Evaluation of Autologous Hematopoietic Stem Cell Transplantation and Drug Combination in Aggressive Relapsing-Remitting Multiple Sclerosis
- Trial ID
- 2024-515470-26-00
- Protocol
- NET-MS
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the occurrence of any evidence of **multiple sclerosis** disease activity, specifically No Evidence of Disease Activity (NEDA-3), over a 36-month period. This is analyzed as a time-to-event outcome, which is clinically relevant as it provides insight into the long-term efficacy of autologous haematopoietic stem cell transplantation in managing aggressive forms of Relapsing Remitting Multiple Sclerosis. Understanding the time to disease activity can inform treatment decisions and patient management strategies.
Secondary objectives include assessing various outcomes at 36 months, such as:
- Incidence of serious adverse events and all-cause mortality
- Annual relapse rate
- Number of new T2/gadolinium-enhancing T1 lesions
- Incidence of confirmed disability improvement and progression
- Changes in brain volume and serum neurofilament light chain concentration
- Changes in BICAMS and MSFC scores
- Changes in the IgG/IgM index in cerebrospinal fluid
- Changes in peripheral retinal nerve fiber layer and inner nuclear layer thickness
- Changes in patient-reported outcomes
- Percentage of patients of child-bearing potential who maintain or resume menstruation
- Variation in anti-Mullerian hormone levels, antral follicular count, sperm count, motility, and morphology
- Changes in advanced MRI metrics of tissue integrity, inflammation, and functional plasticity
- Immunological changes associated with immune tolerance
- Changes in the gut microbiota
These secondary objectives are crucial for understanding the broader impact of the treatment on patient health and quality of life, as well as its potential effects on reproductive health and neurological function.
Participants
The clinical trial involves participants diagnosed with **Relapsing Remitting Multiple Sclerosis**. The study population includes both male and female subjects, aged between 18 and 55 years. Participants are required to have a diagnosis of treatment-resistant multiple sclerosis, characterized by disease activity despite at least six months of treatment with an oral agent or monoclonal antibody within the year preceding the screening. The trial includes individuals with an Expanded Disability Status Scale (EDSS) score ranging from 2.0 to 6.0. Participants must be candidates for treatment with specific disease-modifying therapies, such as natalizumab, alemtuzumab, ocrelizumab, and/or ofatumumab, without prior treatment failure or contraindications to these therapies. The sponsor has not provided information regarding the total number of participants. The trial population selection considers the inclusion of a vulnerable population, ensuring a comprehensive assessment of the treatment's efficacy and safety across diverse patient profiles.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of various treatments in patients with **relapsing-remitting multiple sclerosis**. This is a phase 4, randomized, double-blind, controlled trial with an estimated duration of 36 months. The primary objective is to assess the occurrence of any evidence of multiple sclerosis disease activity over the trial period, analyzed as time-to-event. Participants will be randomly assigned to receive one of the investigational products, including **cytarabine**, **carmustine**, **filgrastim**, **cyclophosphamide**, **natalizumab**, **alemtuzumab**, **etoposide**, **ofatumumab**, **melphalan flufenamide**, **rabbit anti-human thymocyte immunoglobulin**, **anti-human T-lymphocyte immunoglobulin from rabbits**, and **ocrelizumab**. The trial will include a screening visit to confirm eligibility based on criteria such as age, disease activity, and prior treatment history. Participants will undergo regular follow-up visits at 12, 24, and 36 months to monitor disease progression, adverse events, and treatment efficacy. The end-of-study visit will occur at the conclusion of the 36-month period. The expected length of participant involvement is up to 36 months, with conditions for early termination including the occurrence of serious adverse events or withdrawal of consent. The trial will adhere to rigorous safety monitoring protocols to ensure participant well-being throughout the study duration.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Cytarabine** is utilized in two forms: as a powder for solution for injection and as a solution for injection. The dosage is set at a maximum of 200 mg/m² per day, administered intravenously. The treatment period for cytarabine is up to 4 days. This medication is classified as a cytostatic agent.
**Carmustine** is provided as a powder and solvent for concentrate for solution for infusion. It is administered via intravenous drip, with a maximum daily dose of 300 mg/m². The treatment duration is limited to 1 day. Carmustine is also categorized as a cytostatic agent.
**Filgrastim** is administered as a solution for injection, delivered subcutaneously. The maximum daily dose is 10 µg/kg, with a treatment period extending up to 7 days. Filgrastim is not classified as a cytostatic agent.
**Cyclophosphamide** is available as a powder for solution for injection, administered through intravenous drip. The maximum daily dose is 4 mg/m², with a treatment period of 1 day. It is classified as a cytostatic agent.
