Safety and Tolerance of RAG-17 in Amyotrophic Lateral Sclerosis Patients With SOD1 Gene Mutation
试验速览
- 阶段
- 早期 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 6
- 试验地点
- 1
- 主要终点
- Respiratory system examinations
研究概览
简要总结
The goal of this clinical trial is to evaluate the safety, tolerability and pharmacokinetics of RAG-17 in adult amyotrophic lateral sclerosis (ALS) patients with SOD1 mutation. Patients will receive drug treamtent via dose escalation which ranging from minimum of 60 mg to the maximum tolerated dose (MTD), after reaching the tolerated dose, a fixed dose of the drug is given once every two months for continuous treatment, and the total treatment cycle is 8 months. The duration of this study is two years.
详细描述
This study is an open-label, single center, first-in-Human dose escalation study to evaluate the safety, tolerability and pharmacokinetics of RAG-17 in adultamyotrophic lateral sclerosis (ALS) patients with SOD1 mutation via dose escalations. Patients will receive 60mg of RAG-17 firstly, within 14 days after the first administration, the subject has no adverse event (AE) and serious adverse event (SAE), the subject can accept dose escalation every 30mg/14 days of observation period. 3 to 4 dose escalations are planned to reach the dose limiting toxicity (DLT), with optimal doses for continual 6-month treatment cycles. For the dose of subsequent continuous treatment, an optimal dose between the safe dose and the maximum tolerated dose (MTD) is selected as the continuous treatment dose. SAS software is used for safety analysis. The sample size of this study is 6 ALS patients with SOD1 mutation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients who are judged by professional medical staff to still be able to carry out the clinical trial project cycle;
- •18 years old ≤ age ≤ 75 years old, males or females;
- •ALS patients with confirmed SOD1 gene mutations document (known SOD1 mutation sites and related disease progression have been reported);
- •Forced vital capacity ≥ 50% of predicted vital capacity during the screening period;
- •Diagnosis of confirmed or probable familial or sporadic ALS in accordance with the revised EI Escorial diagnostic criteria for amyotrophic lateral sclerosis of the World Federation of Neurology;
- •The patient or patient's legal representative clearly understands and voluntarily participates in the study and signs the informed consent form;
- •Subjects (including male subjects) are willing to have no birth plan and voluntarily take effective contraceptive measures during the entire study period and within 3 months after the end of the study, and have no plan to donate sperm or eggs.
排除标准
- •Patients with SOD1 mutations occurring at nucleotides 44 to 66 (calculated from the start of SOD1 protein translation), patients with P.F21C mutation;
- •Patients who have previously received or are currently receiving Tofersen treatment;
- •HIV test positive or history of positive tests;
- •Positive hepatitis C virus antibody or history of positive tests;
- •Active hepatitis B infection (positive hepatitis B surface antigen and/or positive hepatitis B core antibody);
- •Have used other investigational drugs within 1 month or within 5 drug half-lives;
- •Diseases and deformities of the lumbar spine;
- •Have other conditions known to be associated with motor neuron dysfunction that may confuse or obscure an ALS diagnosis;
- •Other psychiatric disorders diagnosed according to DSM-V diagnostic criteria, or significant suicide intent;
- •With severe hepatic insufficiency, renal insufficiency or severe cardiac insufficiency (severe hepatic insufficiency refers to ALT value≥2.0 times the upper limit of normal value or AST value≥2.0 times the upper limit of normal value; severe renal insufficiency refers to CRE≥1.5 times the upper limit of normal value or eGFR<40mL/min/1.73m2; severe cardiac insufficiency refers to NYHA class 3-4);
- •Permanently dependent on ventilator-assisted ventilation;
- •History of alcohol and drug abuse;
- •Patients who are pregnant, breast-feeding, or who are likely to become pregnant and plan to become pregnant;
- •Patients participating in other clinical trials or using other biological agents, drugs or devices under investigation;
- •Patients who have received any vaccinations within 28 days;
- •Contraindications to MRI (eg, claustrophobia);
- •Unable to be cooperative and complete the follow-up due to other reasons.
研究组 & 干预措施
RAG-17
Doses of RAG-17 will range from a minimum of 60 mg to the maximum tolerated dose (MTD). Dosing once every two weeks, starting from 60 mg, with dose escalation. After reaching the tolerated dose, a fixed dose of the drug is given once every two months for continuous treatment, and the total treatment cycle is 8 months.
