A Phase 1-2, Double-Blind, Sham-Controlled Multiple Ascending Dose Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intrathecally-Administered ION440 in Patients With MECP2 Duplication Syndrome
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 48
- 试验地点
- 20
- 主要终点
- Part 2: Number of Participants With Clinically Significant Change From Baseline in ECG
研究概览
简要总结
The primary purpose of this study is to evaluate the safety and tolerability of ION440.
详细描述
This is a phase 1-2 randomized, double-blind, sham-controlled, multiple-ascending dose (MAD) study to evaluate ION440 in pediatric and adult participants with MECP2 Duplication Syndrome (MDS) and will be conducted in two parts. During Part 1 (MAD) (36 weeks), participants will be randomized in a 3:1 ratio to receive ION440 or sham. Individuals who complete Part 1 may enter Part 2, an open label long-term extension study (LTE), where they will receive ION440 for up to approximately 156 weeks. Multiple dose cohorts (Dose A, Dose B, and Dose C) will be evaluated in the study.
All dosing cohorts will be further subdivided by age. Sub cohort A will include participants 8 through 65 years of age, and sub cohort B will include participants 2 through 7 years of age. Dosing cohorts will be enrolled sequentially with sub cohort A initiating prior to sub cohort B.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 2 Years 至 65 Years（Child, Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •for Part 1:
- •Males aged ≥ 2 to ≤ 65 years, depending on specific cohort and group, at the time of informed consent.
- •Group A: ≥ 8 to ≤ 65 years old
- •Group B: 2 to 7 years old, inclusive
- •Participant has at least one parent or caregiver ≥ 18 years old capable of providing informed consent and able to comply with all study requirements and activities.
- •Participant has a documented diagnosis of MDS with genetic confirmation of MECP2 duplication.
- •Is currently receiving stable doses of concomitant medications for at least 1 month prior to screening.
- •Able to complete all study procedures, measurements and visits to support primary and secondary endpoints, in the opinion of the Investigator.
排除标准
- •for Part 1:
- •Documented diagnosis of severe MECP2 duplications including terminal duplication and/or translocation or MECP2 triplication OR clinical features associated with severe variant structure including (a) onset of seizures prior to age 5 (for those aged 5 and above at signing of ICF), (b) oxygen dependence, (c) microcephaly, IF MECP2 genetic structure information is unavailable.
- •Clinically significant vital sign or ECG abnormality at Screening
- •Known brain or spinal disease that would interfere with the LP procedure, or CSF circulation or presence of other factors would affect the safety of the LP procedure.
- •Has any concomitant disease or condition or circumstance, or any finding at Screening that, in the opinion of the Investigator, makes the participant unsuitable for enrollment or that could interfere with the conduct of the study or that would pose an unacceptable risk to the participant in this study.
- •Treatment with an investigational drug, biological agent, or device within 30 days of Screening, or 5 half-lives of investigational agent, whichever is longer.
- •Previous treatment with an oligonucleotide (including siRNA) within 4 months of Screening if single dose received, or within 12 months of Screening if multiple doses received (this exclusion does not apply to vaccines - both mRNA and viral vector vaccines are allowed including COVID-19). For centrally administered ASOs, a minimum of 12 months washout is required irrespective of the number of doses received.
- •Currently enrolled in a clinical trial of an investigational agent or device or has used any investigational agent or device within 5 half-lives of investigational agent, whichever is longer.
- •Has a history of gene therapy or cell transplantation or any other experimental brain surgery.
- •Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Baseline (Day 1).
- •Has experienced Status Epilepticus in the past 6 months.
- •Key Inclusion criteria for Part 2:
- •Participants in ION440-CS1, Part 1/MAD who received at least one dose of Study Drug /Sham in Part 1/MAD, missed no more than 1 study visit, and attended the Follow Up visit (Visit 6).
- •All inclusion criteria in Part 1/MAD apply (participants will not be required to undergo new Screening bloodwork).
- •Key Exclusion criteria for Part 2:
- •1. Has developed any concomitant disease (e.g., gastrointestinal, renal, hepatic, endocrine, respiratory, or cardiovascular system disease) or condition or circumstance, or any finding during Part 1/MAD that, in the opinion of the Investigator, makes the participant unsuitable for continued treatment (e.g., could interfere with the conduct of the study or that would pose an unacceptable risk to the participant in this study).
结局指标
主要结局
Part 2: Number of Participants With Clinically Significant Change From Baseline in ECG
时间窗: Baseline up to approximately 192 weeks
Part 1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
时间窗: Up to approximately 36 weeks
Part 1: Number of Participants With Clinically Significant Change From Baseline in Vital Signs
时间窗: Baseline up to approximately 36 weeks
Part 1: Number of Participants With Clinically Significant Change From Baseline in Physical and Neurological Examination Findings
时间窗: Baseline up to approximately 36 weeks
Part 1: Number of Participants With Clinically Significant Change from Baseline in Laboratory Assessments
时间窗: Baseline up to approximately 36 weeks
Part 1: Number of Participants With Clinically Significant Change From Baseline in Electrocardiogram (ECG)
时间窗: Baseline up to approximately 36 weeks
Part 2: Number of Participants With TEAEs
时间窗: Up to approximately 192 weeks
Part 2: Number of Participants With Clinically Significant Change From Baseline in Vital Signs
时间窗: Baseline up to approximately 192 weeks
Part 2: Number of Participants With Clinically Significant Change From Baseline in Physical and Neurological Examination Findings
时间窗: Baseline up to approximately 192 weeks
Part 2: Number of Participants With Clinically Significant Change from Baseline in Laboratory Assessments
时间窗: Baseline up to approximately 192 weeks
次要结局
- Part 1: Maximum Observed Concentration (Cmax) of ION440 in Plasma(Pre-dose and at multiple points post-dose up to Week 36)
- Part 1: Area Under the Concentration-time Curve (AUC) of ION440 in Plasma(Pre-dose and at multiple points post-dose up to Week 36)
- Part 1: Plasma Terminal Elimination Half-life (t½) of ION440(Pre-dose and at multiple points post-dose up to Week 36)
- Part 1: Trough Concentration (Ctrough) of ION440 in Plasma and CSF(Pre-dose and at multiple points post-dose up to Week 36)
- Part 1: Plasma Concentration of ION440(Pre-dose and at multiple points post-dose up to Week 36)
- Part 2: Trough Concentration (Ctrough) of ION440 in Plasma and CSF(Up to approximately 192 weeks)
研究者
Global Regulatory Affairs
Scientific
Ionis Pharmaceuticals Inc.