Comparative Efficacy and Safety of Autologous Hematopoietic Stem Cell Transplantation Versus Alemtuzumab, Cladribine, or Ocrelizumab in Relapsing-Remitting Multiple Sclerosis
- Trial ID
- 2024-510630-40-00
- Sponsor
- Helse Bergen HF
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this prospective, randomized study is to evaluate the **efficacy** and **safety** of autologous hematopoietic stem cell transplantation (HSCT) compared to a comparator group consisting of alemtuzumab, cladribine, or ocrelizumab in patients with aggressive relapsing-remitting **multiple sclerosis**. This investigation is clinically relevant as it aims to determine the most effective treatment strategy for managing this form of multiple sclerosis, potentially improving patient outcomes and quality of life.
Secondary objectives include conducting a health economic evaluation in Norway, which will provide insights into the cost-effectiveness of the treatments under study, further informing healthcare decision-making and policy development.
Participants
The sponsor does not provide information regarding the total number of participants in this clinical trial. The study population comprises individuals diagnosed with **relapsing-remitting multiple sclerosis** (RRMS), aged between 18 and 50 years, and includes both male and female participants. Participants are required to have a diagnosis of RRMS according to the revised McDonald criteria and an Expanded Disability Status Scale (EDSS) score ranging from 0 to 5.5. The trial targets patients with significant inflammatory disease activity in the past year, despite treatment with standard disease-modifying therapies. Participants are expected to adhere to highly effective birth control methods if applicable. The trial does not include a vulnerable population, and participants are referred from neurological departments in several European countries. Lifestyle considerations such as diet and physical activity are not specified in the provided data.
Plans and Procedures
The clinical trial is designed to evaluate the **efficacy** and safety of autologous hematopoietic stem cell transplantation (HSCT) compared to alemtuzumab, cladribine, or ocrelizumab in patients with aggressive relapsing-remitting **multiple sclerosis** (RRMS). This is a prospective, randomized, controlled study with a double-blind design to ensure unbiased results. The trial is expected to last until December 31, 2028, with recruitment starting on September 1, 2024. Participants will be involved in the study for a period of up to five years, with primary and secondary endpoints assessed at 96 weeks and 240 weeks.
Study visits are structured to include an initial screening visit to confirm eligibility based on criteria such as age, gender, and disease activity. Participants must have a diagnosis of RRMS according to the revised McDonald criteria and exhibit significant inflammatory disease activity despite standard therapy. Follow-up visits will occur at regular intervals to monitor disease activity, treatment response, and safety. These visits will include assessments such as MRI scans, clinical evaluations, and patient-reported outcomes. The end-of-study visit will occur at the conclusion of the participant's involvement, where final assessments will be conducted to evaluate long-term outcomes.
Participants are expected to adhere to the study protocol, including the use of effective birth control methods for women of childbearing potential and men in sexual relationships with such women. Conditions that may lead to early termination from the study include non-compliance with the protocol, withdrawal of consent, or adverse events that compromise participant safety. The primary efficacy endpoint is the proportion of patients with no evidence of disease activity (NEDA) after two and five years. Secondary endpoints include changes in MRI lesion volume, disability progression, and quality of life measures. The trial aims to provide comprehensive data on the comparative effectiveness of HSCT and the comparator drugs in managing RRMS.
Treatment
The clinical trial involves the administration of several treatments to evaluate their efficacy and safety in patients with **relapsing-remitting multiple sclerosis**. The experimental medication **MAVENCLAD** (cladribine) is provided in the form of 10 mg tablets. It is administered orally with a maximum daily dose of 20 mg and a total dose not exceeding 3.5 mg/kg over a treatment period of up to 24 months. The active substance, cladribine, is a chemical compound also known as 2-chlorodeoxyadenosine.
**Thymoglobuline** is used as a comparator treatment in the form of a 25 mg powder for solution for infusion. The active substance is antithymocyte immunoglobulin, a protein derived from rabbits. It is administered intravenously with a maximum daily dose of 1.5 mg/kg and a total dose not exceeding 6 mg/kg over a treatment period of up to 5 days.
