Phase II Randomized, Double-Blind, Placebo-Controlled Study of NX210c in Adult Patients with Amyotrophic Lateral Sclerosis (ALS)
- Trial ID
- 2023-508895-13-00
- Sponsor
- Axoltis Pharma
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the effect of **NX210c** on blood neurofilament light chain (NfL) or on a blood and cerebrospinal fluid (CSF) biomarker of blood-brain barrier (BBB) integrity at a 6-week follow-up in patients with **Amyotrophic Lateral Sclerosis (ALS)**. This is clinically relevant as changes in NfL levels and BBB integrity biomarkers can provide insights into disease progression and the therapeutic impact of NX210c.
Secondary objectives include:
- Assessing the effect of NX210c on blood NfL at other follow-up periods.
- Evaluating the effect of NX210c on CSF NfL at a 6-week follow-up.
- Evaluating the effect of NX210c on select secondary blood, urine, and CSF biomarkers related to BBB integrity, systemic/neuroinflammation, and neuronal/synaptic transmission.
- Evaluating the effect of NX210c on functional capacities and quantitative strength in ALS.
- Evaluating the effect of NX210c on disease progression in ALS.
- Evaluating the effect of NX210c on composite time to event outcomes.
- Evaluating the effect of NX210c on ALS survival.
- Assessing the effect of NX210c on the Combined Assessment of Function and Survival (CAFS).
- Assessing the effect of NX210c on ALS patients' Quality of Life.
- Assessing the safety and tolerability of NX210c.
- Evaluating the pharmacokinetics (PK) profile of NX210c in plasma on a subset of patients.
Participants
The clinical trial involves participants diagnosed with **Amyotrophic Lateral Sclerosis (ALS)**, including both sporadic and familial cases, as per the El Escorial Revised criteria. The study population comprises both male and female subjects, aged 18 years and older. Participants are required to have a disease duration of 36 months or less from ALS symptom onset to the baseline timepoint and must be at King’s Clinical Staging Stage 3 or lower at baseline. The trial includes individuals with satisfactory peripheral venous access and a minimum cerebrospinal fluid volume of 1.5 mL at screening. Female participants must not be pregnant or breastfeeding and must use effective contraception if of childbearing potential. Male participants must also adhere to contraception guidelines and abstain from sperm donation during the study period. Participants may be on a stable dose of riluzole or symptomatic treatment for ALS, or they may be riluzole-naïve or have discontinued riluzole at least two weeks prior to screening. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed as a **double-blind**, **randomized**, **placebo-controlled**, multicentric, phase II study aimed at evaluating the efficacy, safety, tolerability, and pharmacokinetics of multiple intravenous infusions of NX210c in adult patients diagnosed with **amyotrophic lateral sclerosis (ALS)**. The trial will involve the administration of NX210c, a synthetic peptide, and a placebo, which is a glucose solution for infusion. The study is expected to commence recruitment in September 2024 and conclude by February 2026, with a maximum treatment period of four weeks for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as satisfactory peripheral venous access, CSF volume, and body weight, among others. The primary objective is to assess the effect of NX210c on blood neurofilament light chain (NfL) or a biomarker of blood-brain barrier integrity at a six-week follow-up. The trial will also evaluate changes in serum and CSF NfL, secondary blood and urine biomarkers, and various clinical scales over a four-month follow-up period.
The sequence of study visits includes baseline assessments, multiple dosing visits, and follow-up visits at six weeks and four months post-dosing. The end-of-study visit will mark the completion of the participant's involvement, which is expected to last approximately four months. Conditions that may lead to early termination from the study include the occurrence of treatment-emergent adverse events (TEAEs) or local tolerability issues that necessitate discontinuation of treatment.
Throughout the trial, participants will be monitored for changes in vital signs, electrocardiogram (ECG) assessments, laboratory tests, and physical and neurological examinations. The study will also assess the pharmacokinetic parameters of NX210c in a subset of patients. The trial's primary endpoints focus on changes in serum NfL and albumin CSF/serum quotient, while secondary endpoints include various clinical and safety measures. The trial is not classified as low intervention and is conducted under the auspices of Axoltis Pharma and B.Braun Medical SAS.
