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

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.

Study Overview

• Status: Enrolling by invitation
• Conditions: Gene Mutation
• Intervention / Treatment: Drug: RAG-17

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.

• Study Type: Interventional
• Enrollment (Estimated): 6
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100050
    • Beijing Tiantan Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: RAG-17; RAG-17 60mg is used

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lung function (including forced vital capacity)	Changes in lung function (including forced vital capacity) in adult ALS patients treated with RAG-17 on day 15, day 29, day 90, and day 180	day 15, day 29, day 90, and day 180
Severity of Fatigue (Fatigue Severity Scale - FSS)	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 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.	day 15, day 29, day 90, and day 180
Muscle strength (Medical Research Council Scale - MRC Scale)	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, day180. MRC Scales ranges from grade 0 to grade 5, where grade 0 means no muscle contraction, grade 5 means muscle has full strength.	day 15, day 29, day 90, and day 180
Electromyography (EMG) measures	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, and day180 after RAG-17 treatment	day 29, day 90, day 180
Electromyography (EMG) Measures	Changes in EMG measures (motor unit number index) from baseline on day 29, day 90, day180 after RAG-17 treatment in adult ALS patients	day 29, day 90, day 180
Electromyography (EMG) Measures	Changes in EMG measures (motor unit size index) from baseline on day 29, day 90, day180 after RAG-17 treatment in adult ALS patients	day 29, day 90, day 180
7T magnetic resonance imaging measures	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 and day180.	day 29, day 90 and day 180
Kinetic Gait Analysis-Gait Function	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, and day180 after RAG-17 treatment.	day15, day 29, day 90, and day180
Kinematic Gait Analysis-Gait Function	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, and day180 after RAG-17 treatment.	day15, day 29, day 90, and day180
Short Physical Performance Battery (SPPB) - Gait Function	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, and day 180 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.	day 15, day 29, day 90, and day 180
Scale for the Assessment and Rating of Ataxia (SARA) - First Item: Gait	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, and day 180 after RAG-17 treatment. Gait function is scored from 0point (normal) to 8points (unable to walk).	day 15, day 29, day 90, and day 180
6-meter Walking Speed - Gait function	6-meter walking speed 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, and day 180 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.	day 15, day 29, day 90, and day 180
The Modified Norris Test Score - Functional ability	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, and day 180 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).	day 15, day 29, day 90, and day 180
Amyotrophic Lateral Sclerosis Assessment Questionnaire -40 (ALSAQ-40) - The Quality of Life	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, and day180. 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.	day 15, day 29, day 90, and day 180
The EuroQol 5 Dimension 5 Level (EQ-5D-5L)- The Quality of Life	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, and day180. 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).	day 15, day 29, day 90, and day 180
Hamilton Anxiety Scale (HAM-A) - The Quality of Life	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, and day180. 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.	day 15, day 29, day 90, and day 180
Hamilton Depression Scale (HAM-D)-The Quality of Life	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, and day180. 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.	day 15, day 29, day 90, and day 180
King's Staging System - Clinical staging of patients	King's staging system is used to measure the change in clinical stages of adult ALS patients on day 15, day 29, day 90, and day 180 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.	day 15, day 29, day 90, and day 180
The Milano-Torino (MiToS) Staging - Clinical staging of patients	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, and day 180 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.	day 15, day 29, day 90, and day 180

Collaborators and Investigators

• Sponsor: Beijing Tiantan Hospital
• Collaborators: Ractigen Therapeutics
• Investigators: Principal Investigator: YiLong Wang, Beijing Tiantan Hospital

Publications and helpful links

General Publications

• Emery AE, Holloway S. Familial motor neuron diseases. Adv Neurol. 1982;36:139-47. No abstract available.
• Feldman EL, Goutman SA, Petri S, Mazzini L, Savelieff MG, Shaw PJ, Sobue G. Amyotrophic lateral sclerosis. Lancet. 2022 Oct 15;400(10360):1363-1380. doi: 10.1016/S0140-6736(22)01272-7. Epub 2022 Sep 15.
• Chen L, Zhang B, Chen R, Tang L, Liu R, Yang Y, Yang Y, Liu X, Ye S, Zhan S, Fan D. Natural history and clinical features of sporadic amyotrophic lateral sclerosis in China. J Neurol Neurosurg Psychiatry. 2015 Oct;86(10):1075-81. doi: 10.1136/jnnp-2015-310471. Epub 2015 Jun 29.
• Rosenbohm A, Liu M, Nagel G, Peter RS, Cui B, Li X, Kassubek J, Rothenbacher D, Lule D, Cui L, Ludolph AC; ALS Registry Swabia Study Group. Phenotypic differences of amyotrophic lateral sclerosis (ALS) in China and Germany. J Neurol. 2018 Apr;265(4):774-782. doi: 10.1007/s00415-018-8735-9. Epub 2018 Feb 1.
• Amyotrophic Lateral Sclerosis (ALS) Fact Sheet. National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/amyotrophic-lateral-sclerosis-als-fact-sheet#treatment. October 2022.
• Miller RG, Jackson CE, Kasarskis EJ, England JD, Forshew D, Johnston W, Kalra S, Katz JS, Mitsumoto H, Rosenfeld J, Shoesmith C, Strong MJ, Woolley SC; Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009 Oct 13;73(15):1218-26. doi: 10.1212/WNL.0b013e3181bc0141. Erratum In: Neurology. 2009 Dec 15;73(24):2134. Neurology. 2010 Mar 2;74(9):781.
• Barrington CJ, Burruano M, Carney C, Choi J, Januska J, Lachuk L, Oskarsson B, Rodriguez C, Speicher L, Tereso G. Addressing the role of edaravone in the management of amyotrophic lateral sclerosis and gaps in care and access: expert panel recommendations. Am J Manag Care. 2021 Aug;27(12 Suppl):S231-S237. doi: 10.37765/ajmc.2021.88732.
• Chattopadhyay M, Valentine JS. Aggregation of copper-zinc superoxide dismutase in familial and sporadic ALS. Antioxid Redox Signal. 2009 Jul;11(7):1603-14. doi: 10.1089/ars.2009.2536.
• Shahrizaila N, Sobue G, Kuwabara S, Kim SH, Birks C, Fan DS, Bae JS, Hu CJ, Gourie-Devi M, Noto Y, Shibuya K, Goh KJ, Kaji R, Tsai CP, Cui L, Talman P, Henderson RD, Vucic S, Kiernan MC. Amyotrophic lateral sclerosis and motor neuron syndromes in Asia. J Neurol Neurosurg Psychiatry. 2016 Aug;87(8):821-30. doi: 10.1136/jnnp-2015-312751. Epub 2016 Apr 19.
• Brown RH, Al-Chalabi A. Amyotrophic Lateral Sclerosis. N Engl J Med. 2017 Jul 13;377(2):162-172. doi: 10.1056/NEJMra1603471. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): May 22, 2023
• Primary Completion (Estimated): February 28, 2024
• Study Completion (Estimated): February 28, 2024

Study Registration Dates

• First Submitted: May 7, 2023
• First Submitted That Met QC Criteria: June 11, 2023
• First Posted (Actual): June 15, 2023

Study Record Updates

• Last Update Posted (Actual): June 15, 2023
• Last Update Submitted That Met QC Criteria: June 11, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Amyotrophic Lateral Sclerosis; SOD1 Gene Mutation; RAG-17
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: HX-A-2023004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No