Evaluation of Immediate Versus Delayed Azathioprine or Rituximab Therapy in Pediatric Anti-MOG Antibody-Associated Acute Demyelinating Syndromes
- Trial ID
- 2024-516243-81-00
- Protocol
- APHP211057
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the efficacy of **immediate** treatment with azathioprine (AZA) or rituximab (RTX) at the first attack versus delayed treatment at the second attack in children with myelin oligodendrocytes glycoprotein antibody-associated diseases (MOGAD). The focus is on the annualized relapse rate over a 24-month period. This is clinically relevant as it aims to determine the optimal timing of treatment initiation to reduce relapse rates in pediatric patients with MOGAD, potentially improving long-term outcomes.
Secondary objectives include:
- Comparing the efficacy between immediate AZA and RTX treatments at the first attack.
- Comparing the efficacy of immediate AZA and RTX treatments with delayed treatment.
- Evaluating the efficacy of immediate versus delayed treatment on other clinical outcomes.
- Assessing the efficacy on MRI outcomes.
- Evaluating the modulation of immunological mechanisms between treated and untreated patients.
- Monitoring immunological markers of treatment efficacy, such as neurofilament (Nfl, tau, and GFAP).
- Verifying the safety and tolerance of the treatment.
Participants
The clinical trial focuses on children diagnosed with **myelin oligodendrocytes glycoprotein antibody associated diseases (MOGAD)**. The study population includes both male and female participants aged between 6 and 18 years, with a minimum weight of 20 kg. Participants are required to have confirmed anti-MOG antibodies at onset, presenting with acute neurological symptoms of inflammatory origin lasting more than 24 hours, such as optic neuritis, transverse myelitis, rhombencephalitis, ADEM, or NMOSD, without prior treatment other than steroids. The trial does not involve a vulnerable population. The sponsor has not provided the total number of participants. Participants must have an Expanded Disability Status Scale (EDSS) score of less than 5.5 and be affiliated with the French social security regime. Informed consent is required from both parents and the child. The trial does not specify any particular lifestyle considerations such as diet or physical activity.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **azathioprine** and **rituximab** in children with myelin oligodendrocyte glycoprotein antibody-associated diseases (MOGAD). This is a phase III, multicenter, randomized controlled, open-label, parallel-group study. The trial aims to compare immediate treatment at the first attack with delayed treatment at the second attack, focusing on the annualized relapse rate over a 24-month period. The trial is expected to commence recruitment on October 1, 2024, and conclude by June 1, 2029.
Participants will be randomly assigned to receive either immediate or delayed treatment with **azathioprine** or **rituximab**. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess the primary and secondary endpoints. The primary endpoint is the annualized relapse rate at 24 months, while secondary endpoints include comparisons of relapse rates at 12 and 24 months, clinical outcomes, radiological outcomes, and immunological studies.
Participant involvement is expected to last up to 24 months, with conditions for early termination including significant adverse events or withdrawal of consent. The trial will adhere to strict inclusion criteria, such as age between 6 and 18 years, weight of at least 20 kg, and confirmed anti-MOG antibodies. Participants must not have received any previous treatment other than steroids and must be affiliated with the French social security regime. The study will ensure informed consent is obtained from both parents and the child.
Treatment
The clinical trial involves the administration of several **experimental medications** and comparator treatments to evaluate their efficacy in children with anti-myelin oligodendrocytes glycoprotein (anti-MOG) antibodies associated acute demyelinating syndromes. **Azathioprine** is one of the primary experimental medications used in this study. It is administered in the form of a film-coated tablet for **oral use**. The maximum daily dose is 150 mg, with a total maximum dose of 108,000 mg over a treatment period of up to 24 months. Azathioprine is a chemical substance and is not formulated for pediatric use in this trial.
**Rituximab** is another experimental medication used in the trial. It is provided as a concentrate for solution for infusion and is administered via **intravenous use**. The dosing regimen allows for a maximum daily dose of 375 mg/m², with a total maximum dose of 3,750 mg/m² over a 24-month period. Rituximab is classified as a biological product and is not specifically formulated for pediatric use in this study.
In addition to the experimental medications, the trial includes the use of **methylprednisolone** as a comparator treatment. Methylprednisolone is administered as a solution for injection via **intravenous use**. The maximum daily dose is 1 g, with a total maximum dose of 3 g over a treatment period of up to 3 months. This chemical substance is not formulated for pediatric use in this trial.
**Prednisone** is also used as a comparator treatment in the study. It is administered in tablet form for **oral use**. The maximum daily dose is 60 mg, with a total maximum dose of 5,040 mg over a 12-month treatment period. Prednisone is a chemical substance and is not specifically formulated for pediatric use in this trial.
