Prospective registration

A Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intrathecal Administration of TRCN-1023 in Patients with Amyotrophic Lateral Sclerosis

A Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intrathecal Administration of TRCN-1023 in Patients with Amyotrophic Lateral Sclerosis

Weiqi Chen 

Yilong Wang 

No. 119, South Fourth Ring Road West, Fengtai District, Beijing

No. 119, South Fourth Ring Road West, Fengtai District, Beijing

Beijing Tiantan Hospital, Capital Medical University

Beijing Tiantan Hospital, Capital Medical University

Yes

IRB of Beijing Tiantan Hospital, Capital Medical University

Lingling Xu

No. 119, South Fourth Ring Road West, Fengtai District, Beijing

Beijing Tiantan Hospital, Capital Medical University

No. 119, South Fourth Ring Road West, Fengtai District, Beijing

Trace Neuroscience,Inc.; Tenacia Biopharmaceuticals (Shanghai) Co.. Ltd.

Amyotrophic Lateral Sclerosis

Interventional study

N/A

Single arm 

To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of intrathecal (IT) administration of TRCN-1023 in People living with Amyotrophic Lateral Sclerosis (PlwALS).

1. Men or women who were >= 18 and <= 75 years of age at the first screening visit. The investigators believed that the study participants could and were willing to meet all trial requirements, including traveling to the trial center, following the procedures specified in the protocol, completing all measurements, and attending planned visits. 7. Before the first screening visit, participants who received a stable dose of the approved ALS drug for at least 4 weeks or without such drug treatment. a. If treated with riluzole: The study participants must receive a stable dose (e.g., BID 50 mg) and are expected to maintain this dose until the final trial visit. b. If treated with edaravone: The study participants must have completed at least 2 treatment cycles before the screening period and are expected to maintain a stable dose until the follow-up end-of-trial (EoF) visit. For study participants receiving IV edaravone treatment, edaravone administration and TRCN-1023 administration must be spaced at least 1 week apart. 8. Participants were not previously exposed to any other unapproved drugs and had no planned use during the study. 9. Screening values of coagulation parameters (including platelet count, international normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT)) should be within the normal range. If the coagulation parameters exceed the range, but the investigators consider it clinically insignificant, the parameter can be re-tested once. If the values exceeding the range persist, but the investigators consider the study participants suitable for inclusion, the investigators should consult the principal investigator. Note that platelet count must reach 100,000/mm^3 or above to be eligible. 10. Female study participants: a. Study participants with reproductive capacity must agree to use at least one highly effective contraceptive method from the time of signing the informed consent until the final administration of TRCN-1023, with the expected plasma concentration of TRCN-1023 being below the detection limit by the end of the study. b. Post-menopausal status (defined as having ceased menstruation for at least 12 months prior to the first screening visit, and without any other medical reasons), and confirmed at the first screening visit through FSH measurement results (if the duration of amenorrhea does not reach 12 months, it must be confirmed by two FSH measurement results within the post-menopausal range). c. Had undergone surgical sterilization (i.e., hysterectomy, bilateral tubal resection, or bilateral oophorectomy) at least 1 month before the first screening visit. d.2. Diagnosed as clinically confirmed, clinically probable, or laboratory-supported clinically probable ALS according to the revised EI Escorial World Federation of Neurology criteria. (3) Disease duration <=24 months, disease onset time was defined as the first onset of muscle weakness and/or upper motor neuron dysfunction, including fasciculation and/or painful spasms. At the first screening visit, slow vital capacity (SVC) was measured in a seated position. This assessment can be repeated up to five times until three technically acceptable results are obtained. The best value, adjusted for age, sex, and height, had to be 60% or more of the predicted value. 