Randomized Autologous heMatopoietic Stem Cell Transplantation Versus Alemtuzumab, Cladribine or Ocrelizumab for Patients With Relapsing Remitting Multiple Sclerosis (RAM-MS)
Phase: PHASE3
Conditions: Multiple Sclerosis
Sponsor: Haukeland University Hospital

 
 
 
 
Side 1 av 96 
Clinical Trial Protocol 
 
 
Randomized Autologous heMatopoietic stem cell 
transplantation versus Alemtuzumab  
for patients with relapsing remitting Multiple Sclerosis 
Protocol Identification:   RAM-MS 
EudraCT Number:   2017-001362-25 
 
Sponsor:  
 
Helse Bergen HF, Haukeland University Hospital  
Håkon Nordli 
Head of Department 
Neuro Clinic 
N-5021, Bergen, Norway 
Tel :55975857  
E-mail: hakon.taule.nordli@helse-bergen.no 
Coordinating Investigator: Lars Bø 
Consultant neurologist/professor 
Department of Neurology 
Haukeland University Hospital 
Helse Bergen HF  
N-5021, Bergen, Norway 
Tel :55976186/97432421  
E-mail: lars.bo@helse-bergen.no 
 
PROTOCOL VERSION NO. 4.2, 20-Dec-2017 
 
 

  
 
  
Study: RAM-MS  
CLINICAL STUDY PROTOCOL 
20-Dec-2017 
RAM-MS Version no. 4.1, 08-Dec-2017 
Page 2 of 96 
 
SIGNATURE PAGE 
 
Title 
Randomized autologous hematopoietic stem cell transplantation versus Alemtuzumab  
for patients with relapsing remitting Multiple Sclerosis 
 
Protocol ID no: 
RAM-MS 
EudraCT no: 
2017-001362-25 
 
 
I hereby declare that I will conduct the study in compliance with the Protocol, ICH GCP and the applicable 
regulatory requirements: 
 
Name 
Title 
Role 
Signature 
Date 
Håkon Taule Nordli 
Department 
head 
Sponsor 
representative 
 
 
Lars Bø 
Consultant 
neurologist/ 
professor 
Coordinating 
Investigator 
 
 
 
 
 
 
 
 

  
 
  
Study: RAM-MS  
CLINICAL STUDY PROTOCOL 
20-Dec-2017 
RAM-MS Version no. 4.1, 08-Dec-2017 
Page 3 of 96 
PROTOCOL SYNOPSIS 
 
Randomized autologous hematopoietic stem cell transplantation versus Alemtuzumab  
for patients with relapsing remitting Multiple Sclerosis  
 
Sponsor:  
 
Helse Bergen HF, Haukeland University Hospital 
Håkon Taule Nordli 
Neuro Clinic 
N-5021, Bergen, Norway 
Tel :55975857  
 
Phase and study type: 
Phase III, interventional 
Protocol date and version: 
20-Dec-2017, version 4.2 
Protocol Revision date and 
version: 
NA 
Investigational Medical 
Product (IMP):        
Study treatment arm A: Cyclophosphamide and anti-thymocyte globuline 
Study treatment arm B: Alemtuzumab 
Objectives:  
The objective of this study is to investigate the efficacy and the safety of HSCT, 
compared to alemtuzumab in patients with aggressive relapsing remitting MS. 
Study Design: 
Prospective multicentre, interventional, unblinded, randomized, parallel group study 
Number of patients: 
Approximately  100 patients, 50 in each treatment arm. 
Study duration: 
 
Estimated date of first patient enrolled: 01-Jan 2018.  
Anticipated recruitment period: 2 years 
2 years follow-up from Treatment day “0” (baseline) in both arms. 
Estimated date of last patient completed: 31-December-2021  
Follow-up duration: 
A pre-planned study extension with additional 3 years follow-up may be conducted 
depending on future funding. 
Treatment administration: 
Arm A: mobilization and harvesting; 10 days, conditioning and reinfusion; 6 days.  
Arm B: At start of treatment; infusion for 5 consecutive days, and 1 year later; infusion 
for 3 consecutive days 

  
 
  
Study: RAM-MS  
CLINICAL STUDY PROTOCOL 
20-Dec-2017 
RAM-MS Version no. 4.1, 08-Dec-2017 
Page 4 of 96 
Main Inclusion Criteria:    
o Age between ≥18 to ≤50, both genders  
o Diagnosis of RRMS using revised McDonald criteria of clinically definite MS1  
o An EDSS score of 0 to 5.5  
 
o Significant inflammatory disease activity in the last year despite treatment with 
standard disease modifying therapy (interferon beta, glatiramer acetate, 
dimethyl fumarate, teriflunomide, fingolimod, natalizumab)  
o Significant  inflammatory disease activity is defined by:  
 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)  
 
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.   
Endpoints: 
Primary endpoint: 
The primary efficacy endpoint is to determine differences between patients in the 2 
treatment arms according to the following criteria: 
 
Proportion of patients with no evidence of disease activity (NEDA, as defined per 
protocol) during a 2 year (96 week) period 
 
Pre-planned study extension: Proportion of patients with NEDA (as defined per 
protocol) during a 5 year (240 week) period. 
NEDA is the absence of a protocol defined disease activity event. 
 
A protocol-defined disease activity event is the occurrence of at least one of the 
following:                                                                                                                               
- A new T1Gd-enhanced lesion on MRI of the brain and spinal cord                                     
- A new T2 hyperintense lesion on MRI of brain and spinal cord                                           
- A protocol-defined MS relapse (see definition below) 
- 24 week confirmed disability progression based on increases in Expanded Disability 
Status Scale (EDSS) (see definition below and Appendix C)  
MS relapse is defined as new or worsening neurological symptoms attributable to MS, 
lasting at least 48 hours, without pyrexia, after at least 30 days of clinical stability with 
an objective change on neurological examination3. 
Disability progression is defined as an increase of one point in the EDSS score (or half 

  
 
  
Study: RAM-MS  
CLINICAL STUDY PROTOCOL 
20-Dec-2017 
RAM-MS Version no. 4.1, 08-Dec-2017 
Page 5 of 96 
a point if the baseline EDSS score was equal to 5.5), confirmed after 24 weeks, with an 
absence of relapse at the time of assessment. MRI imaging will be performed according 
to the Revised Consortium of Multiple Sclerosis Centers (CMSC) MRI Protocol and 
Guidelines4                                                                                                
Secondary endpoints:  
The secondary efficacy endpoint for this study is to evaluate the efficacy of the study 
treatments on the basis of the following endpoints: 
 
Proportion of patients who have no evidence of disease activity, including atrophy 
(NEDA 4), as per protocol defined disease activity events (as defined in section 
2.2) plus atrophy (measured yearly atrophy above threshold of 0, 4 %) during a 2 
year (96 week) period5. 
o Pre-planned study extension: Proportion of patients who have NEDA 
4 during a 5 year (240 week) period.  
 