Treatment
The clinical trial involves the administration of **NX210c**, a lyophilisate for solution for injection, developed by Axoltis Pharma. The active substance in NX210c is a synthetic peptide, specifically **H-L-TRYPHOPHANYL-L-SERYL-GLYCYL-L-TRYPTOPHANYL-L-SERYL-L-SERYL-L-CYSTEINYL-L-SERYL-L-ARGINYL-L-SERYL-L-CYSTEINYL-GLYCYL-OH (DISULFIDE BOND), ACETATE SALT**. This investigational drug is administered intravenously. The dosing regimen involves a maximum daily dose of 10 mg/kg, with a total maximum dose of 120 mg/kg over a treatment period of 4 weeks. The trial aims to evaluate the efficacy, safety, tolerability, and pharmacokinetics of NX210c in adult patients with amyotrophic lateral sclerosis (ALS).
In addition to the experimental treatment, the study utilizes **GLUCOSE 5% B.BRAUN**, a solution for infusion, as a comparator treatment. This product, manufactured by B.Braun Medical SAS, contains **glucose** as its active substance. The glucose solution is also administered intravenously, with a maximum daily dose of 1 ml/kg and a total maximum dose of 12 ml/kg over the same 4-week treatment period. The glucose solution serves as a standard-of-care therapy to provide a baseline for evaluating the effects of NX210c.
Efficacy
The efficacy of the investigational product NX210c in the treatment of **amyotrophic lateral sclerosis (ALS)** will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoints include changes in serum neurofilament light chain (NfL) levels and changes in the Albumin cerebrospinal fluid (CSF)/serum quotient (Qalb) from predose to a 6-week follow-up. These biomarkers are indicative of disease progression and blood-brain barrier integrity, respectively.
Secondary endpoints will evaluate additional biomarkers and clinical outcomes. These include changes in serum and CSF NfL levels, secondary blood and urine biomarkers, and CSF biomarkers at various intervals up to a 4-month follow-up. Clinical assessments will involve changes in the Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised (ALSFRS-R), Slow Vital Capacity (SVC), hand-held dynamometry (HHD) muscle strength, and bilateral hand grip strength from baseline to 4-month follow-up. The rate of disease progression will be evaluated using the Delta FS (ΔFS) metric, and time to significant clinical events such as death, tracheotomy, or permanent assisted ventilation will be recorded.
Additional assessments will include changes in the ALS Assessment Questionnaire (ALSAQ-40) and the Combined Assessment of Function and Survival (CAFS) from baseline to 4-month follow-up. Safety and tolerability will be monitored through the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and changes in vital signs, ECG assessments, and laboratory tests. Pharmacokinetic parameters of NX210c, including Cmax, Tmax, AUC0-last, AUC0-inf, T1/2, CL, and Vz, will be assessed in a subset of patients.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient able to provide informed consent, geographically accessible to the site and able and willing to comply with all study requirements of the protocol, including two lumbar punctures.
- Satisfactory peripheral venous access; no central catheterization will be permitted.
- Satisfactory CSF volume at screening (i.e., 1.5 mL minimum).
- Maximum body weight ≤110 kg at baseline.
- For female patients: not pregnant and have a negative pregnancy blood test (women of childbearing potential [WOCBP] only) at screening and baseline.
- For female patients: must not be breastfeeding, have no intention of becoming pregnant during the study, and use acceptable methods of contraception or abstain from intercourse. WOCBP must agree to use highly effective contraception consisting of two forms of birth control, one of which must be a male barrier method such as a latex or polyurethane condom from the start of dosing throughout the clinical study period, and for 90 days after the final administration of study treatment. Women of non-childbearing potential (WONCBP) will be considered those who are sterilized or post-menopausal. A sterilized patient will have either undergone surgical sterilization (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy; participant reported information) at least 90 days prior to baseline; postmenopausal patients will have been amenorrheic for > 12 consecutive months before screening and FSH levels > 30 IU/L. Essure® fallopian tube coil placement is not accepted as surgical sterilization because of the high failure rate.
- Male patients must either declare and confirm abstinence or must be willing and able to use effective contraception. Male patients engaging in sexual intercourse with WOCBP, both the male patient and his female partner must use highly effective contraception consisting of 2 forms of birth control, one of which must be a male barrier method such as a latex or polyurethane condom from the start of dosing throughout the clinical study period, and for 90 days after the final administration of study treatment. Males who have had a vasectomy must have a confirmed zero sperm count or must agree after receiving the first dose of study drug either to use acceptable methods of contraception or abstain from intercourse.
