic brain injury and needs to be relaxed. |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10041416 |
E.1.2 | Term | 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 |
Stage 1
• To assess the safety and tolerability of increasing doses of a single treatment of IPN59011 in subjects with the clenched fist pattern compared with Dysport and placebo, and to select two dose levels for further investigation in Stage 2 based on safety and efficacy criteria.
Stage 2
• To determine the safety of two doses of IPN59011 selected after Stage 1, for the treatment of AUL spasticity in subjects with the flexed elbow pattern (mandatory of the two permitted clinical patterns in Stage 2) compared with Dysport at the peak of treatment effect, and to select the lowest dose which is safe and effective and providing 6-month duration of response for further investigation in Stage 3.
Stage 3
• To determine the safety of one total dose of IPN59011 selected from Stage 2 for the treatment of AUL spasticity in subjects with several clinical patterns on the adducted/rotated shoulder pattern (mandatory clinical pattern in Stage 3) compared with Placebo. |
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E.2.2 | Secondary objectives of the trial |
All Stages
• To evaluate PD characteristics of IPN59011 for the treatment of subjects with AUL spasticity in the corresponding PTMG per stage by using MAS to assess the:
- time to onset,
- peak of effect,
- time to peak, and
- duration of effect.
• To assess the efficacy of IPN59011 overtime compared with Dysport and/or placebo in reducing upper limb muscle tone in hemiparetic subjects as measured by MAS in the corresponding PTMG.
• To compare the PD profile of IPN59011 to Dysport including duration of treatment response as measured by MAS in the corresponding PTMG.
• To evaluate the Physician’s Global Assessment (PGA) of overall treatment response as assessed by the investigator.
• To evaluate the treatment benefit as assessed by the subject using Patient Global Impression of change (PGI-C).
• To assess the presence of IPN59011 and BoNT-A antibodies and titers (binding and neutralising). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects must fulfil all the following criteria to be included in the study:
(1) Provision of written informed consent prior to any study related procedures.
(2) Female and male subjects between:
• For Stage 1: 18 and 65 years of age, inclusive.
• For Stage 2 and Stage 3: 18 and 70 years of age, inclusive.
(3) Have spastic hemiparesis following stroke or TBI.
(4) Are at least 6 months post-stroke or TBI.
(5) Have never received BoNT or if previously treated, should have received their last
injection of any commercialised BoNT-A or B at least 4 months prior to study Baseline.
(6) Have a MAS score ≥2 in the PTMG to be injected:
• For Stage 1: subjects should have a clenched fist with a MAS score ≥2 in the
extrinsic finger flexors.
• For Stage 2: subjects should have one or more clinical pattern(s) in addition to
flexed elbow with a MAS score ≥2 in elbow flexors.
• For Stage 3: subjects should have two or more clinical pattern(s) in addition to
adducted/rotated shoulder with a MAS score ≥2 in adducted/rotated shoulder
flexors.
(7) Should also be eligible to receive a total recommended dose 1000 U Dysport in the upper limb for Stage 2.
(8) Angle of spasticity ≥5° in the PTMG to be injected.
(9) Should not have any fixed contractures as defined by:
• Complete fingers extension with XV1 ≥160°
• Complete wrist extension with XV1 ≥90°
• Complete elbow extension with XV1 ≥160°
(10) Physical therapy, occupational therapy, splinting, use of benzodiazepine, and muscle
relaxants had to be stable from at least 30 days preceding the study Baseline until the end of the study.
(11) Subjects in good health (i.e. absence of any uncontrolled systemic disease or other significant medical condition) as determined by medical history, physical and
neurological examinations, clinical laboratory studies, electrocardiograms (ECGs), vital signs, and Investigator's judgement prior to randomisation. |
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E.4 | Principal exclusion criteria |
Subjects will be excluded from the study if they meet any of the following criteria:
(1) Likely treatment with any serotype of BoNT for any condition during the study.
(2) Undergone previous surgery to treat spasticity in the affected upper limb.
(3) Has initiated physiotherapy within 30 days prior to Baseline (if physiotherapy initiated
more than 30 days prior to Baseline and ongoing, the therapy regimen should be
maintained at the same frequency and intensity throughout the study if possible or at least
up to post-injection 3-months).
(4) Has received previous treatment with phenol and or alcohol in the targeted upper limb any time before the study.
(5) Has been treated or is likely to be treated with intrathecal baclofen during the 30 days
prior to study Baseline or during the course of the study.
(6) Current or planned treatment with any medications that interfere either directly or indirectly with neuromuscular transmission, such as curare-like non-depolarising agents, lincosamides, polymyxins, anticholinesterases and aminoglycoside antibiotics, within
30 days prior to Baseline.