Time to first protocol-defined disease activity event as defined in section 2.2  
 
Change in EDSS from baseline (Visit 4.1) to Weeks 96 and 240 
 
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 
 
Annualized rate of protocol-defined relapses during 96 weeks 
 
Time to onset of first protocol-defined relapse 
 
Change in MRI T2-weighted hyperintense lesion volume from baseline to 
Weeks 48 and 96 (and 240) 
 
Change in MRI T1-weighted hypointense lesion volume from baseline to Weeks 48 
and 96 (and 240) 
 
Change in brain volume from baseline to week 48 and week 96 (and week 240), 
and from week 48 to week 96 (and week 240)5  
 
Time to detection of a new MRI T2 lesion 
 
Total number of MRI T1-weighted Gd-enhanced lesions at weeks 24, 48, 96 (and 
240) 
 
Proportion of patients free from T1 Gd-enhancing lesions at weeks 24, 48, 96 (and 
240) 
 
Change in Nine-Hole-Peg Test (9-HPT) score from baseline to week 48, 96 (and 
240) 
 
Change in Timed 25 Foot Walk (T25FW) score from baseline to week 48, 96 (and 
240) 
 
Change in the Brief International Cognitive Assessment for Multiple Sclerosis 
(BICAMS) score from baseline to week 96 (and 240)   
Efficacy Assessments: 
MS relapse, Expanded disability scale (EDSS), Magnetic resonance imaging (MRI), 
Nine Hole Peg Test (9-HPT), Timed 25-foot walk (T25FW), Brief International Cognitive 
Assessment for Multiple Sclerosis (BICAMS) 
 

  
 
  
Study: RAM-MS  
CLINICAL STUDY PROTOCOL 
20-Dec-2017 
RAM-MS Version no. 4.1, 08-Dec-2017 
Page 6 of 96 
Safety Assessments: 
Adverse events, physical examinations, vital signs, laboratory evaluations (blood and 
urine), pregnancy testing, chest X-ray, concomitant medication, Karnofsky Performance 
Status 
Other Assessments:  
Patient related outcomes (PROs), European Quality of 
Life 5 dimensions (EQ-5D-5L), Multiple Sclerosis Impact Scale (MSIS), Fatigue severity 
scale (FSS), health economy assessments, immunological/biomarker analyses 
 Statistical methods: 
The primary analysis will use a univariable logistic regression model, conducted as an 
ITT analysis. Two sensitivity analyses of the ITT analysis will be conducted. First, the 
analysis above  will be repeated in the per protocol population, and secondly, if 
imbalance in stratification variables  in the treatment arms, these covariates will be 
included in separate multivariable logistic regression models as independent variables 
to evaluate the influence of these on the results. 
The secondary efficacy endpoints will be tested in a hierarchal order, to account for 
multiple comparisons. The secondary endpoints will only be tested and interpreted as 
confirmatory if the primary efficacy endpoint reach a significance level of 0.05. 
Subsequent secondary endpoints will only be tested and interpreted as confirmatory if 
the endpoint listed ahead reaches a significance level of 0.05. Otherwise, the endpoints 
will be interpreted as non-confirmatory (i.e. descriptive only) independing on the p-
values.  

  
 
  
 
Study: RAM-MS  
CLINICAL STUDY PROTOCOL 
20-Dec-2017 
RAM-MS Version no. 4.1, 08-Dec-2017 
Page 7 of 96 
FLOW CHART - A 
Arm A – HSCT 
Screen. Rand.1 
Pre-
transplantation 
evaluation, 
fertility measures 
Treatment Period 
(Mobilization/harvesting, 
conditioning/ HSCT) 
Follow-up period 
Follow-up extension 
period3 
Unscheduled 
Visit/ Relapse 
Visit 
HSCT 
Day 
+100 
6M 
12M 
18M 
(EOS2) 
24M 
(EOS2) 
30M, 
42M, 
54M 
36M, 48M, 
60M/EOXS2 
- 
Visits 
V1 
V2 
V34 
 
V4.1 
V4.2 
V5 
V6 
V7 
V8 
V9 
V10, 
V12, 
V14 
V11, V13, V15 
- 
Study Week 
-12 to 
-9 
-11 to 
-7 
-10 to -4 
-6 to -4 
0 
3 to 6 
- 
24 
48 
72 
96 
120, 
168, 
216 
144, 192,  240 
- 
Days from treatment start 
-84 to 
-63 
-77 to 
-49 
-70 to -28 
0 
+21 to +42 
- 
+168 
±7 
+336 
±7 
+504 
±7 
+672 
±7 
+X±7 
+X±7 
- 
Days after stem cell 
reinfusion 
- 
- 
- 
 
- 
- 
+100 
±3 
- 
- 
- 
- 
- 
- 
- 
Informed consent 5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Wash out immunomodulatory 
treatment6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
evaluation 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Pretransplantation check7 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Fertility conserving 
measures8 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Stem cell mobilization and 
harvesting9 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Conditioning and autologous 
HSCT10 
 
 
 
 
X 
 
 
 
 
 
 
 
 

  
 
  
 
Study: RAM-MS  
CLINICAL STUDY PROTOCOL 
20-Dec-2017 
RAM-MS Version no. 4.1, 08-Dec-2017 
Page 8 of 96 
Arm A – HSCT 
Screen. Rand.1 
Pre-
transplantation 
evaluation, 
fertility measures 
Treatment Period 
(Mobilization/harvesting, 
conditioning/ HSCT) 
Follow-up period 
Follow-up extension 
period3 
Unscheduled 
Visit/ Relapse 
Visit 
HSCT 
Day 
+100 
6M 
12M 
18M 
(EOS2) 
24M 
(EOS2) 
30M, 
42M, 
54M 
36M, 48M, 
60M/EOXS2 
- 
Visits 
V1 
V2 
V34 
 
V4.1 
V4.2 
V5 
V6 
V7 
V8 
V9 
V10, 
V12, 
V14 
V11, V13, V15 
- 
Study Week 
-12 to 
-9 
-11 to 
-7 
-10 to -4 
-6 to -4 
0 
3 to 6 
- 
24 
48 
72 
96 
120, 
168, 
216 
144, 192,  240 
- 
Days from treatment start 
-84 to 
-63 
-77 to 
-49 
-70 to -28 
0 
+21 to +42 
- 
+168 
±7 
+336 
±7 
+504 
±7 
+672 
±7 
+X±7 
+X±7 
- 
Days after stem cell 
reinfusion 
- 
- 
- 
 
- 
- 
+100 
±3 
- 
- 
- 
- 
- 
- 
- 
Hematological follow-up 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Baseline data 
(Demographics11, medical 
history, MS disease history) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PRO questionnaires12  
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
9-HPT13, T25FW, BICAMS 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
Physical Examination14 
X 
 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chest X-ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eccocardiography 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Spirometry with DLCO 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Oral/dental status15 
 
