Comparing stem cell transplantation to standard MS treatments for patients with active disease

Randomized Autologous heMatopoietic Stem Cell Transplantation Versus Alemtuzumab, Cladribine or Ocrelizumab for Patients With Relapsing Remitting Multiple Sclerosis (RAM-MS)

This study is testing whether stem cell transplantation can work better than standard MS treatments for people with active relapsing-remitting multiple sclerosis who are still having problems despite their current medications.

Quick facts

• Phase: Phase 3
• Study type: Interventional
• Enrollment: 100 (estimated)
• Ages: 18 Years to 50 Years
• Sex: All
• Sponsor: Haukeland University Hospital (Academic / other)
• Drugs / interventions: natalizumab, rituximab, alemtuzumab, ocrelizumab, chemotherapy, cyclophosphamide
• Locations: 8 sites (Copenhagen and 7 other locations)
• Trial ID: NCT03477500 on ClinicalTrials.gov

What this trial studies

This study is a randomized, multicenter trial that evaluates the effectiveness of autologous hematopoietic stem cell transplantation (HSCT) compared to standard immunomodulatory treatments (alemtuzumab, cladribine, or ocrelizumab) in patients with relapsing-remitting multiple sclerosis (RRMS) who continue to experience significant disease activity despite ongoing treatment. Participants will be assigned to one of two treatment arms: HSCT or one of the standard medications. The study aims to assess both the efficacy and side effects of HSCT over a planned follow-up period of three years. The goal is to determine whether HSCT provides a greater treatment effect than currently available therapies for RRMS.

Who should consider this trial

Good fit: Ideal candidates for this study are adults aged 18 to 50 with relapsing-remitting multiple sclerosis and significant inflammatory disease activity despite standard treatment.

Not a fit: Patients with stable RRMS or those who have not experienced significant disease activity while on treatment may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could offer a more effective treatment option for patients with RRMS who are not responding adequately to existing therapies.

How similar studies have performed: Previous studies have indicated that HSCT may have a significantly higher treatment effect than current immunomodulatory therapies, suggesting potential success for this approach.

Eligibility criteria

Inclusion Criteria:

1. Age between ≥18 to ≤50, both genders
2. 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.
3. Diagnosis of RRMS using revised McDonald criteria of clinically definite MS1
4. An EDSS score of 0 to 5.5
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 been treated with iv or oral high dose corticosteroids prescribed by a neurologist, and 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 more2.
6. The patient is a RRMS-patient referred from neurological departments in Norway, Denmark, Sweden or possibly other European countries to an assigned study site.
7. 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:

1. Known hypersensitivity or other known serious side effects for any of the study medications, including co-medications such as high-dose glucocorticosteroids
2. 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
3. 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
4. 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.
5. 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 rituximab, mitoxantrone, alemtuzumab, cladribin and ocrelizumab
6. Immunocompromised patients, or patients currently reveiving immunosuppressive or myelosuppressive therapy
7. Treatment with glucocorticoids or ACTH within one month prior to start of study treatment
8. Having experienced an MS relapse within one month prior to study inclusion
9. Prior or current major depression
10. 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.
11. Prior or current alcohol or drug dependencies
12. Cardiac insufficiency, cardiomyopathy, significant cardiac dysrhytmia, unstable or advanced ischemic heart disease (NYHA III or IV)
13. Significant hypertension: BP \> 180/110
14. Active malignancy, or prior history of malignancy except localized basal cell, squamous skin cancer or carcinoma in situ of the cervix.
15. Known untreated or unregulated thyroid disease
16. Failure to willingly accept or comprehend risk of irreversible sterility as a side effect of therapy
17. 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.
18. Platelet (thrombocyte) count \< 100 x 109/L
19. ALAT and/or ASAT more than 2 times the upper normal reference limit (UNL)
20. Serum creatinine \> 200 µmol/L
21. Serum bilirubin \> ULN
22. Moderate or severely impaired kidney function (creatinine-clearance below 60 ml/min)
23. Presence of metallic objects implanted in the body that would preclude the ability of the patient to safely have MRI exams
24. Diagnosis of primary progressive MS
25. Diagnosis of secondary progressive MS
26. 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.
27. 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.
28. Any hereditary neurological disease such as Charcot-Marie-Tooth disease or Spinocerebellar ataxia
29. Any disease that can influence the patient safety and compliance, or the evaluation of disability
30. History of hypersensitivity reaction to rabbit
31. Women who are pregnant, breast-feeding, or who plan to become pregnant within the timeframe of this study
32. 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.

Where this trial is running

Copenhagen and 7 other locations

• Rigshospitalet — Copenhagen, Denmark (Recruiting)
• VUmc — Amsterdam, Netherlands (Recruiting)
• Haukeland University Hospital — Bergen, Norway (Recruiting)
• Akershus University Hospital — Oslo, Norway (Recruiting)
• University Hospital of North Norway — Tromsø, Norway (Recruiting)
• St. Olav's University Hospital — Trondheim, Norway (Recruiting)
• Sahlgrenska University Hospital — Gothenburg, Sweden (Recruiting)
• Akademiska sjukhuset — Uppsala, Sweden (Recruiting)

Study contacts

• Principal investigator: Trygve Holmøy, MD, PhD — University Hospital, Akershus
• Study coordinator: Øivind Torkildsen, MD, PhD

Conditions Multiple Sclerosis; multiple sclerosis,; HSCT; alemtuzumab; RCT