Gene Mutation
Conditions
Keywords
RAG-17, SOD1 Gene Mutation, Amyotrophic Lateral Sclerosis
Brief summary
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
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.
Interventions
DRUGRAG-17
RAG-17 60mg is used
Sponsors
Ractigen Therapeutics.
Beijing Tiantan Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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 ≥ 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.
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse events (AE) and serious adverse events (SAE) | 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 |
| ECG results | Within 240 days after treatment | Incidence rate of abnormalities in ECG results within 240 days after RAG-17 treatment |
| Abdominal examinations | Within 240 days after treatment | Incidence rate of abnormalities in abdominal examinations within 240 days after RAG-17 treatment |
| Respiratory system examinations | Within 240 days after treatment | Incidence rate of abnormalities in respiratory system examinations within 240 days after RAG-17 treatment |
| Heart circulatory system examinations | Within 240 days after treatment | Incidence rate of abnormalities in heart circulatory system examinations within 240 days after RAG-17 treatment |
| Neurological examinations | Within 240 days after treatment | Incidence rate of abnormalities in neurological examinations within 240 days after RAG-17 treatment |
| Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) | 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. |
| Physiological Parameter-Vital Signs: Weight | 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. |
| Physiological Parameter-Vital Signs: Height, Hip Circumference and Waist | 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 Sign: Blood Pressure | 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 Sign: Respiration Rate | 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: Pulse Rate | 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. |
| Physiological Parameter-Vital Sign: Body Temperature | 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. |
| Clinical laboratory examination index | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| SOD1 protein levels | baseline, day 15, day 29, day 60, day 120, day 180 and day 240 | 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 |
| Plasma neurofilament light (NFL) levels | baseline, day 1, day 15, day 29, day 60, day 120, day 180 and day 240 | 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 |
| Pharmacokinetic Changes of RAG-17 | day 1, day 15, day 29, day 60, day 120, day 180 and day 240 | 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 |
| Mechanical ventilation | From day1 to day240 | Time to invasive mechanical ventilation in adult ALS patients treated with RAG-17 |
| Death | From randomization date to date of death from any cause. The assessment period is up to 8 months | Time of death in adult ALS patients treated with RAG-17 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Electromyography (EMG) Measures | day 29, day 90, day 180, and day 240 | Changes in EMG measures (motor unit number index) from baseline on day 29, day 90, day 180, and day 240 after RAG-17 treatment in adult ALS patients |
| Electromyography (EMG) measures | day 29, day 90, day 180, and day 240 | Electromyography(EMG) is used to determine the functional performance of muscle and the index change including compound muscle action potential（CAMP）of EMG in adult ALS patients from baseline on day 29, day 90, day 180, and day 240 after RAG-17 treatment |
| Muscle strength (Medical Research Council Scale - MRC Scale) | day 15, day 29, day 90, day 180, and day 240 | Medical Research Council Scale (MRC Scale) is an assessment that is used to measure the change in muscle strength of abductor pollicis brevis muscle, abductor digiti minimi, and tibial anterior muscle in adult ALS patients treated with RAG-17 on day 15, day 29, day 90, day 180, and day 240. MRC Scales ranges from grade 0 to grade 5, where grade 0 means no muscle contraction, grade 5 means muscle has full strength. |
| Severity of Fatigue (Fatigue Severity Scale - FSS) | day 15, day 29, day 90, day 180, and day 240 | Fatigue Severity Scale(FSS) is a questionnaire-based scale that is used to measure the change in severity of fatigue in adult ALS patients on day 15, day 29, day 90, day 180, and day 240 after RAG-17 treatment. FSS scale is 9-items questionnaire, and each item is scored on a 7 points scale from 1 (strongly disagree) to 7 (strongly agree). The minimum score in total is 9 points, and the maximum score possible is 63. The higher the score means the greater fatigue severity. |
| Hamilton Anxiety Scale (HAM-A) - The Quality of Life | day 15, day 29, day 90, day 180, and day 240 | Hamilton Anxiety Scale (HAM-A) is a rating scale that is used to measure the changes in severity of anxiety of adult ALS patients treated with RAG-17 on day 15, day 29, day 90, day 180, and day 240. The scale is composed of 14 items, Each item is scored on a scale of 0 (no symptom) to 4 (severe), with a total score range of 0 to 56, where \<7 means no symptom of anxiety, over 24 means mild to moderate severity, \>29 means extreme severity. |
| The EuroQol 5 Dimension 5 Level (EQ-5D-5L)- The Quality of Life | day 15, day 29, day 90, day 180, and day 240 | The EuroQol 5 Dimension 5 Level (EQ-5D-5L) is a self-report survey that is used to measure the changes in the quality of life of adult ALS patients treated with RAG-17 on day 15, day 29, day 90, day 180, and day 240. EQ-5D-5L contains 5 domains including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, and each domain is scored on a 5-level severity from Level1(no difficulty) to Level5 (extreme difficulty). |