 
X 
 
 
 
 
 
 
 
 
 
 

  
 
  
 
Study: RAM-MS  
CLINICAL STUDY PROTOCOL 
20-Dec-2017 
RAM-MS Version no. 4.1, 08-Dec-2017 
Page 9 of 96 
Arm A – HSCT 
Screen. Rand.1 
Pre-
transplantation 
evaluation, 
fertility measures 
Treatment Period 
(Mobilization/harvesting, 
conditioning/ HSCT) 
Follow-up period 
Follow-up extension 
period3 
Unscheduled 
Visit/ Relapse 
Visit 
HSCT 
Day 
+100 
6M 
12M 
18M 
(EOS2) 
24M 
(EOS2) 
30M, 
42M, 
54M 
36M, 48M, 
60M/EOXS2 
- 
Visits 
V1 
V2 
V34 
 
V4.1 
V4.2 
V5 
V6 
V7 
V8 
V9 
V10, 
V12, 
V14 
V11, V13, V15 
- 
Study Week 
-12 to 
-9 
-11 to 
-7 
-10 to -4 
-6 to -4 
0 
3 to 6 
- 
24 
48 
72 
96 
120, 
168, 
216 
144, 192,  240 
- 
Days from treatment start 
-84 to 
-63 
-77 to 
-49 
-70 to -28 
0 
+21 to +42 
- 
+168 
±7 
+336 
±7 
+504 
±7 
+672 
±7 
+X±7 
+X±7 
- 
Days after stem cell 
reinfusion 
- 
- 
- 
 
- 
- 
+100 
±3 
- 
- 
- 
- 
- 
- 
- 
Karnofsky16 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Neurology examination 
(including EDSS) 17 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 MRI18 
 
 
 
X 18 
 
 
X 
X 
 
X 
 
X18 
X 
MS relapse19 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety laboratory (blood, 
urine) 20,21 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood 
Thyroid status 
X22 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Blood 
Serology 23 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
Pregnancy test 24 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
 
  
 
Study: RAM-MS  
CLINICAL STUDY PROTOCOL 
20-Dec-2017 
RAM-MS Version no. 4.1, 08-Dec-2017 
Page 10 of 96 
Arm A – HSCT 
Screen. Rand.1 
Pre-
transplantation 
evaluation, 
fertility measures 
Treatment Period 
(Mobilization/harvesting, 
conditioning/ HSCT) 
Follow-up period 
Follow-up extension 
period3 
Unscheduled 
Visit/ Relapse 
Visit 
HSCT 
Day 
+100 
6M 
12M 
18M 
(EOS2) 
24M 
(EOS2) 
30M, 
42M, 
54M 
36M, 48M, 
60M/EOXS2 
- 
Visits 
V1 
V2 
V34 
 
V4.1 
V4.2 
V5 
V6 
V7 
V8 
V9 
V10, 
V12, 
V14 
V11, V13, V15 
- 
Study Week 
-12 to 
-9 
-11 to 
-7 
-10 to -4 
-6 to -4 
0 
3 to 6 
- 
24 
48 
72 
96 
120, 
168, 
216 
144, 192,  240 
- 
Days from treatment start 
-84 to 
-63 
-77 to 
-49 
-70 to -28 
0 
+21 to +42 
- 
+168 
±7 
+336 
±7 
+504 
±7 
+672 
±7 
+X±7 
+X±7 
- 
Days after stem cell 
reinfusion 
- 
- 
- 
 
- 
- 
+100 
±3 
- 
- 
- 
- 
- 
- 
- 
Sampling for biobank and 
research: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood26,30 
X32 
 
X32 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum26 
X32 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Plasma26  
X32 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
DNA (optional)25,26,29 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Fertility related hormone 
status(optional) 25,27,31 
X 
 
 
 
 
 
X 
X 
X 
X 
 
X 
 
Stool (optional) 25,26,28,31 
 
 
 
X 
 
 
 
 
 
X 
 
X28 
 
Cerebrospinal fluid 
(optional)25,26,28  
 
 
 
X 
 
X 
 
X 
 
X 
 
X28 
 
Transvaginal ultrasound of 
ovaries (optional)25,31,32 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
Sperm sampling 
(optional)25,31,32 
 
 
X 
 
 
 
X 
X 
 
X 
 
 
 
Stem cell product32 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Adverse event 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

  
 
  
 
Study: RAM-MS  
CLINICAL STUDY PROTOCOL 
20-Dec-2017 
RAM-MS Version no. 4.1, 08-Dec-2017 
Page 11 of 96 
Arm A – HSCT 
Screen. Rand.1 
Pre-
transplantation 
evaluation, 
fertility measures 
Treatment Period 
(Mobilization/harvesting, 
conditioning/ HSCT) 
Follow-up period 
Follow-up extension 
period3 
Unscheduled 
Visit/ Relapse 
Visit 
HSCT 
Day 
+100 
6M 
12M 
18M 
(EOS2) 
24M 
(EOS2) 
30M, 
42M, 
54M 
36M, 48M, 
60M/EOXS2 
- 
Visits 
V1 
V2 
V34 
 
V4.1 
V4.2 
V5 
V6 
V7 
V8 
V9 
V10, 
V12, 
V14 
V11, V13, V15 
- 
Study Week 
-12 to 
-9 
-11 to 
-7 
-10 to -4 
-6 to -4 
0 
3 to 6 
- 
24 
48 
72 
96 
120, 
168, 
216 
144, 192,  240 
- 
Days from treatment start 
-84 to 
-63 
-77 to 
-49 
-70 to -28 
0 
+21 to +42 
- 
+168 
±7 
+336 
±7 
+504 
±7 
+672 
±7 
+X±7 
+X±7 
- 
Days after stem cell 
reinfusion 
- 
- 
- 
 
- 
- 
+100 
±3 
- 
- 
- 
- 
- 
- 
- 
Concomitant medication 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Compliance/drug 
accountability 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
1. 
Randomization visit can be performed as a phone visit by study investigator or delegated study personnell to inform the patient about what treatment group he/she is randomized to, 
and to confirm no relevant changes in patient status since the screening visit. 
2. 
End of study visit (EOS) for patients who prematurely discontinues,  preferably all, but as a minimum the following procedures should be performed; hematology, clinical chemistry, 
liver function parameters, pregnancy test. 
3. 
Depending on future funding of the study extension. 
4. 
Time point for Visit 3 in the HSCT arm will be -10 to -4 weeks before Visit 4.1 depending on fertility conserving measures performed before treatment or not. 
5. 
Visit 1 should be performed within 30 days of signing the informed consent form.   
6. 
Initiate wash out of immunomodulatory treatments according to Table 5.1 in section 5.1.  
7. 
In-depth interview of the patient to collect any additional information to medical history relevant for HSCT, to evaluate the patient’s ability to endure the HSCT with regards to both 
physical and mental health. In addition to blood sampling, this includes lung functions test (spirometry incl. DLCO), echo cardiography, dental examination. Refer to section 6.1.3 for 
details, and Appendix A for an overview of the plan/logistics.  
8. 
For men and female patients who have accepted to receive fertility conserving measures. Procedures according to national guidelines: For male patients – collection of sperm for 
storage av Visit 3 only. For female patients - start of hormone therapy for fertility conserving measures and return to clinic for collection of additional samples day 2-5 in menstruation 
cycle. Harvesting for storage 2-4 weeks later. 
9. 
Harvesting of stem cells takes place10 days after the mobilization.  
10. Start of conditioning = ”study week 0” and “study day 0”. The reinfusion will take place 1 week later and is considered as “HSCT Day 0”. 
11. Demographics to be collected in this study are gender, year of birth, race and ethnicity. 