Another comparator, **Sendoxan** (cyclophosphamide), is provided as a 1000 mg powder for solution for injection. This chemical compound is administered via infusion with a maximum daily and total dose of 2000 mg/m² over a single day of treatment.
**Ocrevus** (ocrelizumab) is also used as a comparator and is available as a 300 mg concentrate for solution for infusion. The protein-based medication is administered through intravenous infusion with a maximum daily dose of 600 mg and a total dose not exceeding 3600 mg over a treatment period of up to 60 months.
Lastly, **LEMTRADA** (alemtuzumab) is provided as a 12 mg concentrate for solution for infusion. This protein-based treatment is administered via intravenous infusion with a maximum daily dose of 12 mg and a total dose not exceeding 60 mg over a treatment period of up to 12 months.
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 and safety of these treatments in managing aggressive relapsing-remitting multiple sclerosis.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint is the proportion of patients with no evidence of disease activity (NEDA) after a 2-year (96-week) and 5-year (240-week) period. NEDA is defined as the absence of a protocol-defined disease activity event. Secondary endpoints include the proportion of patients with NEDA including atrophy (NEDA 4), time to first protocol-defined disease activity event, and changes in various scales and measures from baseline to specified timepoints. These include the EQ-5D-5L, Fatigue Severity Scale (FSS), Multiple Sclerosis Impact Scale (MSIS)-29, and Expanded Disability Status Scale (EDSS). Additional secondary endpoints involve the annualized rate of protocol-defined relapses, time to onset of first protocol-defined relapse, and changes in MRI lesion volumes and brain volume.
Measurements will be collected at multiple timepoints, including weeks 24, 48, 96, 144, 192, and 240, to evaluate changes in MRI T2-weighted hyperintense lesion volume, MRI T1-weighted hypointense lesion volume, and brain volume. The trial will also assess the total number of MRI T1-weighted Gd-enhanced lesions and the proportion of patients free from T1 Gd-enhancing lesions at these timepoints. Functional assessments such as the Nine-hole-peg test (9-HPT), Timed 25-foot walk (T25FW), and The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) will be evaluated from baseline to weeks 48, 96, and 240. Overall survival rate and work productivity and activity impairment will also be assessed at specified intervals. These efficacy parameters will be analyzed to determine the comparative effectiveness of the treatment regimens in patients with **relapsing-remitting multiple sclerosis**.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age between ≥18 to ≤50, both genders
- Women of childbearing potential* (WOCBP) and men in a sexual relation with WOCBP must be ready and able to use highly effective methods of birth control¥ per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly for the duration of the study OR until 4, 6 and 12 months after last dose administered for alemtuzumab, cladribine or ocrelizumab respectively (the longest alternative applies). If treated with cladribine, women must use double barrier method during each treatment course and until 4 weeks after last dose in each treatment course is administered.
- Diagnosis of RRMS using revised McDonald criteria of clinically definite MS
- An EDSS score of 0 to 5.5
- Significant inflammatory disease activity in the last year despite treatment with standard disease modifying therapy (interferon beta, glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod, natalizumab) a. Significant inflammatory disease activity is defined by: i. One or more clinically reported multiple sclerosis (MS) relapse(s), ii. AND 1 or more T1 Gd-enhanced lesion(s), iii. OR three or more new or enlarging T2 lesions on magnetic resonance imaging (MRI) The relapse(s) must have occurred 3 or more months after the onset of an immunomodulatory treatment, as MS immunomodulatory treatment may reach full effect after 3 months or more.
- The patient is a RRMS-patient referred from neurological departments in Norway, Denmark, Sweden, the Netherlands (or potentially from other countries participating in the study), to an assigned study site.
- Signed informed consent and expected patient cooperation regarding the treatment schemes and procedures planned in the treatment and follow-up periods must be obtained and documented according to ICH GCP and national/local regulations.
Exclusion Criteria
- Known hypersensitivity or other known serious side effects for any of the study medications, including co-medications such as high-dose glucocorticosteroids
- Any illness or prior treatment that in the opinion of the investigators would jeopardize the ability of the patient to tolerate aggressive chemotherapy or high-dose glucocorticosteroids
- Any ongoing infection, including Tbc, CMV, EBV, HSV, VZV, hepatitis virus, toxoplasmosis, HIV or syphilis infections, as well as heaptitis B surface antigen positivity and/or hepatitis C PCR positivity verified at Visit 1
- Patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV), unless tested for antibodies to VZV. VZV negative patients can only be included if they receive vaccination against VZV at least 6 weeks prior to inclusion.