**Etoposide** is provided as a concentrate for solution for infusion, administered via intravenous drip. The maximum daily dose is 200 mg/m², with a treatment period of up to 4 days. Etoposide is classified as a cytostatic agent.
**Melphalan Flufenamide** is administered as a solution for infusion via intravenous drip. The maximum daily dose is 140 mg/m², with a treatment period of 1 day. It is classified as a cytostatic agent.
**Rabbit Anti-Human Thymocyte Immunoglobulin** is provided as a powder for solution for infusion, administered via intravenous drip. The maximum daily dose is 2.5 mg/kg, with a total dose of 5 mg/kg over 2 days. This substance is not classified as a cytostatic agent.
**Anti-Human T-Lymphocyte Immunoglobulin from Rabbits** is administered as a concentrate for solution for infusion via intravenous drip. The maximum daily dose is 2.5 mg/kg, with a total dose of 5 mg/kg over 2 days. This substance is not classified as a cytostatic agent.
In addition to the experimental treatments, the trial includes comparator treatments such as **Tysabri** (natalizumab), **LEMTRADA** (alemtuzumab), **Kesimpta** (ofatumumab), and **Ocrevus** (ocrelizumab). These are administered as solutions for infusion or injection, with specific dosing schedules and routes of administration. Participant compliance is monitored throughout the trial to ensure adherence to the dosing schedules.
Efficacy
The efficacy of the clinical trial will be assessed through a comprehensive evaluation of multiple parameters related to **Multiple Sclerosis** disease activity and patient outcomes over a 36-month period. The primary endpoint is the occurrence of any evidence of disease activity, known as NEDA-3 (No Evidence of Disease Activity), which will be analyzed as a time-to-event from randomization up to 36 months post-randomization. Secondary endpoints include a variety of measures such as the annual relapse rate at 12, 24, and 36 months, the incidence of 6-month confirmed disability improvement as measured by the Expanded Disability Status Scale (EDSS), and changes in MRI-based metrics such as the number of new brain lesions and changes in brain volume.
Additional secondary endpoints involve assessments of functional abilities and quality of life, including changes in the Multiple Sclerosis Functional Composite (MSFC) z-scores, the Multiple Sclerosis Impact Scale, and the Modified Fatigue Impact Scale at specified intervals. Biomarker analysis will also be conducted, with changes in serum neurofilament light chain concentration and the IgG/IgM index in cerebrospinal fluid being measured. The trial will also monitor the presence of oligoclonal bands in cerebrospinal fluid and variations in reproductive health parameters. These efficacy parameters will be collected and analyzed at multiple timepoints, including 12, 24, and 36 months, using validated scales and laboratory tests to ensure accurate and reliable data collection.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Diagnosis of relapsing remitting MS according to the 2017 Mc Donald’s criteria.
- Treatment-resistant MS, defined as the occurrence of disease activity following ≥ 6 months of treatment with an oral agent or a monoclonal antibody in the 12 months prior to the screening visit (≥ 1 relapse AND the occurrence of MRI evidence of disease activity, defined as ≥ 1 gadolinium-enhancing lesion or ≥ 1 new non-enhancing T2 lesion compared to a reference scan obtained not more than 18 months prior to the screening visit). OR aggressive-highly active MS, characterized by the presence of at least one disabling relapse in the 6 months prior to the screening visit AND the evidence at MRI of ≥ 1 gadolinium enhancing lesion or ≥ 1 new non-enhancing T2 lesion compared to a reference scan obtained not more than 6 months prior to the screening visit. For aggressive-highly active MS, the following additional inclusion criteria must be present: high brain lesion load or the presence of spinal cord lesions.
- Age ≥ 18 and ≤ 55.
- Expanded Disability Status Scale (EDSS) ≥ 2.0 and ≤ 6.0.
- Candidacy for treatment with at least one of the following diseases modifying treatments (DMT): natalizumab, alemtuzumab, ocrelizumab and/or ublituximab. Candidacy must include no prior treatment failure with the candidate DMT and no contraindication to the candidate DMT.
Exclusion Criteria
- Diagnosis of primary and secondary progressive MS according to the 2017 McDonald criteria
- Treatment with natalizumab, fingolimod and dimethyl-fumarate within the last 4 weeks to allow for proper wash-out. For previously natalizumab-treated patients with a positive John Cunningham virus antibody index, a negative CSF JCV-PCR is required.
- Treatment with teriflunomide within the last 2 years unless cleared from the body (plasma concentration < 0.02 mcg/ml following elimination from the body with cholestyramine or activated powdered charcoal).
- Treatment with ocrelizumab, ofatumumab, ublituximab, alemtuzumab and cladribine within the last 3 months.
