Ocrelizumab or Alemtuzumab Compared With Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis - a Phase-2 Randomised Controlled Trial

A multicentre controlled phase II trial to compare the efficacy and safety of ocrelizumab or alemtuzumab and autologous Hematopoietic Stem Cell Transplantation (aHSCT). Active relapsing-remitting MS-Patients will be included and randomised to ocrelizumab or alemtuzumab versus aHSCT. Primary endpoint will be the time to treatment failure as assessed by failure of NEDA (no evidence of disease activity) as represented by: no expanded disability status scale (EDSS) progression, no relapse, no new T2 lesion and no Gd-enhancing lesion.

This trial offers the opportunity to gain further information about efficacy and safety of all treatments and will give new insights into the immunology of highly active RRMS.

A rater-blinded multicentre randomised controlled phase II trial to compare the efficacy and safety of ocrelizumab or alemtuzumab and aHSCT. Active RRMS-Patients will be included and randomised to ocrelizumab or alemtuzumab versus aHSCT. Primary endpoint will be the time to treatment failure as assessed by failure of NEDA (no evidence of disease activity) as represented by: no expanded disability status scale (EDSS) progression, no relapse, no new T2 lesion and no Gd-enhancing lesion.

aHSCT appears highly efficacious in reducing inflammatory disease activity and relapses in active relapsing-remitting MS. Cohort data show a long-term stagnation of inflammatory disease activity for up to 10 years and more after aHSCT. However, efficacy data from randomised controlled trials comparing aHSCT with approved treatments are still lacking.

The best available data concerning disease activity in MS patients with a documented treatment failure are from the CARE-MS II trial. The rate of patients without clinical or radiological disease activity after 2 years was 32% with alemtuzumab. aHSCT trial data on absence of disease activity show NEDA rates between 70 and 90% after 2 years. Here we assume 40% and 80% after 2 years for the ocrelizumab/alemtuzumab and aHSCT groups, respectively.

For all three treatments, a potential long-term benefit has to be balanced with potentially harmful treatment related risks. A randomised controlled trial offers the opportunity to gain further information about efficacy and safety of all treatments and will give new insights into the immunology of high active RRMS.

Eligibility Criteria:
Inclusion Criteria (Based on CARE-MS-II3, guidelines and Rio-criteria for treatment failure):

* Written informed consent and agreement to comply to study protocol
* Age: 18-55 years
* EDSS: 0.0 - 6.0
* RRMS according to McDonald 2010
* \< 10 years of disease course after symptom onset
* Active disease with one of the following treatment failures occur-ring not earlier than 6 months after initiation of an approved DMT
* 2 or more relapses within the last 12 months

or

* 1 relapse within the last 12 months and a Gd-enhancing lesion on MRI \> 3 mm \> 3 months before or after relapse onset or 2 new T2-lesions

or

* On-going signs of MRI activity in the last 6 months (either Gd-en-hancing of ≥ 3 mm lesion at any exam in the last year; or more than 5 new T2 lesions (≥ 3 mm)

or

* Patients stable under natalizumab but who have to stop treatment due to an increasing PML risk are defined as active, if a MRI within 6 months after termination of natalizumab shows new T2 or Gd-enhancing lesions and at least one other treatment fail-ure prior to natalizumab is documented.

Exclusion Criteria:

* Secondary or primary progressive MS
* Pregnancy, or other medical condition incompatible with aHSCT
* Any treatment or medical condition that, according to the haematologist / transplant specialist precludes the use of aHSCT
* John Cunningham virus (JCV) antibody index of \> 1.5 in previ-ously natalizumab-treated patients, if a negative CSF JCV-PCR prior to screening is not available
* Relapse during 30 days before initiation of treatment. If a relapse occurs during this period and eligibility criteria are otherwise ful-filled, start of treatment will be delayed until at least 30 days after receiving steroids.
* Concurrent clinically significant (as determined by the investiga-tors and haematologist / transplant specialist) cardiac, immuno-logical, pulmonary, neurological, renal or other major disease such as:

  * Prominent cardial disease (Left ventricular ejection frac-tion (LVEF) \< 40%, myocardial infarction or ischemia, un-controlled arrhythmias, pericardial effusion \> 1 cm)
  * Cerebrovascular disease
  * Renal disease (creatinine clearance \< 30 ml/min/m2)
  * Respiratory disease (DLCO \< 40% predicted)
  * Active bleeding or clotting disease
  * History of human immunodeficiency virus (HIV) or posi-tive HIV antibody testing
  * Any uncontrolled acute or chronic infection, including HIV, hepatitis B surface antigen positivity and hepatitis C PCR positivity
  * Cancer except in situ cervix or cutaneous
* Unwillingness or inability to comply with the requirements of this protocol including the presence of any condition (physical, men-tal, or social) that is likely to affect the patient returning for follow-up visits on schedule. Unwillingness to use contraception.
* Previous participation in this study, previous treatment with aHSCT or already both comparators
* Ongoing immunotherapy. Treatment with interferon or glati-rameracetate will need no wash-out. Treatment pause before oc-relizumab/alemtuzumab or aHSCT will be:

  * for dimethylfumarate and fingolimod: 8 weeks
  * for natalizumab: 8 weeks
  * for ocrelizumab: 12 weeks
  * for alemtuzumab: 12 months
  * for teriflunomide: 4 weeks after elimination with cholesty-ramine
  * for cladribine: 24 weeks
* Patients with cognitive impairments who are unable to provide written, informed consent prior to any testing under this protocol, including screening and baseline investigations that are not con-sidered part of routine patient care.