A study investigating single injection of new botulinum toxin to determine safety and efficacy for treating spasticity in the upper limb

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ipsen Innovation

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

29 Apr 2021 → ongoing

Decision date (initial)

2024-05-31

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Ipsen Innovation

External identifiers

EU CT number

2023-507202-14-00

EudraCT number

2020-003623-42

ClinicalTrials.gov

NCT04752774

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Dose response, Safety

Stage 1: To assess the safety and tolerability of increasing doses of a single treatment of IPN10200 in participants’ in the PTMG compared with Dysport and placebo, and to select two dose levels for further investigation in Stage 2.

Stage 2: To determine the safety of two doses of IPN10200 selected after Stage 1, for the treatment of AUL spasticity in participants in the PTMG (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 required duration of response for the further investigation in Stage 3.

Open-label extension period: To determine the safety of IPN10200 for the treatment of AUL spasticity in participants from Stage 3 with several clinical patterns over multiple treatment cycles.

Stage 3: To assess the efficacy of IPN10200 compared to placebo for the treatment of AUL spasticity in participants in the PTMG (mandatory clinical pattern in Stage 3)

Secondary objectives 14

1. All Stages: To assess the efficacy of IPN10200 over time compared with Dysport and/or placebo in reducing the upper limb muscle tone in hemiparetic participants
2. All Stages: 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
3. All Stages: To compare the PD profile of IPN10200 to Dysport including duration of treatment Response
4. All Stages: To evaluate overall IPN10200 treatment response as assessed by the investigator
5. All Stages: To evaluate the treatment benefit of IPN10200 as assessed by the participant
6. Stage 3: To assess the safety and tolerability of IPN10200 for the treatment of AUL spasticity
7. Stage 3: To evaluate the benefit of IPN10200 treatment on spasticity
8. Stage 3: To assess the functional treatment response by measuring active range of motion (AROM) in all injected muscles including the PTMG
9. Open-label Extension Period: To evaluate the efficacy of IPN10200 in reducing upper limb muscle tone over multiple treatments
10. Open-label Extension Period: 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 over multiple treatment cycles
11. Open-label Extension Period: To evaluate overall IPN10200 treatment response as assessed by the investigator over multiple treatment cycles
12. Open-label Extension Period: To evaluate the treatment benefit of IPN10200 as assessed by the participant over multiple treatment cycles
13. Open-label Extension Period: To evaluate the efficacy of IPN10200 in the upper limb spasticity status over multiple treatment cycles
14. Open-label Extension Period: To evaluate the efficacy of IPN10200 in the functional treatment response over multiple treatment cycles

Conditions and MedDRA coding

Upper limb spasticity after stroke or traumatic brain injury

Study design 5 periods

Regulatory references

Scientific advice from competent authorities

Health Products Regulatory Authority

Plan to share IPD

Yes

IPD plan description

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, annotated case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of study participants. Any requests should be submitted to www.vivli.org for assessment by an independent scientific review board. Supporting Information Time Frame: Where applicable, data from eligible studies are available 6 months after the studied medicine and indication have been approved in the US and EU or after the primary manuscript describing the results has been accepted for publication, whichever is later. Access Criteria: Further details on Ipsen's sharing criteria, eligible studies and process for sharing are available at https://vivli.org/members/ourmembers/.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

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.
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. Has the angle of arrest as measured by the Tardieu scale (XV1) in the muscle groups to be injected as follows: • XV1 ≥160° for finger flexors • XV1 ≥90° for wrist flexors • XV1 ≥160° for elbow flexors
9. Stage 1 and 2: 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. Stage 3: Physiotherapy, occupational therapy, splinting, use of benzodiazepine, and muscle relaxants had to be stable from at least 3 months 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
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) OR  Is a WOCBP and using an acceptable contraceptive method 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)  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.
12. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and protocol.