- Known hypersensitivity or other known serious side effects for any of the study medications, including co-medications such as high-dose steroids and rabbit anti-thymocyte globulin.
- Brain MRI or Cerebrospinal fluid (CSF) examination indicating or suggesting a diagnosis of progressive multifocal leukoencephalopathy (PML).
- If white blood cells < 1,5 x 109/L and/or lymphocytes CD4+ < 200/mm3 because of a reversible effect of documented ongoing medication, the WBC count must be ≥ 1,5 x 109/L and lymphocytes CD4+ ≥ 200/mm3 before start of study treatment.
- In case of unexplained cytopenia, polycythemia, thrombocythemia diagnosis of myelodysplastic syndrome must be ruled out before including patient in the protocol.
- History of malignancy, with the exception of adequately treated localized basal cell or squamous skin cancer, or carcinoma in situ of the cervix.
- Any active uncontrolled viral, bacterial, fungal, endoparasitic, or opportunistic infection.
- Serological positivity to HCV or HIV
- Patients who are unwilling to practice pharmacological prophylaxis in case of HBsAg or HBcAb positivity
- Receipt of live or live-attenuated vaccines within 6 weeks of randomization.
- Presence or history of Child-Pugh score B and C hepatic cirrhosis.
- Hepatic disease with the presence at two consecutive assessments 15 days apart of either of the following: total bilirubin ≥ 1.5 times the upper limit of normal (ULN) or total bilirubin ≥ 3.0 times the ULN in the presence of Gilbert's syndrome, or alanine aminotransferase or aspartate aminotransferase ≥ 3.0 times the ULN.
- Presence or history of clinically significant cardiac disease (including coronary artery disease, moderate to severe valve stenosis or insufficiency, symptomatic mitral valve prolapse, presence of prosthetic mitral or aortic valve).
- Left ventricular ejection fraction (LVEF) < 50%.
- eGFR < 60 mL/min/1.73m2
- Forced expiratory volume in one second (FEV1) <70% predicted (no bronchodilator).
- Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for Hgb) < 70% predicted
- Known untreated or unregulated thyroid disease.
- Positive pregnancy test or breast-feeding.
- Patients who are unwilling to practice adequate contraception during the duration of the study. Female participants of child-bearing potential should use highly effective contraception for 12 months after AHSCT, 4 months after the last infusion of alemtuzumab and for the entire time of natalizumab, ocrelizumab, ofatumumab and ublituximab treatment. Female highly effective contraception methods include: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal); Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable implantable); Intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion; vasectomised partner; sexual abstinence. Male participants with female partners of child-bearing potential must be willing to use highly effective contraception if they are randomized to the AHSCT arm for 12 months after treatment. Male highly effective contraception methods include: vasectomy, sexual abstinence or the use of male condom with or without spermicide plus one highly effective contraception method for the female partner.
- Prior history of solid organ transplantation.
- Prior history of AHSCT.
- Prior exposure to mitoxantrone.
- Prior exposure to cyclophosphamide.
- Inability to understand the contents of the Informed Consent form.
- Failure to willingly accept or comprehend risk of irreversible sterility as a side effect of therapy.
- Any condition that precludes the participant from undergoing MRI with gadolinium administration.
- Presence or history of genetically inherited progressive central nervous system disorder, or central nervous system tumors.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Recruiting | 31 Oct 2024 | 90 |
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 |
|---|---|---|---|---|---|---|
Ocrevus 300 mg concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS DRIP USE | 600 | 60 | PRD5771848 |
CYTARABINE | Test | — | INTRAVENOUS USE | 200 | 4 | SUB06880MIG |
CARMUSTINE | Test | — | INTRAVENOUS DRIP USE | 300 | 1 | SUB06132MIG |
CYCLOPHOSPHAMIDE | Test | — | INTRAVENOUS DRIP USE | 4 | 1 | SUB06859MIG |
CYCLOPHOSPHAMIDE | Test | — | INTRAVENOUS DRIP USE | 4 | 1 | SUB06859MIG |
Tysabri 300 mg concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS DRIP USE | 300 | 60 | PRD10194542 |
CARMUSTINE | Test | — | INTRAVENOUS DRIP USE | 300 | 1 | SUB06132MIG |
ETOPOSIDE | Test | — | INTRAVENOUS DRIP USE | 200 | 4 | SUB07337MIG |
CARMUSTINE | Test | — | INTRAVENOUS DRIP USE | 300 | 1 | SUB06132MIG |
UBLITUXIMAB | Comparator | — | INTRAVENOUS DRIP USE | 450 | 60 | SUB182428 |