| Amyotrophic Lateral Sclerosis Assessment Questionnaire -40 (ALSAQ-40) - The Quality of Life | day 15, day 29, day 90, day 180, and day 240 | Amyotrophic Lateral Sclerosis Assessment Questionnaire -40 (ALSAQ-40) is a patient self-report health status PRO that is used to measure the changes in the quality of life of adult ALS patients treated with RAG-17 on day 15, day 29, day 90, day 180, and day 240. There are 40 items in ALSAQ-40 with 5 domains: physical mobility (10 items), activities of daily living and independence (10 items), eating and drinking (3 items), communication (7 items), emotional reactions (10 items), each domain has a total score of 100 points, where 0 point means the worst health condition, and 100points means the best health condition. |
| The Modified Norris Test Score - Functional ability | day 15, day 29, day 90, day 180, and day 240 | The Modified Norris Test Score is a rating scale that is used to measure the change in functional ability of adult ALS patients on day 15, day 29, day 90, day 180, and day 240 after RAG-17 treatment. This scale is composed with two parts: the Limb Norris Scale (21 items) and the Norris Bulbar Scale (13 items), each item is scored from 0 point (cannot do anything) to 3 points (normal). |
| 6-meter Walking Test - Gait function | day 15, day 29, day 90, day 180, and day 240 | 6-meter walking test is a performance test to assess walking speed over a short distance, which determine the changes in gait function of adult ALS patients on day 15, day 29, day 90, day 180, and day 240 after RAG-17 treatment. The test will be perform in 4 trials, as the first trial is practise trial, and the average of last three trials are calculated. |
| Scale for the Assessment and Rating of Ataxia (SARA) - First Item: Gait | day 15, day 29, day 90, day 180, and day 240 | Scale for the Assessment and Rating of Ataxia (SARA) is a performance based scale that has eight categories to assess different impairments. The first category - gait of SARA is used to measure the change in gait function of adult ALS patients on day 15, day 29, day 90, day 180, and day 240 after RAG-17 treatment. Gait function is scored from 0point (normal) to 8points (unable to walk). |
| Short Physical Performance Battery (SPPB) - Gait Function | day 15, day 29, day 90, day 180, and day 240 | Short Physical Performance Battery (SPPB) is an objective assessment that is used to measure the change in gait functions including balance, lower extremity strength, and functional capacity of of adult ALS patients on day 15, day 29, day 90, day 180, and day 240 after RAG-17 treatment. The test includes three different assessments: walking, sit-to-stand and balance. A 0- to 12-point scale is used to score the sum of the three assessments with higher point values corresponding with greater levels of physical function and lower disability, and vise versa. |
| Kinematic Gait Analysis-Gait Function | day15, day 29, day 90, day 180, and day 240 | Kinematic gait is studied via 3D motion analysis, Construction of the coordinates and orientation of the rigid body segments allow calculation of joint angles of the proximal and distal segment, joint angular velocity, and joint acceleration. Measurements are collected for each joint in all three cardinal planes of motion, and it further measures the change in gait functions of of adult ALS patients on day 15, day 29, day 90, day 180, and day 240 after RAG-17 treatment. |
| Kinetic Gait Analysis-Gait Function | day15, day 29, day 90, day 180, and day 240 | Kinetic gait analysis is used to determine the forces created by and during movement, and measurements are collected to further determine the change in gait functions of of adult ALS patients on day 15, day 29, day 90, day 180, and day 240 after RAG-17 treatment. |
| 7T magnetic resonance imaging measures | day 29, day 90, day 180, and day 240 | 7T magnetic resonance imaging (7T MRI) is used to measure the change in the value of body indexes in adult ALS patients treated with RAG-17 on day 29, day 90, day 180, and day 240. |
| Hamilton Depression Scale (HAM-D)-The Quality of Life | day 15, day 29, day 90, day 180, and day 240 | Hamilton Depression Scale (HAM-D) is a rating scale that is used to measure the changes in severity of depression of adult ALS patients treated with RAG-17 on day 15, day 29, day 90, day 180, and day 240. For the 17-item version, scores can range from 0 to 54. Scores between 0 and 6 indicate a normal person , scores between 7 and 17 indicate mild depression, scores between 18 and 24 indicate moderate depression, and scores over 24 indicate severe depression. |
| London ALS Stage - Clinical staging of patients | day 15, day 29, day 90, day 180, and day 240 | London ALS Stage is used to measure the change in clinical stages of adult ALS patients on day 15, day 29, day 90, day 180, and day 240 after RAG-17 treatment. The King's staging system consists of five disease stages, with Stage 5 being death. Stage 4 is nutritional failure.Stages 1-3 are based upon the number of El Escorial central nervous system (CNS) regions involved in the disease, measured by weakness, wasting, spasticity, dysphagia, or dysarthria. |
| The Milano-Torino (MiToS) Staging - Clinical staging of patients | day 15, day 29, day 90, day 180, and day 240 | The Milano-Torino (MiToS) Staging is used to measure the change in clinical stages of adult ALS patients on day 15, day 29, day 90, day 180, and day 240 after RAG-17 treatment. The Milano-Torino (MiToS) Staging is composed with six stages, where stage 0 is no functional impairment, stage 1 is loss of one type of function, stage 2 is loss of two type of function, stage 3 is loss of three type of function, stage 4 is loss of four type of function, and stage 5 is death. |
| Lung function (including forced vital capacity) | day 15, day 29, day 90, day 180, and day 240 | Changes in lung function (including forced vital capacity) in adult ALS patients treated with RAG-17 on day 15, day 29, day 90, day 180, and day 240 |
Countries
China
Outcome results
None listed