Exclusion criteria 19

1. Any medical condition (including, but not limited to: severe dysphagia or airway disease, severe impairment of ability to walk (e.g. wheelchair-bound) and/or living in long-term care facilities due to loss of autonomy) that may increase, in the opinion of the investigator, the likelihood of adverse events related to BoNT treatment.
2. A history of drug or alcohol abuse
3. 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.
4. Known disease of the neuromuscular junction (e.g. Lambert-Eaton myasthenic syndrome, myasthenia gravis or amyotrophic lateral sclerosis etc.).
5. Has a history of hypersensitivity to the investigational medicinal products (or other BoNTs) or any excipient used in their formulation.
6. 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.
7. Likely treatment with any serotype of BoNT for any condition during the study.
8. Undergone previous surgery to treat spasticity in the affected upper limb.
9. 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)
10. Has received previous treatment with phenol and or alcohol in the targeted upper limb any time before the study.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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 and for the duration of the study.
18. Inability to understand protocol procedures and requirements
19. Infection at the injection site(s)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 8

1. Percentage of participants with treatment emergent adverse events (TEAEs).
2. Percentage of participants with adverse events of special interest (AESI).
3. Change from baseline in vital sign parameter (blood pressure)
4. Change from baseline in vital sign parameter (Heart rate)
5. Change from baseline in clinical laboratory test results.
6. Presence of IPN10200 and BoNT-A antibodies (binding and neutralising)
7. Change from baseline in physical examination findings
8. Response to treatment measured by at least one grade reduction in Modified Ashworth Scale (MAS) score in the primary targeted muscle group (PTMG).

Secondary endpoints 37

1. Change from Baseline to all post-treatment visits in Modified Ashworth scale (MAS) score in the Primary target muscle group (PTMG)
2. Change from Baseline to post-treatment Day 29 in MAS score in the PTMG
3. Change from Baseline in MAS score in all injected muscle Groups
4. PD characteristics of IPN10200 in the 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
5. Response to treatment as measured by at least one grade reduction in MAS score in the PTMG from Baseline
6. Response to treatment as measured by at least one grade reduction in MAS score in all injected muscle groups
7. Physician’s Global Assessment (PGA) score of overall treatment response
8. Patient Global Impression of Change in the Spastic Clinical Pattern using specific scale (PGI-c)
9. Change from Baseline in the Disability Assessment Scale (DAS)
10. Reduction of pain in the shoulder using the Numeric Rating Scale
11. Change from Baseline in the Tardieu Scale (TS) in the PTMG
12. Change from Baseline in the active range of motion (AROM) in all injected muscle groups including the PTMG
13. Percentage of participants with TEAEs.
14. Percentage of participants with AESIs.
15. Percentage of participants with clinically significant changes from baseline in vital signs
16. Percentage of participants with clinically significant change from baseline in 12-lead Electrocardiogram (ECG) readings
17. Percentage of Participants with clinically significant changes from baseline in Laboratory Parameters
18. Percentage of participants with Binding antibodies of IPN10200 and BoNT-A
19. Percentage of participants with neutralising antibodies of IPN10200 and BoNT-A
20. Percentage of participants with clinically significant change from baseline in physical examination
21. Change from Baseline in MAS score in the PTMG.
22. Change from Baseline in MAS score in all injected muscle groups.
23. Response to treatment as measured by at least one grade reduction in MAS score in the PTMG
24. Response to treatment as measured by at least one grade reduction in MAS score in all injected muscle groups
25. Time to onset - time to the response to treatment (a reduction of at least one grade in the MAS score).
26. Peak of effect - maximal decrease in the MAS score from Baseline.
27. Time to peak - time to reach the peak of effect (maximal decrease in the MAS score from Baseline).
28. Duration of effect - duration between time to onset and last timepoint with a response to treatment.
29. PGA score of overall treatment response at all post treatment visits
30. PGIC at all post-treatment visits.
31. Change from Baseline to all post-treatment visits in the DAS.
32. Change from baseline to all post-treatment visits in NRS pain in the shoulder.
33. Change from Baseline in the Tardieu Scale in shoulder adductors
34. Change from Baseline in the Tardieu Scale in elbow flexors
35. Change from Baseline in the Tardieu Scale in wrist flexors (when applicable)
36. Change from Baseline in the Tardieu Scale in finger flexors (when applicable) at all timepoints
37. Change from Baseline to all post-treatment visits in AROM in all injected muscle groups.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ipsen Innovation

Sponsor organisation

Ipsen Innovation

Address

70 Rue Balard

City

Paris

Postcode

75015

Country

France

Scientific contact point

Organisation

Ipsen Innovation

Contact name

Ipsen Clinical Study Enquiries

Public contact point

Organisation

Ipsen Innovation

Contact name

Ipsen Clinical Study Enquiries

Third parties 8

Sponsor responsibilities

Article 77 compliance

Ipsen Innovation

Contact point sponsor

Ipsen Innovation

Article 77 implementation

Ipsen Innovation

Locations

10 EU/EEA countries · 50 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 113 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

16 submissions — initial application plus substantial / non-substantial modifications