- Current or previous treatments with long-term effects that may influence the treatment effects or potential toxicities/side effects of the treatment arms. This includes, but is not restricted to previous treatment with mitoxantrone, alemtuzumab, cladribin and ocrelizumab, and treatment with rituximab with the last 9 months prior to start of study treatment.
- Treatment with glucocorticoids or ACTH within one month prior to start of study treatment
- Having experienced an MS relapse within one month prior to study inclusion
- Prior or current major depression
- Prior or current psychiatric illness, mental deficiency or cognitive dysfunction influencing the patient ability to make an informed consent or comply with the treatment and follow-up phases of this protocol.
- Prior or current alcohol or drug dependencies
- Cardiac insufficiency, cardiomyopathy, significant cardiac dysrhytmia, unstable or advanced ischemic heart disease (NYHA III or IV)
- Significant hypertension: BP > 180/110
- Active malignancy or prior history of malignancy except localized basal cell, squamous skin cancer or carcinoma in situ of the cervix.
- Known untreated or unregulated thyroid disease
- Failure to willingly accept or comprehend risk of irreversible sterility as a side effect of therapy
- WBC < 1,5 x 109/L if not caused by a reversible effect of documented ongoing medication. If WBC < 1,5 x 109/L is caused by a reversible effect of documented ongoing medication the WBC count must be > 1,5 x 109/L before start of study treatment.
- Platelet (thrombocyte) count < 100 x 109/L
- ALAT and/or ASAT more than 2 times the upper normal reference limit (ULN)
- Serum creatinine > 200 µmol/L
- Serum bilirubin > ULN
- Presence of metallic objects implanted in the body that would preclude the ability of the patient to safely have MRI exams
- Diagnosis of primary progressive MS
- Diagnosis of secondary progressive MS
- Treatment with natalizumab and fingolimod within the last 2 months, and treatment with dimetylfumurat within the last month (washout must be performed as specified in section 5.1) prior to start of study medication.
- Use of teriflunomide (Aubagio®) within the previous 2 years unless cleared from the body (plasma concentration < 0.02 mcg/ml following elimination from the body with cholestyramine or activated powdered charcoal) as specified in section 5.1 prior to start of study medication.
- Any hereditary neurological disease such as Charcot-Marie-Tooth disease or Spinocerebellar ataxia
- Any disease that can influence the patient safety and compliance, or the evaluation of disability
- History of hypersensitivity reaction to rabbit
- Women who are pregnant, breast-feeding, or who plan to become pregnant within the timeframe of this study
- Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational treatment(s). Patients participating in a purely observational trial will not be excluded.
- Immunocompromised patients, or patients currently reveiving immunosuppressive or myelosuppressive therapy
- Moderate or severely impaired kidney function (creatinine-clearance below 60 ml/min)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Not Recruiting | 01 Sept 2024 | 5 |
 The Netherlands | Not Recruiting | 01 Sept 2024 | — |
 Norway | Not Recruiting | 01 Sept 2024 | 85 |
 Sweden | Not Recruiting | 01 Sept 2024 | 2 |
| Netherlands | — | — | 8 |
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 |
|---|---|---|---|---|---|---|
MAVENCLAD 10 mg tablets | Comparator | TABLETS | ORAL USE | 20 | 24 | PRD5373276 |
Thymoglobuline 25 mg powder for solution for infusion | Test | POWDER FOR SOLUTION FOR INFUSION | INTRAVENOUS | 1.5 | 5 | PRD441260 |
Sendoxan 1000 mg pulver til injeksjonsvæske, oppløsning | Test | PULVER TIL INJEKSJONSVÆSKE, OPPLØSNING | INFUSION | 2000 | 1 | PRD1974142 |
Ocrevus 300 mg concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 600 | 60 | PRD5771848 |
LEMTRADA 12 mg concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | IV INFUSION | 12 | 12 | PRD3337642 |