  
 
  
 
Study: RAM-MS  
CLINICAL STUDY PROTOCOL 
20-Dec-2017 
RAM-MS Version no. 4.1, 08-Dec-2017 
Page 12 of 96 
12. PROs include EQ-5D-5L, FSS and MSIS–29. Additional questionnaires regarding health conditions, work and social status will only be completed by Norwegian patients.  
13. To eliminate training effect, the tests should at Visit 4.1 be performed three times in a row. All recordings must be documented in the source documents, and results from the last 
recording is to be entered in the eCRF. 
14. Full clinical examination by physician including; skin (colour, rash, lesions, oedema), lymph nodes, blood pressures, heart rate, body temperature, body height/weight, oral inspection, 
lung/heart/abdominal examination, peripheral pulse.  
15. Dental/oral investigation by dentist/oral or maxillofacial surgeon to identify, prevent or  eradicate potenicially infectious foci before the HSCT-associated neutropenic phase 
16. Karnofsky performance status score must be entered in source documents and uploaded in the EBMT registry.   
17. EDSS should be performed by the same person throughout the study, trained/certified in EDSS scoring.  
18. Visit 4.1 MRI should be performed preferably 1-2 days before start of treatment, using the same MRI-machine and administered preferably by the same person per patient during the 
course of the study. The study specific MRI-protocol is available in the ISF and must be followed. During an extended follow-up periode, MRI will be performed only in week 240.  
19. If MS relapse is suspected an unscheduled visits must be performed as soon as possible and preferably within 7 days of onset of symptoms.  
20. Hematology; HgB, WBC with differentials, thrombocytes. Liver parameters; ALAT, ASAT, ALP, GT and bilirubin. Clinical chemistry; CRP, creatinine, sodium, potassium, calcium, 
magnesium, albumin. During Hospital Stay III (conditioning, reinfusion and isolation periode) daily blood sampling for routine clinical monitoring is required (ref. section 6.1.4) 
21. Urine strip analysis 
22. s-TSH and s-fT4. If abnormal thyroid status at screening (Visit 1) the patient should be excluded from study participation. 
23. Serology at screening visit; Quantiferone, hepatitis Bs-virus ag, hepatitis Bs-virus ag and ab, hepatitis Bc-virus ag, EBV ab, CMV ab, hepatitis C virus ab (and hepatitis C PCR when 
indicated),  HIV ab, HTVL ab, toxoplasmosis ab, herpes simplex virus IgM/IgG, varicella zoster virus IgM/IgG. EBV and CMV should be checked weekly from HSCT Day 0 until HSCT 
Day +100.  
24. For female patients of childbearing potential, monthly serum human chorionic gonadotropin (hCG) pregnancy test from start of conditioning until 12 months after last dose of 
cyclophosphamide.    
25. Optional. Separate informed consent must be signed.  
26. Samples will be collected for long term storage in Biobank Haukeland, HUS.  
27. Required for both male and female patients in both study arms. Fertility related hormones for female patients includes; LH, FSH, AMH, SHBG and E2 estradiol, and for male patients; 
LH, FSH, SHBG and testosterone. 
28. Only to be drawn at 5 year visit during study extension period. 
29. DNA biobankning requires only one blood sample to be taken, preferably at Visit 4.1. However, collection at later visits is permitted as long as the informed consent for biobanking 
remains valid. 
30. Whole blood for collection of cells for PBMC and for fixed cells from whole blood (and the stem cell product from patients treated at HUS). PBMC will be done at selected sites only. 
Fixed whole blood should be collected at all sites and shipped to Sponsor for storage in the biobank. Details are specified in the Laboratory protocol. 
31. Applicable only for sites in Norway. 
32. Applicable only for Haukeland University Hospital. 
 
 
 

  
 
  
 
Study: RAM-MS  
CLINICAL STUDY PROTOCOL 
20-Dec-2017 
RAM-MS Version no. 4.1, 08-Dec-2017 
Page 13 of 96 
FLOW CHART - B 
 
Arm B - 
Alemtuzumab 
Screen. 
Rand.1 
Pre-transpl. 
evaluation, 
fertility 
measures 
Treatment Period 
Follow-up period 
Follow-up extension 
period3 
Unscheduled 
Visit/ Relapse 
Visit 
Treatment 
course 1, 
0M 
- 
4M 
6M 
Treatment 
course 2, 
12M 
18M 
24M/ 
EOS2 
30M, 42M, 
54M 
36M , 48M, 
60M/EOXS2 
 
Visits 
V1 
V2 
V3 
V4.1 
V4.2 
V5 
V6 
V7 
V8 
V9 
V10, V12, 
V14 
V11, V13, 
V15 
 
Study Week 
-3 to -1 
-2 to 0 
- 
0 
- 
- 
24 
48 
72 
96 
120, 168, 
216 
144, 192,  
240 
 
Days from treatment start 
-21 to -7 
-14 to -1 
- 
0 
- 
+121 ±7 
+168 ±7 
+336 ±7 
+504 ±7 
+672 ±7 
+X ±7 
+X ±7 
 
Informed consent4 
X 
 
- 
 
- 
 
 
 
 
 
 
 
 
Wash out 
immunomodulatory 
treatment5 
 
X 
- 
 
- 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
evaluation 
X 
X 
- 
 
- 
 
 
 
 
 
 
 
 
Randomization 
 
X 
- 
 
- 
 
 
 
 
 
 
 
 
Baseline data 
(Demographics6, medical 
history, MS disease 
history) 
X 
 
- 
 
- 
 
 
 
 
 
 
 
 
PRO questionnaires7 
 
 
- 
X 
- 
 
 
 
 
X 
 
X 
 
9-HPT8, T25FW, 
BICAMS 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
Physical Examination9 
X 
 
- 
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
Neurology examination10 
(including EDSS) 
X 
 
- 
X 
- 
 
X 
X 
X 
X 
X 
X 
X 

  
 
  
 
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Page 14 of 96 
 
Arm B - 
Alemtuzumab 
Screen. 
Rand.1 
Pre-transpl. 
evaluation, 
fertility 
measures 
Treatment Period 
Follow-up period 
Follow-up extension 
period3 
Unscheduled 
Visit/ Relapse 
Visit 
Treatment 
course 1, 
0M 
- 
4M 
6M 
Treatment 
course 2, 
12M 
18M 
24M/ 
EOS2 
30M, 42M, 
54M 
36M , 48M, 
60M/EOXS2 
 
Visits 
V1 
V2 
V3 
V4.1 
V4.2 
V5 
V6 
V7 
V8 
V9 
V10, V12, 
V14 
V11, V13, 
V15 
 
Study Week 
-3 to -1 
-2 to 0 
- 
0 
- 
- 
24 
48 
72 
96 
120, 168, 
216 
144, 192,  
240 
 
Days from treatment start 
-21 to -7 
-14 to -1 
- 
0 
- 
+121 ±7 
+168 ±7 
+336 ±7 
+504 ±7 
+672 ±7 
+X ±7 
+X ±7 
 
Chest X-ray  
X 
 
- 
 
- 
 
 
 
 
 
 
 
 
 MRI 11 
 
 
- 
X 9 
- 
 
X 
X 
 
X 
 
X 
X 
MS relapse12 
 
 
- 
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event 
X 
X 
- 
X 
- 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
 
X 
- 
X 
- 
 
X 
X 
X 
X 
 
X 
X 
Safety laboratory  
(blood, urine)12,13 
X 
 
- 
X 
- 
X 
X 
X 
X 
X 
X 
X 
X 
Blood 
Thyroid status14 
X14 
 
- 
X 
- 
X 
X 
X 
 
X 
 
X 
X 
Blood 
Serology15 
X 
 
- 
 
- 
 
 
 
 
 
 
 
 
Pregnancy test16 
X 
 
- 
X 
- 
X 
X 
X 
 
 
 
 
 
Sampling for biobank and 
research 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood17 
X25 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 

  
 
  
 
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RAM-MS Version no. 4.1, 08-Dec-2017 
Page 15 of 96 
 
Arm B - 
Alemtuzumab 
Screen. 
Rand.1 
Pre-transpl. 
evaluation, 
fertility 
measures 
Treatment Period 
Follow-up period 
Follow-up extension 
period3 
Unscheduled 
Visit/ Relapse 
Visit 
Treatment 
course 1, 
0M 
- 
4M 
6M 
Treatment 
course 2, 
12M 
18M 
24M/ 
EOS2 
30M, 42M, 
54M 
36M , 48M, 
60M/EOXS2 
 
Visits 
V1 
V2 
V3 
V4.1 
V4.2 
V5 
V6 
V7 
V8 
V9 
V10, V12, 
V14 
V11, V13, 
V15 
 
Study Week 
-3 to -1 
-2 to 0 
- 
0 
- 
- 
24 
48 
72 
96 
120, 168, 
216 
144, 192,  
240 
 
Days from treatment start 
-21 to -7 
-14 to -1 
- 
0 
- 
+121 ±7 
+168 ±7 
+336 ±7 
+504 ±7 
+672 ±7 
+X ±7 
+X ±7 
 
Serum 
X25 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Plasma 
X25 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
DNA (optional)18,19,21 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Fertility related hormone 
status (optional)18,20,24 
X 
 
- 
 
- 
 
X 
X 
X 
X 
 
X 
 
Stool (optional)18,21 
 
 
 
X 
- 
 
 
 
 
X 
 
X 
 
Cerebrospinal fluid  
(optional)18,21,22 
  
 
- 
X 
- 
X 
 
X 
 
X 
 
X 21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Compliance/drug 
accountability 
 
 
 
X 
- 
 
 
X 
 
 
 
 
 
Alemtuzumab 
administration 23 
 
 
- 
X 
- 
 
 
X 
 
 
 
 
 
1. 
Can be performed as a phone visit by neurologist to inform the patient about what treatment group he/she is randomized to, and to confirm no relevant changes in patient status 
since the screening visit. 
2. 
End of study visit (EOS) – for patients who prematurely discontinues, preferably all, but as a minimum the following procedures should be performed; hematology, clinical chemistry, 
liver function parameters, pregnancy test. 

  
 
  
 
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Page 16 of 96 
3. 
Depending on future funding of the study extension. 
4. 
Visit 1 should be performed within 30 days of signing the informed consent form.   
5. 
Initiate wash out of immunomodulatory treatments according to Table 5.1 in section 5.1.  
6. 
Demographics to be collected in this study are gender, year of birth, race and ethnicity. 
7. 
PROs include EQ-5D-5L, FSS and MSIS–29. Additional questionnaires regarding health conditions, work and social status will only be completed by norwegian patients. 
8. 
To eliminate training effect, 9-HPT should at Visit 1 be performed three times in a row. All recordings must be documented in the source documents, and results from the last 
recording is to be entered in the eCRF. 
9. 
Full clinical examination by physician including; skin (colour, rash, lesions, oedema), lymph nodes, blood pressures, heart rate, body temperature, body height/weight, oral 
inspection, lung/heart/abdominal examination, peripheral pulse.  
10. EDSS must be performed by the same person throughout the study, trained/certified within the trial. 
11. Visit 4.1 MRI should be performed preferably 1-2 days before start of treatment, using the same machine and administered by the same person per patient during the course of the 
study. The study specific MRI-protocol is available in the ISF and must be followed. During an extended follow-up periode, MRI will be performed only in week 240. 
12. If MS relapse is suspected an unscheduled visits must be performed as soon as possible and preferably within 7 days of onset of symptoms. 
13. Hematology; HgB, WBC with differentials, thrombocytes. Liver parameters; ALAT, ASAT, ALP, GT and bilirubin. Clinical chemistry; CRP, creatinine, sodium, potassium, calcium, 
magnesium, albumin. Urine strip analysis. 
14. s-TSH and s-fT4. If abnormal thyroid status at screening (visit 1) the patient should be excluded from study participation. 
15. Serology; Quantiferone, hepatitis Bs-virus ag, hepatitis Bs-virus ab, hepatitis Bc-virus Ig, hepatitis C virus ab (and hepatitis C PCR when indicated),  HIV ag/ab, HTV types 1 and 2 
ag/ab, toxoplasmosis IgM/IgG, herpes simplex virus IgM/IgG, varicella zoster virus IgM/IgG 
16. For female patients of childbearing potential, serum human chorionic gonadotropin (hCG) pregnancy test monthly until 4 months after last administration of alemtuzumab. 
17. Blood sampling for collection of cells for PBMC and for fixed whole blood. PBMC will be done at selected sites only. Fixed whole blood should be collected at all sites and shipped to 
Sponsor for storage in the biobank. Details are specified in the Laboratory protocol. 
18. Optional. Separate informed consent must be signed.  
19. DNA biobankning requires only one blood sample to be taken, preferably at Visit 4.1. However, collection at later visits is permitted as long as the informed consent for biobanking 
remains valid. 
20. Fertility related hormones includes for female patients; LH, FSH, AMH, SHBG and E2 estradiol, and for male patients; LH, FSH, SHBG and testosterone.  
21. Sample will be collected for long term storage in the Biobank Haukeland, HUS. 
22. CSF only to be drawn at 5 year visit during study extension period. 
23. Administration according to current guidelines: at Visit 4.1 (Treatment day “0”) a 5 day cure, at Visit 7 (1 year) a 3 day cure. 
24. Applicable only for sites in Norway. 
25. Applicable only for Haukeland University Hospital. 
 