Another comparator treatment used in the trial is **prednisolone**, which is administered in tablet form for **oral use**. The dosing schedule allows for a maximum daily dose of 60 mg, with a total maximum dose of 5,040 mg over a 12-month period. Prednisolone is a chemical substance and is not formulated for pediatric use in this study.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to compare the efficacy of immediate versus delayed treatment with azathioprine or rituximab on the annualized relapse rate at 24 months in the target population.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the **annualized relapse rate (ARR)** at 24 months, which serves as the primary endpoint. This trial aims to compare the efficacy of immediate treatment with **azathioprine** or **rituximab** against delayed treatment in children with anti-myelin oligodendrocytes glycoprotein (anti-MOG) antibodies associated acute demyelinating syndromes. Secondary endpoints include comparisons of the annualized relapse rate at 12 and 24 months between immediate and delayed treatments, as well as other clinical outcomes, radiological outcomes, and immunological studies.
The trial will involve a randomized controlled design, with participants being children aged between 6 and 18 years, weighing at least 20 kg, and having confirmed anti-MOG antibodies at onset. The efficacy parameters will be collected and analyzed at specified timepoints, including 12 and 24 months, to determine the differences in relapse rates and other clinical outcomes between the treatment groups. The study is designed as a phase III, multicentre, open-labelled, parallel group study, ensuring a robust evaluation of the treatment efficacy.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Children <18 years old and ≥ 6 years old at baseline
- Children weight ≥ 20 kg
- All ADS with confirmed anti-MOG-Abs at onset including any acute neurologic symptom with a duration of more than 24H of inflammatory causes (including optic neuritis, transverse myelitis, rhombencephalitis, ADEM, NMOSD) Without any previous treatment other than steroids
- Informed consent signed by both parents and the child
- Expanded Disability Status Scale (EDSS) < 5.5 Affiliated to French social security regime
- Affiliated to French social security regime
Exclusion Criteria
- Current infection with SARS-COV2 (positive PCR)
- Any prior allergy to azathioprine or rituximab with hypersensitivity to active substances, murine proteins or to any of the excipients.
- Any prior history of uncontrolled cancer during the last 2 years
- Uncontrolled infections (Hepatitis B, C and HIV)
- Any prior history of cardiac dysfunction and/or hypertension
- Any progressive or non-relapsing form demyelinating diseases
- Any previous treatment with natalizumab, daclizumab, fingolimod, methotrexate, cyclosporine, mycophenolate mofetil, rituximab in the last 6 months, or determined by the treating physician to have residual immune suppression from these or other immunosuppressive treatments
- CD4+, CD8+, or CD19+ absolute cell count, wbc, neutrophiles in blood at screening below lower limits of normal (LLN)
- Creatinine>80μmol/L - Platelets <70 000mm3 - Haemoglobin < 8g/dL - Acute renal insufficiency (clearance < 30 ml/min) - Prior documented history of hemostase perturbation (TP and/or TCA more than twice of the witnesse’s TP and/or TCA) - Prior documented history of increased liver enzyme level (ASAT and/or ALAT) > 2N. - TP <70% - Total bilirubin > 2N
- Any patient with allopurinol treatment and immunosupressive treatment with concomitant use of xanthine oxidase inhibitors (e.g. allopurinol, oxipurinol/thiopurinol, febuxostat)
- Pregnancy or lactating woman or wish for future pregnancy
- Refusal to have a highly effective contraception during traitment and for one year
- participation to another interventional study within 5 half-lives prior to baseline.
- Active, severe infections (including tuberculosis, HBV and HCV, HIV, herpes, VZV, EBV and CMV)
- Psychosis not controlled by treatment - Patients with Lesch Nyhan syndrome - Pheochromocytoma - Scleroderma - Untreated peptic ulcer - Myasthenia gravis
- Any other medical illness or disability that, in the opinion of the investigator, would compromise effective trial participation.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 01 Oct 2024 | 86 |
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 |
|---|---|---|---|---|---|---|
AZATHIOPRINE | Test | — | ORAL USE | 150 | 24 | SUB05647MIG |
METHYLPREDNISOLONE | Comparator | — | INTRAVENOUS USE | 1 | 3 | SUB08872MIG |
PREDNISONE | Comparator | — | ORAL USE | 60 | 12 | SUB10020MIG |
AZATHIOPRINE | Test | — | ORAL USE | 150 | 24 | SUB05647MIG |
PREDNISOLONE | Comparator | — | ORAL USE | 60 | 12 | SUB10018MIG |
RITUXIMAB | Test | — | INTRAVENOUS USE | 375 | 24 | SUB12570MIG |