(7) Use of concomitant therapy which, in the investigator’s opinion, would interfere with the evaluation of the safety or efficacy of the study treatment, including medications affecting bleeding disorders, provided the International normalized ratio (INR) is controlled between 2 and 3 (antiplatelet agents and/or anticoagulants given for treatment or prevention of cardiovascular/cerebrovascular diseases).
(8) Use of any experimental device within 30 days or use of any treatment with an experimental drug within five times the documented terminal half-life of the respective drug or its metabolites or if the half-life is unknown within 30 days prior to the study Baseline and during the conduct of the study.
(9) Currently planned or a history of tendon lengthening surgery, significant contracture or muscle atrophy at target joint or muscle in the past 6 months prior to Screening.
(10) Any medical condition (including severe dysphagia or airway disease) that may increase, in the opinion of the investigator, the likelihood of adverse events (AEs) related to BoNT treatment.
(11) Known disease of the neuromuscular junction (e.g. Lambert-Eaton myasthenic syndrome, myasthenia gravis or amyotrophic lateral sclerosis etc.).
(12) Has a history of hypersensitivity to the investigational medicinal products (or other BoNTs) or any excipient used in their formulation.
(13) Infection at the injection site(s).
(14) A history of drug or alcohol abuse.
(15) Clinically diagnosed significant anxiety disorder, or any other significant psychiatric disorder (e.g. depression) that might interfere with the subject’s participation in the study.
(16) Inability to understand protocol procedures and requirements which, in the opinion of the investigator, could negatively impact on protocol compliance or inability or unwillingness to comply with the protocol.
(17) Presence of any other condition (e.g. neuromuscular disorder, muscular dystrophies, cancer cachexia, sarcopenia or other disorder that could interfere with neuromuscular function), laboratory finding or circumstance that, in the judgement of the investigator, might increase the risk to the subject or decrease the chance of obtaining satisfactory data to achieve the objectives of the study.
(18) Pregnant women, or women of childbearing potential not willing to practice a highly effective form of contraception method at the beginning of the study, for the duration of the study and for a minimum of 12 weeks following last administration of study treatment. Highly effective methods of contraception are defined as methods of birth control which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, intrauterine devices, or vasectomised partner. Non-childbearing potential is defined as postmenopausal for at least
1 year without an alternative medical cause or permanent surgical Sterilisation.
(19) Male subjects who are not vasectomised and who have female partners of childbearing potential and are not willing to use condoms with spermicide throughout study participation for a minimum of 12 weeks following initial double-blind administration of study treatment. |
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E.5 End points |
E.5.1 | Primary end point(s) |
All Stages- Safety
• Incidence, severity and nature of treatment emergent adverse events (TEAEs).
• Incidence, severity and nature of adverse events of special interest (AESIs).
• Vital signs (absolute values and change from Baseline).
• Clinical laboratory evaluations (absolute and change from Baseline values).
• Presence of BoNT-A and IPN59011 antibodies (binding and neutralising).
• Abnormal Physical examination findings. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At each post treatment visit. |
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E.5.2 | Secondary end point(s) |
All Stages
• Change from Baseline to all post-treatment visits (except Day 22, telephone call) in MAS score in the PTMG.
• Change from Baseline to all post-treatment visits in MAS score in all injected muscle
groups.
• PD characteristics of IPN59011 in the PTMG:
- Time to onset - time to the response to treatment (a reduction of at least one grade in the MAS score).
- Peak of effect - maximal decrease in the MAS score from Baseline.
- Time to peak - time to reach the peak of effect (maximal decrease in the MAS score
from Baseline).
- Duration of effect - duration between time to onset and last timepoint with a response
to treatment.
• Response to treatment as measured by at least one grade reduction in MAS score in the PTMG from Baseline to all post-treatment visits.
• Response to treatment as measured by at least one-grade reduction in MAS score in all injected muscles from Baseline to all post-treatment visits.
• PGA score of overall treatment response at all post-treatment visits.
• PGI-C (as assessed by the subject) in the spastic clinical pattern at all post-treatment visits.
Stage 2
• Change from Baseline to post-treatment Day 29 in MAS score in the PTMG (flexed elbow pattern).
Note: if PD profile of IPN59011 in Stage 1 indicates a peak of effect different than Day 29, the endpoint in Stage 2 will be modified accordingly.
• Change from Baseline to all post-treatment visits in the Tardieu Scale (TS) in the PTMG.
Stage 3
• Change from Baseline to post-treatment Day 29 in MAS score in the PTMG (adducted/rotated shoulder pattern).
Note: if PD profile of IPN59011 in Stage 1 indicates a peak of effect different than Day 29, the endpoint in Stage 3 will be modified accordingly.
• Change from baseline to all post-treatment visits in Disability Assessment Scale (DAS).
• Reduction of pain in the shoulder (adducted/rotated pattern) using the Numeric Rating Scale (NRS). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At each post treatment visit. |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |