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

Official Summary

This study is a randomized multicentre, multinational, treatment interventional study of RRMS patients with breakthrough inflammatory disease activity in spite of ongoing standard immunomodulatory medication. The study has two treatment arms; arm A: HSCT (hematopoietic stem cell transplantation) and arm B: alemtuzumab, cladribine or ocrelizumab. A pre-planned 3-year follow-up extension period will be performed depending on future funding. The aim of the study is to assess the effectiveness and side effects of a new treatment intervention in RRMS; HSCT, and, thereby, the value of HSCT in clinical practice. Data from recently published patient series indicate that HSCT may have a significantly higher treatment effect than currently registered RRMS immunomodulatory treatments. This study will determine the relative role of HSCT versus alemtuzumab, cladribine or ocrelizumab.

Eligibility Requirements

• Minimum Age: 18 Years
• Maximum Age: 50 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: SINGLE
• Enrollment: 100 participants

Study Arms

• HSCT (Cyclophosphamide and ATG) (EXPERIMENTAL)
  Day 1: Cyclophosphamide 2.0 g/m2 body surface area Days 5-10: Granulocyte colony stimulating factor (filgrastim) 5 mcg/kg body weight/day sc. Day 11 and until apheresis is discontinued: Granulocyte colony stimulating factor (filgrastim) 5 mcg/kg body weight x 2 sc/day. HSCT days -5 to -2: Cyclophosphamide 50 mg/kg/day. HSCT days -5 to -1: Anti-thymocyte globulin (ATG-rabbit, Thymoglobuline®) 0.5 mg/kg body weight iv on day -5, 1.0 mg ATG-rabbit/kg will be given iv on day -4, and 1.5 mg ATG-rab
• Alemtuzumab, Cladribine or Ocrelizumab (ACTIVE_COMPARATOR)
  Alemtuzumab, Cladribine or Ocrelizumab administered after the label of the study drug.

Interventions

• DRUG: Cyclophosphamide and ATG — Hematopoetic stem cell transplantation
• DRUG: Alemtuzumab — Alemtuzumab (Lemtrada)
• DRUG: Cladribine Pill — Cladribine (Mavenclad)
• DRUG: Ocrelizumab — Ocrelizumab (Ocrevus)

Primary Outcomes

• Proportion of patients with no evidence of disease activity (NEDA, as defined per protocol). (2 year (96 week) period with a 5 year (240 week) planned extension)

Secondary Outcomes

• NEDA-4 (2 year (96 week) period)
• Pre-planned study extension: (5 year (240 week) period.)
• Time to first protocol-defined disease activity event (2 year (96 week) period, with planned extension for 5 year (240 week) period)
• Change in Expanded Disability Status scale (EDSS) from baseline (Visit 4.1) to Weeks 96 and 240 (2 year (96 week) period, with planned extension for 5 year (240 week) period)
• The proportion of patients who, at Week 96, have protocol-defined Confirmed Disability Improvement (CDI) , confirmed stable EDSS or Confirmed Disability Progression (CDP) compared to baseline (2 year (96 week) period, with planned extension for 5 year (240 week) period)

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 secti

Trial Locations

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

Study Officials

• Lars Bø, MD, Phd — STUDY_DIRECTOR
  Haukeland University Hospital
• Anne Kristine Lehmann, MD, PhD — STUDY_CHAIR
  Haukeland University Hospital
• Astrid Kittang, MD, PhD — STUDY_CHAIR
  Haukeland University Hospital
• Einar Kristoffersen, MD, PhD — STUDY_CHAIR
  Haukeland University Hospital
• Øivind Torkildsen, MD, PhD — STUDY_CHAIR
  Haukeland University Hospital

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