A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel Study to Assess the Efficacy, Safety, Tolerability, PK, and Biomarker Effects of PTC857 in Adult Subjects With Amyotrophic Lateral Sclerosis (CARDINALS)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 336
- 试验地点
- 55
- 主要终点
- Combined Assessment of Function (ALS Functional Rating Scale-Revised [ALSFRS-R]) and Survival (CAFS) Rank After 24 Weeks of Treatment (Intention-to-Treat [ITT] 1 Analysis Population)
研究概览
简要总结
This study will assess the efficacy and safety of PTC857 treatment in participants diagnosed with ALS.
详细描述
Participants will be randomized to 1 of the 2 treatment groups: PTC857 or matching placebo. Following successful completion of the Treatment Period, participants who enter the LTE Period, will receive open-label PTC857 for 28 weeks. Following completion of the LTE period, participants who enter the Continued LTE Period will receive open-label PTC857 for an additional 108 weeks.
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 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •ALS with preserved function, defined as:
- •Onset of the first symptom leading to the diagnosis of ALS ≤24 months at the time of the initial Screening Visit
- •Revised EL Escorial criteria of either:
- •(i) Clinically definite ALS (ii) Clinically probable ALS
- •A total ALSFRS-R score of at least 34 at the start of the Screening Period
- •No significant respiratory compromise as evidenced by slow vital capacity ≥60% at the start of the Screening Period
- •All chronic concomitant medications (both prescription and over the counter), and non-pharmacologic therapy regimens, excluding standard-of-care therapy riluzole, edaravone, or sodium phenylbutyrate/taurursodiol, should be stable and unchanged from 14 days prior to the start of the Screening Period and intend to remain stable and unchanged throughout the course of the study
- •Female participants must have a negative breast cancer imaging screening status (not considered clinically abnormal and/or requiring further evaluation/treatment) within 6 months prior to the Screening Visit, or during the Screening Period.
- •Standard-of-care therapy for the treatment of ALS (riluzole, edaravone, or sodium phenylbutyrate/taurursodiol) should be stable and unchanged from 30 (-3) days prior to the start of the Screening Period and intend to remain stable and unchanged throughout the course of the study.
排除标准
- •Females who are pregnant or nursing or plan to become pregnant during the study
- •Participants with clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, or cardiovascular/ischemic disease or any other condition that, in the opinion of the investigator would jeopardize the safety of the participant or impact the validity of the study results
- •Any clinically significant medical or psychiatric condition or medical history that, in the opinion of the investigator or the medical monitor, would interfere with the participant's ability to participate in the study or increase the risk of participation for that participant
- •Current participation in any other investigational study with an investigational product or participation within 30 days prior to the start of the Screening Period or 5 half-lives of the previously taken investigational drug, whichever is longer
- •Participant has previously received PTC857
- •Participant is receiving a combination of edaravone and sodium phenylbutyrate/taurursodiol treatment, where applicable, within 30 days prior to the start of the Screening Period
- •For female participants, any past medical history of breast cancer, regardless of remission status, or any first degree relative with history of breast cancer
研究组 & 干预措施
Placebo
Participants will receive matching placebo during the 24-Week Treatment Period.
Following successful completion of the Treatment Period, participants who enter the LTE Period, will receive open-label PTC857 for 28 weeks. Following completion of the LTE period, participants who enter the Continued LTE Period will receive open-label PTC857 for an additional 108 weeks.
干预措施: Placebo (Drug)
PTC857
Participants will receive PTC857 during the 24-Week Treatment Period.
Following successful completion of the Treatment Period, participants who enter the Long-term Extension (LTE) Period, will receive open-label PTC857 for 28 weeks. Following completion of the LTE period, participants who enter the Continued LTE Period will receive open-label PTC857 for an additional 108 weeks.
干预措施: PTC857 (Drug)
结局指标
主要结局
Combined Assessment of Function (ALS Functional Rating Scale-Revised [ALSFRS-R]) and Survival (CAFS) Rank After 24 Weeks of Treatment (Intention-to-Treat [ITT] 1 Analysis Population)
时间窗: Week 24
The CAFS is a composite endpoint based on time to earlier occurrence of death and change from baseline in ALSFRS-R score. ALSFRS-R is a rating scale where 12 functions were rated on 5-point scales (from 0 to 4) with a maximum score of 48 (sum of all 12 items), with a higher score indicating better function. Each participant's outcome was compared to every other participant's outcome in a pairwise fashion by time to death and change on ALSFRS-R, assigned a score which was sum of comparisons (+1 \[better\], 0 \[tie\], -1 \[worse\]), and summed scores were ranked, from 1 to 306 (ITT1 Analysis Set) lowest rank corresponds to participant who died first and highest rank to the participant with best ALSFRS-R outcome among those who survived. Multiple imputation was used to impute participants with missing ALSFRS-R score at Week 24. A higher rank was considered a better outcome. Least square (LS) means and standard error (SE) were calculated using analysis of covariance (ANCOVA) model.
次要结局
- Change From Baseline in Modified Norris Scale Total Score at Week 24(Baseline, Week 24)
- Change From Baseline in ALS Assessment Questionnaire (ALSAQ-40) Total Score at Week 24(Baseline, Week 24)
- Change From Baseline in Neurofilament Light Chain (NfL) Activity at Week 24(Baseline, Week 24)
- Area Under the Concentration-time Curve From 0 to Measurable Timepoint (AUC0-t) of Utreloxastat in Plasma(Day 1 and Day 29)
- Combined Assessment of Function (ALSFRS-R) and Survival (CAFS) Rank After 24 Weeks of Treatment (ITT2 Analysis Population)(Week 24)
- Change From Baseline in ALSFRS-R Score at Week 24 (ITT1 Analysis Population)(Baseline, Week 24)
- Change From Baseline in ALSFRS-R Score at Week 24 (ITT2 Analysis Population)(Baseline, Week 24)
- Number of Participants With Treatment-emergent Adverse Events (TEAEs)(Day 1 through Week 24)
- Maximum Observed Concentration (Cmax) of Utreloxastat in Plasma(Day 1 and Day 29)
- Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 24(Baseline, Week 24)
- Overall Survival Rate(Baseline to Week 24)
- Overall Survival(Baseline to Week 24)
- Mean Concentration of Utreloxastat in Cerebrospinal Fluid (CSF)(Day 1 and Day 29)