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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
6
RAG-17 60mg is used
Beijing Tiantan Hospital
Beijing, China
Adverse events (AE) and serious adverse events (SAE)
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
Time frame: Within 240 days after treatment
Clinical laboratory examination index
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.
Time frame: Before RAG-17 treatment and within 240 days after treatment
Physiological Parameter-Vital Sign: Body Temperature
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.
Time frame: Within 240 days after treatment
Physiological Parameter-Vital Sign: Pulse Rate
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.
Time frame: Within 240 days after treatment
Physiological Parameter-Vital Sign: Respiration Rate
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.
Time frame: Within 240 days after treatment
Physiological Parameter-Vital Sign: Blood Pressure
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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.
Time frame: Within 240 days after treatment
Physiological Parameter-Vital Signs: Height, Hip Circumference and Waist
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.
Time frame: Within 240 days after treatment
Physiological Parameter-Vital Signs: Weight
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.
Time frame: Within 240 days after treatment
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R)
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.
Time frame: Within 240 days after treatment
Neurological examinations
Incidence rate of abnormalities in neurological examinations within 240 days after RAG-17 treatment
Time frame: Within 240 days after treatment
Heart circulatory system examinations
Incidence rate of abnormalities in heart circulatory system examinations within 240 days after RAG-17 treatment
Time frame: Within 240 days after treatment
Respiratory system examinations
Incidence rate of abnormalities in respiratory system examinations within 240 days after RAG-17 treatment
Time frame: Within 240 days after treatment
Abdominal examinations
Incidence rate of abnormalities in abdominal examinations within 240 days after RAG-17 treatment
Time frame: Within 240 days after treatment
ECG results
Incidence rate of abnormalities in ECG results within 240 days after RAG-17 treatment
Time frame: Within 240 days after treatment
SOD1 protein levels
Changes of SOD1 protein levels in cerebrospinal fluid from baseline on day 15, day 29, day 60, day 120, day 180 and day 240 of adult ALS patients after RAG-17 treatment
Time frame: baseline, day 15, day 29, day 60, day 120, day 180 and day 240
Plasma neurofilament light (NFL) levels
Changes in plasma neurofilament light (NFL) levels from baseline on day 1, day 15, day 29, day 60, day 120, day 180 and day 240 in adult ALS patients after RAG-17 treatment
Time frame: baseline, day 1, day 15, day 29, day 60, day 120, day 180 and day 240
Pharmacokinetic Changes of RAG-17
Pharmacokinetic Parameter changes of RAG-17 in Plasma: Maximum Observed Concentration (Cmax) on day1, day15, day29, day60, day120, day180 and day240 in adult ALS patients after RAG-17 treatment
Time frame: day 1, day 15, day 29, day 60, day 120, day 180 and day 240
Pharmacokinetic Changes of RAG-17
Pharmacokinetic Parameter changes of RAG-17 in Plasma: Time to Reach Maximum Observed Concentration (Tmax) on day1, day15, day29, day60, day120, day180 and day240 in adult ALS patients after RAG-17 treatment
Time frame: day 1, day 15, day 29, day 60, day 120, day 180 and day 240
Pharmacokinetic Changes of RAG-17
Pharmacokinetic Parameter changes of RAG-17 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) on day1, day15, day29, day60, day120, day180 and day240 in adult ALS patients after RAG-17 treatment
Time frame: day 1, day 15, day 29, day 60, day 120, day 180 and day 240
Pharmacokinetic Changes of RAG-17
Pharmacokinetic Parameter changes of RAG-17 in Plasma: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) on day1, day15, day29, day60, day120, day180 and day240 in adult ALS patients after RAG-17 treatment
Time frame: day 1, day 15, day 29, day 60, day 120, day 180 and day 240
Pharmacokinetic Changes of RAG-17
Pharmacokinetic Parameter changes of RAG-17 in Plasma: Apparent Terminal Elimination Half-life (t1/2) on day1, day15, day29, day60, day120, day180 and day240 in adult ALS patients after RAG-17 treatment
Time frame: day 1, day 15, day 29, day 60, day 120, day 180 and day 240
Mechanical ventilation
Time to invasive mechanical ventilation in adult ALS patients treated with RAG-17
Time frame: From day1 to day240
Death
Time of death in adult ALS patients treated with RAG-17
Time frame: From randomization date to date of death from any cause. The assessment period is up to 8 months