 

  
 
  
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Page 17 of 96 
TABLE OF CONTENTS 
SIGNATURE PAGE ............................................................................................................................................................ 2 
PROTOCOL SYNOPSIS ..................................................................................................................................................... 3 
FLOW CHART - A ............................................................................................................................................................... 7 
FLOW CHART - B ............................................................................................................................................................. 13 
TABLE OF CONTENTS .................................................................................................................................................... 17 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .......................................................................................... 22 
1 
INTRODUCTION....................................................................................................................................................... 25 
1.1 
Background – Multiple sclerosis (MS) ................................................................................................................. 25 
1.2 
Background - Therapeutic Information ................................................................................................................ 25 
1.3 
Clinical Experience with autologous hematopoietic stem cell transplantation (HSCT) ....................................... 25 
1.3.1 
Treatment effect of autologous HSCT in MS ................................................................................................ 25 
1.3.2 
Side effects of autologous HSCT .................................................................................................................. 26 
1.3.3 
Autologous HSCT: Mechanisms of action .................................................................................................... 26 
1.3.4 
Autologous HSCT: Markers of treatment response ...................................................................................... 27 
1.4 
Rationale and purpose for the study ................................................................................................................... 27 
1.5 
Benefit-risk assessment ...................................................................................................................................... 28 
2 
STUDY OBJECTIVES AND RELATED ENDPOINTS .............................................................................................. 28 
2.1 
Study objective.................................................................................................................................................... 28 
2.2 
Primary endpoint ................................................................................................................................................. 29 
2.3 
Secondary endpoints .......................................................................................................................................... 29 
2.4 
Exploratory endpoints ......................................................................................................................................... 30 
2.5 
Safety endpoints ................................................................................................................................................. 30 
3 
OVERALL STUDY DESIGN ..................................................................................................................................... 31 
3.1 
Overall study design and plan ............................................................................................................................. 31 
3.2 
Administrative structure of the study ................................................................................................................... 32 
4 
STUDY POPULATION ............................................................................................................................................. 33 
4.1 
Selection of study population .............................................................................................................................. 33 
4.2 
Inclusion criteria .................................................................................................................................................. 34 
4.3 
Exclusion criteria ................................................................................................................................................. 35 
4.4 
Removal of patients from therapy or assessments ............................................................................................. 36 
4.4.1 
Removal of individual patients ...................................................................................................................... 36 
4.4.2 
Trial Discontinuation ..................................................................................................................................... 37 
5 
TREATMENTS ......................................................................................................................................................... 38 
5.1 
Wash-out of immunomodulatory treatment(s) ..................................................................................................... 38 

  
 
  
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5.2 
Dosage and drug administration (study treatments and supportive care) ........................................................... 39 
5.2.1 
Selection of doses ........................................................................................................................................ 39 
5.2.2 
STUDY ARM A (HSCT): ............................................................................................................................... 39 
5.2.3 
STUDY ARM B (alemtuzumab): ................................................................................................................... 41 
5.3 
Duration of therapy ............................................................................................................................................. 42 
5.4 
Premedication and monitoring ............................................................................................................................ 42 
5.5 
Concomitant medication, restrictions and rescue therapy .................................................................................. 42 
5.5.1 
Restricted therapy ......................................................................................................................................... 42 
5.5.2 
Rescue medication, emergency procedures and additional treatments ....................................................... 42 
5.6 
Drug compliance and accountability ................................................................................................................... 43 
5.7 
Drug labeling, storage and supply ...................................................................................................................... 43 
5.8 
Subject numbering and assignment to treatment groups .................................................................................... 43 
5.9 
Fertility related procedures ................................................................................................................................. 43 
6 
STUDY PROCEDURES ............................................................................................................................................ 44 
6.1 
Details of trial procedures by visits...................................................................................................................... 44 
6.1.1 
Screening...................................................................................................................................................... 44 
6.1.2 
Randomization visit ....................................................................................................................................... 44 
6.1.3 
Pre-transplantation evaluation ...................................................................................................................... 44 
6.1.4 
Treatment and follow-up period .................................................................................................................... 45 
6.1.5 
Unscheduled visits ........................................................................................................................................ 47 
6.1.6 
Withdrawal and early study discontinuation .................................................................................................. 47 
6.1.7 
End of study period ....................................................................................................................................... 48 
6.1.8 
Switch to other therapy ................................................................................................................................. 48 
6.2 
Procedures for discontinuation ........................................................................................................................... 48 
6.3 
Laboratory tests .................................................................................................................................................. 48 
7 
ASSESSMENTS ....................................................................................................................................................... 49 
7.1 
Assessment of efficacy ....................................................................................................................................... 49 
In order to confirm NEDA or evidence of new disease activity events during the study treatment and 
observation periods, the following clinical and radiological parameters and examinations should be performed 
at scheduled and unschedules study visits): .................................................................................................................. 49 
7.1.1 
Lesions and atrophy ..................................................................................................................................... 49 
7.1.2 
Clinical MS relapse ....................................................................................................................................... 49 
7.1.3 
Expanded Disability  Status Scale (EDSS) ................................................................................................... 49 
7.1.4 
For individual patients EDSS scores should preferably be assessed by the same neurologist  (PI or 
co-PI) throughout the study. EDSS certification is compulsory for all study personnel performing EDSS 

  
 
