| 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. |
|
| 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. |
|
| 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 |
|
| 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 |
To assess the safety and tolerability of increasing doses of a single treatment of IPN10200 in participants with the clenched fist pattern compared with Dysport and Placebo.
To determine the safety of IPN10200 selected doses, for the treatment of AUL spasticity in participants
with the flexed elbow pattern 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.
To determine the safety of a selected dose of IPN10200 for the treatment of AUL spasticity in participants
with several clinical patterns including the
adducted/rotated shoulder pattern compared with Placebo. |
|
| E.2.2 | Secondary objectives of the trial |
•To assess the efficacy of IPN10200 over time
compared with Dysport and/or placebo in reducing the upper limb muscle tone in hemiparetic participants
•To evaluate PD characteristics of IPN10200
for the treatment of participants with AUL
including the time to onset, peak of effect, time to peak and duration of effect
•To compare the PD profile of IPN10200 to Dysport including duration of treatment Response
•To evaluate overall IPN10200 treatment
response as assessed by the investigator
•To evaluate the treatment benefit of IPN10200 as assessed by the participant
•To assess the immunogenicity potential of IPN10200 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Age
1. Participant must be 18 to 70 years of age inclusive (except for dose-escalation must be 18 to 65 years of age) at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2. Has spastic hemiparesis following stroke or TBI
3. Is at least 6 months post-stroke or TBI
4. Has 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
5. Has a MAS score ≥2 in the PTMG to be injected
6. Is eligible to receive a total recommended dose 1000 U Dysport in the upper limb when applicable.
7. Has angle of spasticity ≥5° in the PTMG to be injected.
8. Does 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°
9. Physiotherapy, occupational therapy, splinting, use of benzodiazepine, and muscle relaxants had to be stable from at least 30 days preceding the study Baseline up to the
Month 3 visit, and whenever possible until the end of the study.
10. 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
Sex
11. Male and female participants Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Male participants:
Male participants must agree that, if their partner is at risk of becoming pregnant, they
will use an effective method of contraception. The participants must agree to use the contraception during the whole period of the study.
• Female participants:
o A female participant is eligible to participate if she is not pregnant or
breastfeeding, and one of the following conditions applies:
Is a woman of non-childbearing potential (WONCBP) as defined in Section 10.4 Appendix 4:
Contraceptive and Barrier Guidance.
OR
Is a WOCBP and using an acceptable contraceptive method as described in Section 10.4 Appendix 4: Contraceptive and Barrier
Guidance during the study intervention period (at a minimum until after
the last dose of study intervention). The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance,
recently initiated) in relationship to the first dose of study intervention.
o A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations), see Section 8.2.5.
If a urine test cannot be confirmed as negative (e.g., an ambiguous
result), a serum pregnancy test is required. In such cases, the participant
must be excluded from participation if the serum pregnancy result is
positive.
o Additional requirements for pregnancy testing during and after study
intervention are located in Section 8.2.5.
o The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
Informed Consent
12. Capable of giving signed informed consent as described in Appendix 10.1 which includes
compliance with the requirements and restrictions listed in the informed consent form
(ICF) and in this protocol. |
|
| E.4 | Principal exclusion criteria |
Medical Conditions
1. 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.
Known disease of the neuromuscular junction (e.g. Lambert-Eaton myasthenic syndrome, myasthenia gravis or amyotrophic lateral sclerosis etc.).
3. Has a history of hypersensitivity to the investigational medicinal products (or other
BoNTs) or any excipient used in their formulation.
4. Clinically diagnosed significant anxiety disorder, or any other significant psychiatric disorder (e.g. depression) that might interfere with the participant’s participation in the study. Prior/concomitant Therapy
5. Likely treatment with any serotype of BoNT for any condition during the study.
6. Undergone previous surgery to treat spasticity in the affected upper limb.
7. 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 3-months post-injection).
8. Has received previous treatment with phenol and or alcohol in the targeted upper limb any time before the study.
9. 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.
10. 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.
11. Use of concomitant therapy which, in the investigator’s opinion, would interfere with the
evaluation of the safety or efficacy of the study intervention, including medications affecting bleeding disorders. For patients taking vitamin K
antagonists, the INR values should be controlled (between 2 and 3).
12. 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.
Prior/concurrent Clinical Study Experience
13. 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 start of
the study (prior to Baseline) and during the conduct of the study.
Diagnostic Assessments
14. 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 participant or decrease the chance of obtaining satisfactory data to achieve the objectives of the study.
15. Pregnant or lactating 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.
Other Exclusions
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. Infection at the injection site(s)
18. A history of drug or alcohol abuse
19. Male participants 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 Intervention. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Incidence, severity and nature of treatment
emergent adverse events (TEAEs).
• Incidence, severity and nature of adverse events of special interest (AESI).
• Vital signs (absolute values and change
from Baseline).
• Clinical laboratory evaluations (absolute
values and change from Baseline).
• Presence of BoNT-A and IPN10200 antibodies (binding and neutralising).
• Abnormal physical examination findings. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At each post treatment visit. |
|
| E.5.2 | Secondary end point(s) |
• Change from Baseline to all post-treatment visits in MAS score in the PTMG
• Change from Baseline to post-treatment Day 29 in MAS score in the PTMG
(Note: if PD profile of IPN10200 in dose escalation indicates a peak of effect different than Day 29, the endpoint will be modified
accordingly)
• Change from Baseline to all post-treatment visits in MAS score in all injected muscle Groups
• PD characteristics of IPN10200 in the
primary targeted muscle group (PTMG):
o Time to onset - time to the response to treatment (a reduction of at least one
grade in the MAS score).
o Peak of effect - maximal decrease in the MAS score from Baseline.
o Time to peak - time to reach the peak of effect (maximal decrease in the MAS score from Baseline).
o 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 inthe 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 at all post-treatment visits
• Change from Baseline to all post-treatment
visits in the Disability Assessment Scale
• Reduction of pain in the shoulder (adducted/rotated pattern) using the Numeric Rating Scale
• Presence of IPN10200 and BoNT-A antibodies and titres (binding and
neutralising) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At each post treatment visit. |
|
| 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 |
|
| 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 | 40 |
| 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 |
| United States |
| Austria |
| Poland |
| Spain |
| Czechia |
| Germany |
| Hungary |
| Slovakia |
|
| 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
|
|
| 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 months | 43 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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