5. The first five participants at each dose level were enrolled with unlimited genotypes, with the exclusion of individuals with ALS-associated SOD1 and FUS variants. If the second or potential third dose level was anticipated to result in therapeutic exposure in the central nervous system, an expansion cohort of approximately 10 participants would be enrolled. Approximately six to eight of these participants should have been carriers of the risk variant at RV rs12973192. The remaining study participants should be homozygous for the reference allele at this locus. "Risk variant carriers and non-carriers were matched according to age (±5 years), ALSFRS-R score (+/-3), slow vital capacity (SVC) (+/-5%), time to symptom onset (+/-6 months), and neurofilament light chain (NF-L) level at screening (+/-15%), if possible." 6. The study participants were deemed by the investigators to be able and willing to meet all trial requirements, including travel to the trial sites, adhere to protocol-specified procedures, complete all measurements, and attend scheduled visits. 7. Receiving stable doses of approved ALS medications or no such medications for at least 4 weeks before the first screening visit. A. If receiving riluzole: Study participants had to be receiving a stable dose (e.g., 50 mg BID) and were expected to maintain this dose until the final trial visit. b. If receiving edaravone: Study participants had to have completed at least 2 cycles of treatment before the screening period and were expected to maintain a stable dose through the end of follow-up (EoF) visit. For study participants who received IV edaravone, the interval between edaravone treatment and the administration of TRCN-1023 had to be at least 1 week. 8. He had not received any other unapproved medications before enrollment and had no plans to use them during the study. 9. Screening values for coagulation parameters, including platelet count, international normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT), should be within normal limits. A repeat measurement of the coagulation parameter was allowed if it was outside the range but was considered by the investigator to be clinically insignificant. If values outside the range persisted but a study participant was deemed by the investigator to be a fit for enrollment, the investigator consulted with the principal investigator. A platelet count of 100,000 per mm^3 or higher was required for eligibility 10. Female study participants: a. Study participants of childbearing potential had to agree to use at least one highly effective contraceptive method from the time they provided informed consent until at least 112 days after the last dose of TRCN-1023, when plasma concentrations of TRCN-1023 were expected to be below the detection limit. b. Postmenopausal status (defined as at least 12 months of menopause before the first screening visit without other medical reasons), confirmed by FSH measurements at the first screening visit (or, if 12-month duration of amenorrhea was not reached, by two FSH measurements in the postmenopausal range). c. Surgical sterilization (i.e., hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) was performed at least 1 month before the first screening visit. d. A high-sensitivity serum β-human chorionic gonadotropin (β-HCG) pregnancy test had to be negative at the first screening visit if surgical sterilization was not performed. 11. Male study participants: a. You must agree to use at least one highly effective contraceptive method from the time you sign the informed consent until at least 112 days after the last dose of TRCN-1023, and you must not donate sperm for at least 112 days after the last dose of TRCN-1023, at which time the plasma concentration of TRCN-1023 is expected to be below the detection limit. b. The female partner of a male participant had to agree to use a high-efficiency method of contraception (i.e., dual-barrier contraception, consisting of either a condom with a spermicidal diaphragm or a condom with spermicide) for at least 112 days from the first screening visit until the last dose of TRCN-1023 was administered. Condoms were still required if study participants underwent a vasectomy. 12. Study participants undertake not to share any information about their experience, safety, or efficacy on social media or in other public places. 13. Have a comprehensive understanding of trial objectives and risks and can provide signed and dated informed consent in accordance with the GCP and authorize the use of protected health information in accordance with national and local research participant privacy regulations.