- For male patients: The patient must not donate sperm at any time from the start of dosing, throughout the clinical study period, and for 90 days after the final administration of study treatment.
- Male or female, 18 years of age or older at the time of signing the ICF.
- Patients diagnosed as having possible, probable, probable laboratory-supported, or definite ALS, either sporadic or familial, according to El Escorial Revised criteria.
- Disease duration of ≤ 36 calendar months (i.e., ALS symptom onset to the baseline timepoint) at baseline.
- King’s Clinical Staging Stage ≤3 at baseline.
- Any NfL value available before screening should be compatible with the diagnosis of ALS (>10 pg/mL). No NfL value known before screening does not exclude the patient.
- Serum NfL study value available at baseline.
- SVC ≥ 55% predicted value as adjusted for gender, height, and age at baseline.
- Patients who are being treated with riluzole or symptomatic treatment for ALS (including over the counter medication or supplements) must have been on a stable dose for at least 30 days before baseline. Riluzole-naïve patients or having stopped riluzole at least 2 weeks prior to screening are permitted in the study.
- For the extension follow-up only: the patient must be able to provide informed consent, have participated to the SEALS study and have received at least 50% of the treatment doses.
Exclusion Criteria
- Patients with any cognitive or psychological disorder, intellectual disability or other significant impairment that would result in an inability to understand and sign the informed consent.
- Minors, persons deprived of liberty by judicial or administrative decision, persons receiving psychiatric care and persons admitted to a health or social institution, adult patients under legal protection or unable to express consent.
- Exposure to an investigational drug within 12 weeks prior to screening, or at least a period of 5 half-lives for the investigational drug, whichever is longer; for antisense therapy targeting SOD1, if the patient has completed treatment within 6 months of the screening visit. Any drug intended for ALS (other than riluzole and symptomatic treatment) will not be allowed, except during the extension follow-up period.
- Patient with a history of any clinically significant or unstable medical (including hepatic and renal), neurological, psychiatric condition, disorder or disease (other than ALS) or social circumstances that, based on the investigator's judgment, would 1) interfere with the patient's ability to comply with the protocol and all study procedures or 2) compromise study integrity or 3) pose a risk to the patient if they were to participate (e.g., previous acute coronary syndrome within 3 months of screening, major surgery within 2 months of screening) or physical examination, uncontrolled hypertension (blood pressure > 160/100 mm Hg), at screening or baseline.
- History of malignancy within 3 years of screening, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated. Patients with a history of other malignancies that have been treated with curative intent and which have no recurrence within 6 months may be eligible, based on the investigator’s judgement.
- Any clinically significant abnormalities in screening laboratories, including hepatic and renal impairment (e.g., aspartate aminotransferase (AST) >3× upper limit of normal (ULN); alanine aminotransferase (ALT) >3 × ULN; total bilirubin >2 × ULN; serum creatinine >2.0 × ULN). Retesting may be performed, on discussion with the medical monitor.
- Patient under anticoagulant treatment that cannot be held or stopped without putting at risk the patient’s life.
- Positive test to human immunodeficiency virus (HIV) or current chronic/active infection with hepatitis C virus or hepatitis B virus.
- Patients with active infections or, based on the investigator’s judgement, any active/uncontrolled inflammatory condition(s).
- Any contra-indication to glucose 5% and/or any hypersensitivity to any component of the IMP formulation.
- Any known significant brain or spinal disease that would interfere with the lumbar puncture process, CSF circulation or safety assessment.
- Any person who is an employee of the study sponsor or stakeholder partners involved in the conduct of the study, or an immediate relative of an investigator or study staff.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 01 Sept 2024 | 80 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
NX210c | Test | LYOPHILISATE FOR SOLUTION FOR INJECTION | INTRAVENOUS | 10 | 4 | PRD10129725 |
GLUCOSE 5 % B.BRAUN, solution pour perfusion | Placebo | SOLUTION POUR PERFUSION | INTRAVENOUS | 1 | 4 | PRD563785 |