RCT Comparing Autologous Hematopoietic Stem Cell Transplantation Versus Alemtuzumab in MS
RCT Comparing Autologous Hematopoietic Stem Cell Transplantation Versus Alemtuzumab in MS
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, a registered immunomodulatory treatment of
 RRMS. 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.
This is a randomized study of autologous HSCT using a low intensity, non-ablative
 conditioning regimen with cyclophosphamide and ATG versus treatment with the currently
 presumed best available immunomodulatory medication (alemtuzumab) in RRMS patients with
 significant inflammatory disease activity in spite of ongoing immunomodulatory MS treatment.

 Significant disease activity is defined as having one or more clinically reported multiple
 sclerosis (MS) relapse(s), AND 1 or more T1 Gd-enhanced lesion(s), OR three or more new or
 enlarging T2 lesions on magnetic resonance imaging (MRI) over the last year while being
 treated on immunomodulatory medication by standard national guidelines. The relapse(s) must
 have occurred 3 or more months after the onset of an immunomodulatory treatment, as
 immunomodulatory treatment in MS may reach full effect after 3 months or more.

 Both the knowledge of the treatment effect of registered immunomodulatory therapies for RRMS,
 and the number of treatments approved for RRMS by the European Medicines Agency (EMA) are
 rapidly increasing. During the study period, there may thus appear new supplementing
 information on other MS immunomodulatory treatments that favour the use of a new comparator
 (replacing or supplementing alemtuzumab as a comparator). This will be evaluated by the PMC
 if applicable during the study period and the planned extension period.

 If the treatment efficacy obtained by HSCT is better than the currently most efficacious
 standard, immunomodulatory treatment in randomized treatment trials, HSCT will likely be
 approved as a part of the standard treatment recommendations for a significant proportion of
 RRMS patients. A randomized study regarding with statistical power to evaluate the clinical
 outcome of autologous HSCT compared to a standard immunomodulatory treatment in MS has not
 yet been published. Except for Sweden, HSCT is currently not registered as a part of standard
 MS treatment in the public health services of Europe. The HSCT regimen for the study will be
 identical to the regimen used in similar patient populations in Sweden, Norway and Denmark.

 Alemtuzumab has been chosen as the primary comparator, because it is the immunomodulatory
 medication currently authorised by the EMA for treatment of RRMS with the most favourable
 therapeutic effects. In a meta-analysis of immunomodulatory treatment effects in RRMS,
 alemtuzumab was the immunomodulatory drug with the most eminent reduction of annualized
 relapse rate and 3 month confirmed disability progression.

 In this study, a health economic evaluation will be included. Accordingly, the proposed study
 should provide a robust basis for future official decisions regarding the role of HSCT in
 RRMS treatment.
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.