Safety and Tolerability of RAG-17 in the Treatment of Amyotrophic Lateral Sclerosis Patients With SOD1 Gene Mutation

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Safety and Tolerability of RAG-17 in the Treatment of Amyotrophic Lateral Sclerosis Patients With SOD1 Gene Mutation

Conditions
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Gene Mutation

Intervention / Treatment
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* Drug: RAG-17


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 ≥ 80% 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RAG-17<br>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. | Drug: RAG-17<br>* RAG-17 60mg is used<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events (AE) and serious adverse events (SAE) | The incidence of adverse events (AE) and serious adverse events (SAE) within 180 days after RAG-17 treatment, and number of participants with treatment-related adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) V5.0 | Within 180 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 180days after RAG-17 treatment, which including blood testing and urine testing. Eventually to determine the safety and tolerability of RAG-17 on adult ALS patients. | Before RAG-17 treatment and within 180 days after treatment | 
| Physiological Parameter-Vital Sign: Body Temperature | Change in vital signs are monitored within 180 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. | Within 180 days after treatment | 
| Physiological Parameter-Vital Sign: Pulse Rate | Change in vital signs are monitored within 180 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. | Within 180 days after treatment | 
| Physiological Parameter-Vital Sign: Respiration Rate | Change in vital signs are monitored within 180 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. | Within 180 days after treatment | 
| Physiological Parameter-Vital Sign: Blood Pressure | Change in vital signs are monitored within 180 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. | Within 180 days after treatment | 
| Physiological Parameter-Vital Signs: Height, Hip Circumference and Waist | Change in vital signs are monitored within 180 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. | Within 180 days after treatment | 
| Physiological Parameter-Vital Signs: Weight | Change in vital signs are monitored within 180 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. | Within 180 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 180 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. | Within 180 days after treatment | 
| Neurological examinations | Incidence rate of abnormalities in neurological examinations within 180 days after RAG-17 treatment | Within 180 days after treatment | 
| Heart circulatory system examinations | Incidence rate of abnormalities in heart circulatory system examinations within 180 days after RAG-17 treatment | Within 180 days after treatment | 
| Respiratory system examinations | Incidence rate of abnormalities in respiratory system examinations within 180 days after RAG-17 treatment | Within 180 days after treatment | 
| Abdominal examinations | Incidence rate of abnormalities in abdominal examinations within 180 days after RAG-17 treatment | Within 180 days after treatment | 
| ECG results | Incidence rate of abnormalities in ECG results within 180 days after RAG-17 treatment | Within 180 days after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SOD1 protein levels | Changes of SOD1 protein levels in cerebrospinal fluid from baseline on day 1, day 15, day 29, day 60, day 120, day 180 and day 240 of adult ALS patients after RAG-17 treatment | day 1, 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 | 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 | 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 | 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 | 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 | 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 | 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 | From day1 to day240 | 
| Death | Time of death in adult ALS patients treated with RAG-17 | From randomization date to date of death from any cause. The assessment period is up to 8 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RAG-17, SOD1 Gene Mutation, Amyotrophic Lateral Sclerosis