Clinical trial NCT05903690: Safety and Tolerance of RAG-17 in Amyotrophic Lateral Sclerosis Patients With SOD1 Gene Mutation
Official title: Safety and Tolerance of RAG-17 in Amyotrophic Lateral Sclerosis Patients With SOD1 Gene Mutation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Gene Mutation
Keywords: RAG-17
SOD1 Gene Mutation
Amyotrophic Lateral Sclerosis
Lead sponsor: Beijing Tiantan Hospital
Sponsor class: OTHER
Collaborators: name: Ractigen Therapeutics.
First posted: 2023-06-15
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Adverse events (AE) and serious adverse events (SAE)
timeFrame: Within 240 days after treatment
measure: Clinical laboratory examination index
timeFrame: Before RAG-17 treatment and within 240 days after treatment
measure: Physiological Parameter-Vital Sign: Body Temperature
timeFrame: Within 240 days after treatment
measure: Physiological Parameter-Vital Sign: Pulse Rate
timeFrame: Within 240 days after treatment
measure: Physiological Parameter-Vital Sign: Respiration Rate
timeFrame: Within 240 days after treatment
measure: Physiological Parameter-Vital Sign: Blood Pressure
timeFrame: Within 240 days after treatment
measure: Physiological Parameter-Vital Signs: Height, Hip Circumference and Waist
timeFrame: Within 240 days after treatment
measure: Physiological Parameter-Vital Signs: Weight
timeFrame: Within 240 days after treatment
measure: Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R)
timeFrame: Within 240 days after treatment
measure: Neurological examinations
timeFrame: Within 240 days after treatment
measure: Heart circulatory system examinations
timeFrame: Within 240 days after treatment
measure: Respiratory system examinations
timeFrame: Within 240 days after treatment
measure: Abdominal examinations
timeFrame: Within 240 days after treatment
measure: ECG results
timeFrame: Within 240 days after treatment
Secondary outcomes:
measure: SOD1 protein levels
timeFrame: baseline, day 15, day 29, day 60, day 120, day 180 and day 240
measure: Plasma neurofilament light (NFL) levels
timeFrame: baseline, day 1, day 15, day 29, day 60, day 120, day 180 and day 240
measure: Pharmacokinetic Changes of RAG-17
timeFrame: day 1, day 15, day 29, day 60, day 120, day 180 and day 240
measure: Pharmacokinetic Changes of RAG-17
timeFrame: day 1, day 15, day 29, day 60, day 120, day 180 and day 240
measure: Pharmacokinetic Changes of RAG-17
timeFrame: day 1, day 15, day 29, day 60, day 120, day 180 and day 240
measure: Pharmacokinetic Changes of RAG-17
timeFrame: day 1, day 15, day 29, day 60, day 120, day 180 and day 240
measure: Pharmacokinetic Changes of RAG-17
timeFrame: day 1, day 15, day 29, day 60, day 120, day 180 and day 240
measure: Mechanical ventilation
timeFrame: From day1 to day240
measure: Death
timeFrame: From randomization date to date of death from any cause. The assessment period is up to 8 months
Other outcomes:
measure: Lung function (including forced vital capacity)
timeFrame: day 15, day 29, day 90, day 180, and day 240
measure: Severity of Fatigue (Fatigue Severity Scale - FSS)
timeFrame: day 15, day 29, day 90, day 180, and day 240
measure: Muscle strength (Medical Research Council Scale - MRC Scale)
timeFrame: day 15, day 29, day 90, day 180, and day 240
measure: Electromyography (EMG) measures
timeFrame: day 29, day 90, day 180, and day 240
measure: Electromyography (EMG) Measures
timeFrame: day 29, day 90, day 180, and day 240
measure: Electromyography (EMG) Measures
timeFrame: day 29, day 90, day 180, and day 240
measure: 7T magnetic resonance imaging measures
timeFrame: day 29, day 90, day 180, and day 240
measure: Kinetic Gait Analysis-Gait Function
timeFrame: day15, day 29, day 90, day 180, and day 240
measure: Kinematic Gait Analysis-Gait Function
timeFrame: day15, day 29, day 90, day 180, and day 240
measure: Short Physical Performance Battery (SPPB) - Gait Function
timeFrame: day 15, day 29, day 90, day 180, and day 240
measure: Scale for the Assessment and Rating of Ataxia (SARA) - First Item: Gait
timeFrame: day 15, day 29, day 90, day 180, and day 240
measure: 6-meter Walking Test - Gait function
timeFrame: day 15, day 29, day 90, day 180, and day 240
measure: The Modified Norris Test Score - Functional ability
timeFrame: day 15, day 29, day 90, day 180, and day 240
measure: Amyotrophic Lateral Sclerosis Assessment Questionnaire -40 (ALSAQ-40) - The Quality of Life
timeFrame: day 15, day 29, day 90, day 180, and day 240
measure: The EuroQol 5 Dimension 5 Level (EQ-5D-5L)- The Quality of Life
timeFrame: day 15, day 29, day 90, day 180, and day 240
measure: Hamilton Anxiety Scale (HAM-A) - The Quality of Life
timeFrame: day 15, day 29, day 90, day 180, and day 240
measure: Hamilton Depression Scale (HAM-D)-The Quality of Life
timeFrame: day 15, day 29, day 90, day 180, and day 240
measure: London ALS Stage - Clinical staging of patients
timeFrame: day 15, day 29, day 90, day 180, and day 240
measure: The Milano-Torino (MiToS) Staging - Clinical staging of patients
timeFrame: day 15, day 29, day 90, day 180, and day 240
Locations:
city: Beijing
country: China
facility: Beijing Tiantan Hospital
Study officials:
affiliation: Beijing Tiantan Hospital
name: YiLong Wang
role: PRINCIPAL_INVESTIGATOR
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