  
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scorings at defined study visits, and  copies of relevant certificates should be placed in the ISF.Patient 
reported outcomes (PROs) ......................................................................................................................................... 49 
7.1.5 
9-Hole Peg Test  and Timed 25-foot walk..................................................................................................... 50 
7.1.6 
The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) ........................................... 50 
7.2 
Assessment of safety and tolerability .................................................................................................................. 50 
7.2.1 
Physical examination .................................................................................................................................... 51 
7.2.2 
Vital signs ..................................................................................................................................................... 51 
7.2.3 
Body height and  weight ............................................................................................................................... 51 
7.2.4 
Safety laboratory parameters ....................................................................................................................... 51 
7.2.5 
Serology laboratory parameters ................................................................................................................... 52 
7.2.6 
Chest X-ray ................................................................................................................................................... 52 
7.2.7 
Arm A: Pretransplant tolerability investigations ............................................................................................. 52 
7.2.8 
Karnofsky Performance Status ..................................................................................................................... 52 
7.3 
Research assessments ....................................................................................................................................... 52 
7.3.1 
Biobanking .................................................................................................................................................... 53 
7.3.2 
Methods and timing of sample collections .................................................................................................... 53 
7.3.3 
Cerebrospinal fluid ........................................................................................................................................ 54 
7.3.4 
Fertility measures ......................................................................................................................................... 54 
7.3.5 
Microbiota analysis ....................................................................................................................................... 54 
7.3.6 
Blood cells .................................................................................................................................................... 54 
7.3.7 
Cells from graft samples and blood during apheresis procedure .................................................................. 55 
7.3.8 
Analyses of plasma for virus activation of IgG response .............................................................................. 55 
7.3.9 
MRI ............................................................................................................................................................... 55 
7.3.10 Proteomics .................................................................................................................................................... 55 
8 
SAFETY MONITORING AND REPORTING............................................................................................................. 55 
8.1 
Definitions ........................................................................................................................................................... 56 
8.1.1 
Adverse Event (AE) ...................................................................................................................................... 56 
8.1.2 
Serious Adverse Event (SAE) ....................................................................................................................... 56 
8.1.3 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ...................................................................... 56 
8.2 
Expected adverse events .................................................................................................................................... 57 
8.3 
Time Period for Reporting AE and SAE .............................................................................................................. 57 
8.4 
Recording of adverse events .............................................................................................................................. 57 
8.5 
Reporting procedures ......................................................................................................................................... 58 
8.5.1 
AEs and SAEs .............................................................................................................................................. 58 
8.5.2 
SUSARs ....................................................................................................................................................... 58 
8.5.3 
Exemptions to SAE reporting ........................................................................................................................ 58 

  
 
  
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8.5.4 
Annual safety report ...................................................................................................................................... 59 
8.5.5 
Clinical study report ...................................................................................................................................... 59 
8.6 
Procedures in case of emergency ...................................................................................................................... 59 
9 
DATA MANAGEMENT AND MONITORING ............................................................................................................ 59 
9.1 
Case report forms ............................................................................................................................................... 59 
9.2 
Source data......................................................................................................................................................... 59 
9.3 
Study monitoring ................................................................................................................................................. 60 
9.4 
Confidentiality ..................................................................................................................................................... 61 
9.5 
Database management ....................................................................................................................................... 61 
10 STATISTICAL METHODS AND DATA ANALYSIS ................................................................................................. 62 
10.1 Determination of sample size .............................................................................................................................. 62 
10.2 Randomization .................................................................................................................................................... 62 
10.2.1 Allocation- sequence generation .................................................................................................................. 62 
10.2.2 Allocation- procedure to randomize a patient ............................................................................................... 62 
10.3 Population for analysis ........................................................................................................................................ 63 
10.4 Planned analyses................................................................................................................................................ 63 
10.5 Statistical analysis ............................................................................................................................................... 63 
10.5.1 Primary analysis ........................................................................................................................................... 63 
10.5.2 Secondary analyses ..................................................................................................................................... 64 
10.5.3 Safety analyses ............................................................................................................................................ 66 
10.5.4 Exploratory analyses .................................................................................................................................... 66 
10.5.5 Other analyses (eg health economics, patient reported outcomes etc) ........................................................ 67 
10.5.6 Descriptive statistics ..................................................................................................................................... 67 
11 STUDY MANAGEMENT ........................................................................................................................................... 67 
11.1 Investigator-delegation procedure ...................................................................................................................... 67 
11.2 Protocol adherence ............................................................................................................................................. 67 
11.3 Study amendments ............................................................................................................................................. 67 
11.4 Audits and inspections ........................................................................................................................................ 67 
12 ETHICAL AND REGULATORY REQUIREMENTS .................................................................................................. 68 
12.1 Ethics committee approval .................................................................................................................................. 68 
12.2 Other regulatory approvals ................................................................................................................................. 68 
12.3 Informed consent procedure ............................................................................................................................... 68 
12.4 Subject identification ........................................................................................................................................... 68 
13 TRIAL SPONSORSHIP AND FINANCING............................................................................................................... 69 
14 TRIAL INSURANCE ................................................................................................................................................. 69 
15 PUBLICATION POLICY ........................................................................................................................................... 69 

  
 
  
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16 REFERENCES ......................................................................................................................................................... 69 
17 LIST OF APPENDICES ............................................................................................................................................ 72 
18 DESCRIPTION OF GLOBAL AMENDMENT(S) ...................................................................................................... 91 
 

  
 
  
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or special term 
Explanation 
9-HPT 
Nine Hole Peg Test 
ACTH 
Adrenocorticotropic hormone 
AE 
Adverse Event  
ALAT 
Alanine transaminase 
ALP 
Alkaline phosphatase 
ARR 
Annualized rate of protocol-defined relapses  
ASAT 
Aspartate transaminase 
ASCO 
American Society of Clinical Oncology 
ATG 
Anti-thymocyte globulin 
BEAM 
Chemotherapy regimen consisting of carmustine, cytarabine, etoposide 
and melphalan. 
BICAMS 
The Brief International Cognitive Assessment for Multiple Sclerosis 
BMI 
Body mass index 
BP 
Blood pressure 
CMSC 
Consortium of Multiple Sclerosis Centers 
CNS 
Central Nervous System 
CDI 
Confirmed Disability Improvement 
CDP 
Confirmed Disability Progression 
CI 
Coordinating Investigator 
CMV 
Cytomegalovirus 
CRP 
C-reactive protein 
CSA 
Clinical Study Agreement 
CSF 
Cerebrospinal fluid 
DAE 
Discontinuation due to Adverse Event 
DLCO 
Diffusing capacity of the lungs for carbon monoxide 
DSMB 
Data Safety Monitoring Board  
EBMT 
The European Society for Blood and Marrow Transplantation 
EBV 
Epstein-Barr virus 
EC 
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
eCRF 
Electronic Case Report Form 
EDSS 
Expanded Disability  Status Scale 
ELISA 
Enzyme-linked immunosorbent assay 

  
 
  
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EMA 
European Medicines Agency 
EOS 
End of study 
EOSX 
End of study extension 
EQ-5D-5L 
EuroQoL 5 dimensions, 5 levels 
FEV 
Forced expiratory volume 
FVC 
Forced Vital Capacity 
FSS 
Fatigue Severity Scale 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
Gd 
Gadolinium 
hCG 
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
HPV 
Human papillomavirus 
HSCT 
Hematopoietic stem cell transplantation 
HSV 
Herpes simplex virus 
HTLV 
Human T-lymphotropic virus type 1 and 2 
HUS 
Haukeland University Hospital 
IB 
Investigator’s  Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product (includes active comparator) 
ISF 
Investigator Site File 
ITT 
Intention To Treat 
iv 
Intra-venous 
LVEF 
Left ventricular Ejection Fraction 
MR 
Magneitc resonance 
MRI 
Magnetic resonance imaging 
MS 
Multiple Sclerosis 
MSFC 
Multiple sclerosis functional composite  
MSIS 
Multiple Sclerosis Impact Scale - 29  
NEDA 
No evidence of disease activity 
NorCRIN 
Norwegian Clinical Research Infrastructures Network 
NYHA 
New York Heart Association functional class 
PBMC 
Peripheral blood mononuclear cell 
PCR 
Polymerase chain reaction 