1. Confirmed carriers of pathogenic or likely pathogenic SOD1 and FUS gene mutations. 2. Tracheostomy anytime, or continuous assisted ventilation of any type during the preceding 3 months before the first Screening Visit. 3. Significant pulmonary disorder not attributed to ALS, which may complicate the evaluation of the respiratory function. Intermittent non-invasive ventilation is permitted. 4. Use of a diaphragm pacemaker. 5. Speech or communication difficulties precluding normal communication, comprehension or adherence to instructions, or cooperation with treatment and assessments. 6. Any known history of other medical conditions associated with motor neuron dysfunction that could confound the clarity of the ALS diagnosis. 7. Pregnant or breast-feeding females; or females with childbearing potential if no adequate contraceptive measures are used. 8. Any contraindication to brain MRI scans, including presence of claustrophobia, pacemakers, aneurysm clips, artificial heart valves, implants, metal fragments, or foreign objects in the eyes, skin, or body that constitute a contraindication to having a brain MRI scan. 9. Any contraindication to lumbar puncture, IT injections, including but not limited to: a. Clinically relevant thrombocytopenia (platelet count <100,000/mm^3) or other coagulation disorders (including, but not limited to, participants receiving coumarin-derived anticoagulants, or low-molecular-weight heparin, and participants diagnosed with hemophilia, Factor X deficiency, or Von Willebrand’s disease). (Note: Screening INR, PT, aPTT, and platelet counts should be reviewed as part of this assessment of contraindication to lumbar puncture.) b. Antiplatelet treatments that cannot be safely interrupted for the recommended period, depending on the medication participant is receiving, prior to the TRCN-1023 administration and for 24 hours after each TRCN-1023 administration. If in doubt, the Investigator should consult on the withholding period with the Industry Sponsor. c. Daily use of anticoagulants that cannot be safely interrupted for the recommended period, depending on the medication participant is receiving, prior to the TRCN-1023 administration and for 12 hours after the TRCN-1023 administration. If in doubt, the Investigator can consult on the withholding period with the Industry Sponsor. d. Any signs and/or symptoms of increased intracranial pressure (ICP), e.g., suspected intracranial mass, that would preclude safe IT administration or confound safety assessments. e. Previous spinal surgery that could complicate access to the subarachnoid space. 10. Clinically significant laboratory findings that could confound the interpretation of the safety of the TRCN-1023 administration including, but not limited to, the list below. If clinically significant laboratory findings are reported and confirmed during the Screening Period, the TRCN-1023 administration can be postponed (by up to 4 weeks) to allow resolution of the laboratory findings. If a longer delay in TRCN-1023 administration is advised by the Investigator, the Investigator should consult with the Industry Sponsor. Of note, if Investigator considers a laboratory test result not clinically significant but it meets exclusionary criteria, potential participants may be retested once. a. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum bilirubin elevations (>3 × upper limit of normal [ULN]). Of note: An elevation of AST only (>3 × ULN) with normal serum bilirubin and ALT but elevated creatine kinase is not an exclusion. b. Gamma-glutamyl transferase elevation (>3 × ULN). c. Total bilirubin (Tbil) >2 × ULN. d. Serum creatinine elevation (>2 × ULN). e. Estimated glomerular filtration rate (eGFR, using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) <60 mL/min/1.73 m^2. f. Hemoglobin level <9 g/dL (90 g/L). g. Absolute neutrophil count <1,000 cells/μL. 11. Presence of severe cardiac insufficiency, meeting the New York Heart Association (NYHA) Functional Classification Class III or IV. 12. Any known active infection, including but not limited to Human Immunodeficiency Virus (HIV), hepatitis, and syphilis. 13. Vaccines administered within 7 days of a scheduled TRCN-1023 administration. If a vaccination is required during the trial and the above schedule cannot be adhered to, vaccination should be discussed with Trace. 14. Clinically significant electrocardiogram (ECG) abnormalities, including, but not limited to (based on mean values from triplicate recordings): a. Prolonged interval between Q and T wave corrected by Fridericia criteria (QTcF) interval (>450 ms for males and > 470 ms for females). b. QRS or T wave morphology that could, in the Investigator’s opinion, render the QT interval assessment unreliable. c. Symptoms of long QT syndrome or has a personal history of cardiac arrhythmias or risk factors for torsade de pointes and/or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia, and the presence of congenital prolongation of the QT interval. 15. Prior investigational and other medications a. Concurrent enrollment in any other clinical trial (including the follow-up period) or receipt of any concomitant investigational therapy (biologics, drugs, or devices). b. Participated in another clinical trial within 4 weeks, or 5 half-lives of the first TRCN-1023 administration, whichever is greater, prior to the first Screening Visit. c. Prior exposure to small interfering ribonucleic acids (siRNA), ASOs, stem cell or gene therapy. d. Off-label use of drugs or devices that are being used as disease-modifying therapies in ALS prior to the first Screening Visit. f. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed at least 7 days prior to the Day 1 Visit. If the potential participant or participant experiences an infection within 7 days of a scheduled TRCN-1023 administration, the Investigator should discuss the rescheduling of the TRCN-1023 administration with the Industry Sponsor.. 16. History of alcohol or drug abuse or dependence within 6 months prior to the first Screening Visit. 17. History of drug use (including cannabis use) within the past 6 months. 18. Significant suicide risk, defined by any of the below: a. Suicidal ideation as endorsed on items 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) within the past year or during Screening or at the Day 1 Visit. b. Suicidal behaviors within the past year. c. Clinical assessment of significant suicidal risk during clinical interview. 19. Diagnosis of any other psychiatric disorder, as defined by the DSM-V. 20. Any concurrent clinically relevant disease (other than ALS) that could interfere with the participant's ability to complete the study, per protocol definition. 21. Any contraindication to local anesthesia, if needed to perform lumbar punctures and IT injections. 22. Known hypersensitivity or intolerance to ASOs. 23. Any other conditions which, in the opinion of the Investigator would make the participant unsuitable for inclusion or could interfere with the participation in or completion of the trial. 24. Participants who are not able to refrain from alcohol in the 24 hours prior to and after the TRCN-1023 administration. 25. The employees or contractors of the Industry and Medical Sponsor, Investigator or site personnel directly affiliated with this trial, and the immediate families of either of these. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.

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CRF