An Integrated Phase I/II, Multicentre, Double-blind, Randomised, Dysport and Placebo-controlled, Dose Escalation and Dose-finding Study to Evaluate the Safety and Efficacy of IPN10200 in the Treatment of Adult Upper Limb Spasticity.
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- Ipsen
- 入组人数
- 240
- 试验地点
- 106
- 主要终点
- Change from baseline in physical examination findings.
研究概览
简要总结
The purpose of the study is to assess the safety and efficacy of increasing doses of Corabotase (also known as IPN10200) with the aim to evaluate the Pharmacodynamics (PD) profile of Corabotase and to establish the total Corabotase doses(s) that offer the best efficacy/safety profile when used for the treatment of Adult upper limb (AUL) spasticity.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •Has spastic hemiparesis following stroke or Traumatic brain injury (TBI)
- •Is at least 6 months post-stroke or TBI
- •Has never received BoNT or if previously treated, should have received their last injection of any commercialized BoNT-A or B at least 4 months prior to study Baseline
- •Has a MAS score ≥2 in the (PTMG) to be injected
- •Is eligible to receive a total recommended dose 1000 U Dysport in the upper limb when applicable.
- •Has angle of spasticity ≥5° in the PTMG to be injected.
- •Does not have any fixed contractures as defined by:
- •Complete fingers extension with Angle of arrest at slow speed (Tardieu Scale) (XV1) ≥160°
- •Complete wrist extension with XV1 ≥90°
- •Complete elbow extension with XV1 ≥160°
- •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.
- •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 judgment prior to randomization
- •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 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.
- •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 woman of childbearing potential (WOCBP) and using an acceptable contraceptive method (until the end of the study). The investigator should evaluate the potential for contraceptive method failure in relationship to the first dose of study intervention. A WOCBP must have a negative highly sensitive pregnancy test.
排除标准
- •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.).
- •Has a history of hypersensitivity to the investigational medicinal products (or other BoNTs) or any excipient used in their formulation.
- •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.
- •Likely treatment with any serotype of BoNT for any condition during the study.
- •Undergone previous surgery to treat spasticity in the affected upper limb.
- •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).
- •Has received previous treatment with phenol and or alcohol in the targeted upper limb any time before the study.
- •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.
- •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.
- •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)
- •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.
- •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.
- •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 judgment 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.
- •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 the duration of the study
- •Inability to understand protocol procedures and requirements
- •Infection at the injection site(s)
- •A history of drug or alcohol abuse
- •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.
研究组 & 干预措施
Dose escalation
One single administration of study medication (Corabotase, Dysport or placebo) will be injected in a dose-escalation manner. Dose-escalation will include several cohorts.
干预措施: Corabotase (Biological)
Dose ranging
Two fixed doses of Corabotase will be administrated as a single injection into several muscle groups of the upper limb.
Participants will be randomised in the ratio of 3:3:2 (total Corabotase dose 1: 30 participants; total Corabotase dose 2: 30 participants; Dysport: 20 participants)
干预措施: Corabotase (Biological)
Total dose
One single injection of study medication will be administered locally into several muscle groups of the upper limb.
Participants will be randomized in the ratio of 2:1 (Total Corabotase dose: 30 participants; placebo: 15 participants, resulting in a total of 45 participants in Stage 3).
Or
Participants will be randomized in the ratio of 3:1 (Corabotase lower dose: 30 participants; placebo: 10 participants, then Corabotase higher dose: 30 participants; placebo: 10 participants, resulting in a total of 80 participants in Stage 3).
干预措施: Corabotase (Biological)
Dose escalation
One single administration of study medication (Corabotase, Dysport or placebo) will be injected in a dose-escalation manner. Dose-escalation will include several cohorts.
干预措施: Dysport (Biological)
Dose ranging
Two fixed doses of Corabotase will be administrated as a single injection into several muscle groups of the upper limb.
Participants will be randomised in the ratio of 3:3:2 (total Corabotase dose 1: 30 participants; total Corabotase dose 2: 30 participants; Dysport: 20 participants)
干预措施: Dysport (Biological)
Dose escalation
One single administration of study medication (Corabotase, Dysport or placebo) will be injected in a dose-escalation manner. Dose-escalation will include several cohorts.
干预措施: Placebo (Drug)
Total dose
One single injection of study medication will be administered locally into several muscle groups of the upper limb.
Participants will be randomized in the ratio of 2:1 (Total Corabotase dose: 30 participants; placebo: 15 participants, resulting in a total of 45 participants in Stage 3).
Or
Participants will be randomized in the ratio of 3:1 (Corabotase lower dose: 30 participants; placebo: 10 participants, then Corabotase higher dose: 30 participants; placebo: 10 participants, resulting in a total of 80 participants in Stage 3).
干预措施: Placebo (Drug)
结局指标
主要结局
Change from baseline in physical examination findings.
时间窗: 9 months
Number of Participants with change in physical examination findings
Percentage of participants with treatment emergent adverse events (TEAEs).
时间窗: From baseline until the end of study (9 months)
An Adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
Percentage of participants with adverse events of special interest (AESI).
时间窗: From baseline until the end of study (9 months)
Change from baseline in vital sign parameter (blood pressure)
时间窗: 9 months
Change from baseline in vital sign parameter (Heart rate)
时间窗: 9 months
Change from baseline in clinical laboratory test results.
时间窗: 9 months
Number and percentage of participants with low, normal or high values and normal or abnormal examinations will be presented.
Presence of IPN10200 and BoNT-A antibodies (binding and neutralising)
时间窗: From baseline until the end of study (9 months)
次要结局
- Change from Baseline in MAS score in all injected muscle Groups(From baseline until the end of study (9 months))
- Change from Baseline to all post-treatment visits in Modified Ashworth scale (MAS) score in the Primary target muscle group (PTMG)(from baseline until the end of study (9 months))
- Change from Baseline to post-treatment Day 29 in MAS score in the PTMG.(From baseline until post-treatment Day 29)
- Time to onset - time to the response to treatment (a reduction of at least one grade in the MAS score).(From baseline until the end of study (9 months))
- Peak of effect - maximal decrease in the MAS score from Baseline.(From baseline until the end of study (9 months))
- Time to peak - time to reach the peak of effect (maximal decrease in the MAS score from Baseline).(From baseline until the end of study (9 months))
- Duration of effect - duration between time to onset and last timepoint with a response to Treatment.(From baseline until the end of study (9 months))
- Response to treatment as measured by at least one grade reduction in MAS score in the PTMG from Baseline(From baseline until the end of study (9 months))
- Response to treatment as measured by at least one grade reduction in MAS score in all injected muscles from Baseline(From baseline until the end of study (9 months))
- Physician's Global Assessment (PGA) score of overall treatment response(From baseline until the end of study (9 months))
- Patient Global Impression of Change in the Spastic Clinical Pattern using specific scale (PGI-c)(from baseline until the end of study (9 months))
- Change from Baseline in the Disability Assessment Scale (DAS)(From baseline until the end of study (9 months))
- Reduction of pain in the shoulder (adducted/rotated pattern) using the Numeric Rating Scale(From baseline until the end of study (9 months))
- The number and percentage of participants with presence of IPN10200 and BoNT-A antibodies and titres (binding and neutralising)(At baseline)