干预措施: RAG-17 (Drug)
结局指标
主要结局
Respiratory system examinations
时间窗: Within 240 days after treatment
Incidence rate of abnormalities in respiratory system examinations within 240 days after RAG-17 treatment
Abdominal examinations
时间窗: Within 240 days after treatment
Incidence rate of abnormalities in abdominal examinations within 240 days after RAG-17 treatment
Physiological Parameter-Vital Sign: Pulse Rate
时间窗: Within 240 days after treatment
Change in vital signs are monitored within 240 days after RAG-17 treatment to determine the safety and tolerability of RAG-17 on adult ALS patients. Vital sign that is measured including pulse rate in beats per minute.
Adverse events (AE) and serious adverse events (SAE)
时间窗: Within 240 days after treatment
The incidence of adverse events (AE) and serious adverse events (SAE) within 240 days after the first injection of RAG-17, and number of participants with treatment-related adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) V5.0
Clinical laboratory examination index
时间窗: Before RAG-17 treatment and within 240 days after treatment
Monitor the abnormal change of clinical laboratory Index generated from general examination results before RAG-17 treatment, and within 240 days after the first injection of RAG-17, which including blood testing and urine testing. Eventually to determine the safety and tolerability of RAG-17 on adult ALS patients.
Physiological Parameter-Vital Sign: Body Temperature
时间窗: Within 240 days after treatment
Change in vital signs are monitored within 240 days after RAG-17 treatment to determine the safety and tolerability of RAG-17 on adult ALS patients. Vital sign that is measured including body temperature in degree Celsius.
Physiological Parameter-Vital Sign: Respiration Rate
时间窗: Within 240 days after treatment
Change in vital signs are monitored within 240 days after RAG-17 treatment to determine the safety and tolerability of RAG-17 on adult ALS patients. Vital sign that is measured including respiration rate in breaths per minute.
Physiological Parameter-Vital Sign: Blood Pressure
时间窗: Within 240 days after treatment
Change in vital signs are monitored within 240 days after RAG-17 treatment to determine the safety and tolerability of RAG-17 on adult ALS patients. Vital sign that is measured including blood pressure in mmHg.
Physiological Parameter-Vital Signs: Height, Hip Circumference and Waist
时间窗: Within 240 days after treatment
Change in vital signs are monitored within 240 days after RAG-17 treatment to determine the safety and tolerability of RAG-17 on adult ALS patients. Vital signs that are measured including height, hip circumference and waist in centimeter.
Physiological Parameter-Vital Signs: Weight
时间窗: Within 240 days after treatment
Change in vital signs are monitored within 240 days after RAG-17 treatment to determine the safety and tolerability of RAG-17 on adult ALS patients. Vital sign that is measured including body weight in kilogram.
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R)
时间窗: Within 240 days after treatment
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) is a questionnaire-based scale that is used to measure the change in functional impairment of adult ALS patients within 240 days after RAG-17 treatment. ALSFRS-R scale measures 12 aspects of physical function, and each function is scored from 4 (normal) to 0 (no ability), with a maximum total score of 48 and a minimum total score of 0.
Neurological examinations
时间窗: Within 240 days after treatment
Incidence rate of abnormalities in neurological examinations within 240 days after RAG-17 treatment
Heart circulatory system examinations
时间窗: Within 240 days after treatment
Incidence rate of abnormalities in heart circulatory system examinations within 240 days after RAG-17 treatment
ECG results
时间窗: Within 240 days after treatment
Incidence rate of abnormalities in ECG results within 240 days after RAG-17 treatment
次要结局
- Mechanical ventilation(From day1 to day240)
- Death(From randomization date to date of death from any cause. The assessment period is up to 8 months)
- SOD1 protein levels(baseline, day 15, day 29, day 60, day 120, day 180 and day 240)
- Plasma neurofilament light (NFL) levels(baseline, day 1, day 15, day 29, day 60, day 120, day 180 and day 240)
- Pharmacokinetic Changes of RAG-17(day 1, day 15, day 29, day 60, day 120, day 180 and day 240)
研究者
yilong Wang
Vice-President of Beijing Tiantan Hospital,Chief Scientist of Neurology Center
Beijing Tiantan Hospital