  
 
  
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PIS 
Patient Information Sheet 
PG 
Project Group 
PO 
Per oral 
PRO 
Patient reported outcomes 
PPV 
Positive predictive value 
RRMS 
Relapsing remitting multiple sclerosis 
SAE 
Serious Adverse Event   
SC 
Steering Committee 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SPMS 
Secondary progressive multiple sclerosis 
T1 
Spin-lattice relaxation time 
T2  
Spin-spin relaxation time 
T25-FW 
Timed-25-Foot Walk 
TCR 
T-cell receptor 
TMF 
Trial Master File 
TRM 
Treatment related mortality 
TSH 
Thyroid stimulating hormone 
VZV 
Variicella zoster virus 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
 

  
 
  
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1 
INTRODUCTION 
1.1 
Background – Multiple sclerosis (MS)   
MS is a chronic inflammatory disease of the brain and spinal cord. It is most frequently diagnosed at 20-40 years 
of age. In Scandinavia, the prevalence of MS is approximately 200/100 0006.  There is no curative treatment. At 
disease onset, the majority of MS-patients (85 %) have a relapsing remitting disease course (RRMS) with 
exacerbations followed by complete or partial clinical recoveries.  
Relapsing-remitting MS is treated with immunomodulatory medications to prevent relapses and to delay disability 
development. Immunomodulatory treatment reduces the annually MS relapse rate in RRMS 20-70 %, and recent 
studies indicate a slower progression of disability compared to studies prior to the era of immunomodulatory MS-
treatment7, 8. A major proportion of RRMS patients experience disease activity despite the use of registered 
immunomodulatory MS-treatment, and these patients have significant risk of developing severe disability at a 
young age9, 10. Accordingly, there is a need for improved immunomodulatory treatment options that rapidly and 
consistently prevent CNS inflammation, MS-relapses and progression of clinical disabilities.  
1.2 
Background - Therapeutic Information 
Every occurrence of inflammatory MS-disease activity has long-term clinical consequences 11, 12. Pre-relapse 
function is not regained in more than 30% of MS-relapses13. The number/volume of MS-lesions is correlated to 
long-term disability and to reaching the chronic progressive disease stage11. An emerging endpoint is thus the 
proportion of patients achieving “no evidence of disease activity” (NEDA). NEDA has been defined as no new T2 
lesions or T1 gadolinium (Gd) enhancing lesions on MRI, no clinical relapses, and no disability progression2, 14. In 
a longitudinal MS cohort the positive predictive value (PPV) of NEDA at 2 years for progression of disability at 7 
years was 78 %14. The PPV of NEDA at 2 years was greater than each individual component. In the placebo 
groups of immunomodulatory RRMS treatment studies approximately 7-16 % of patients have NEDA after 2 
years14. In a cohort study of patients with a disease duration of 5 years or less, only 12% had NEDA after 5 years, 
and 6 % had NEDA at 7 years14  In a meta-analysis of immunomodulatory treatment effects in RRMS, the highest 
ranking immunomodulatory drug for reduction of annualized relapse rate and 3 month confirmed disability 
progression was  alemtuzumab15. In a randomized treatment study the proportion of patients treated with 
alemtuzumab with NEDA over 2 years was 32 % 3.  
1.3 
Clinical 
Experience 
with 
autologous 
hematopoietic 
stem 
cell 
transplantation (HSCT)  
1.3.1 
Treatment effect of autologous HSCT in MS    
Data from recently published patient series indicate that autologous hematopoietic stem cell transplantation 
(HSCT) may have a significantly higher treatment effect than standard RRMS immunomodulatory treatment16-18. 
The premise of autologous hematopoietic stem cell transplantation (HSCT) in MS is that the self-reactive immune 
response is eradicated by the conditioning regime, and that the immune system is “reset” after reinfusion of 
autologous hematopoietic stem cells, producing an immune system that is less self-reactive. Early HSCT– studies 
were mainly small patient series or cohort studies on MS patients with predominantly progressive disease and 
advanced disability19. A large percentage of patients in these studies experienced continued disability 
progression, consistent with a significant role of neurodegenerative mechanisms at this late disease stage20. In 
more recent non-randomized treatment studies, a major proportion of the study population are RRMS patients 
with short disease durations and clinically/radiologically highly active inflammatory activity. The study results 
indicate that HSCT may be an effective treatment option in the RRMS patient group17, 18, 21, 22. After HSCT, the 
inflammatory disease process is halted for several years in a majority of MS patients. In a study of 145 MS 

  
 
  
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patients (81 % RRMS, 19 % SPMS) treated with HSCT, using low intensity conditioning based on 
Cyclophosphamide, 80 % of patients had NEDA over 2 years, and 68 % had NEDA over 4 years after 
treatment17. In a patient series of 41 MS patients (34 patients with RRMS) treated with medium or high intensity 
conditioning HSCT in a multicentre study in Sweden, 68 % had NEDA over 5 years18. In an interim analysis of an 
ongoing, multicentre, single-arm clinical trial of HSCT for RRMS patients who experienced treatment failure on 
other immunomodulatory treatment, 24 patients received HSCT. The study participants received medium intensity 
conditioning with carmustine, etoposide, cytarabine, and melphalan (BEAM). 78.4% of the treated patients had 
NEDA at 3 years22. In a recent single-group phase 2 trial at three hospitals in Canada 24 patients (50 % RRMS, 
50 % SPMS) received high intensity myeloablative conditioning with busulfan, cyclophosphamide, and rabbit anti-
thymocyte globulin, followed by autologous HSCT21. 70% of patients had no disease activity (NEDA) at 3 years 
after transplantation. The patients had no MS relapses, new Gd-enhancing lesions or new T2 lesions during a 
median follow-up of 6.7 years. The yearly rate of brain atrophy decreased to a level comparable with healthy 
controls. These results are not directly comparable to data from randomized and controlled studies with 
registered immunomodulatory treatments due to differences in patient populations and study designs. A 
significant proportion of patients in several of the HSCT studies had progressive MS or did not meet the inclusion 
criteria, or the inclusion criteria were significantly different than criteria used in randomized trials of 
immunomodulatory MS treatment. The autologous HSCT-studies were not randomized, and did not include a 
control group. The proportion of patients with NEDA may also vary depending on the clinical and radiological pre– 
and post-treatment follow-up protocols.  
1.3.2 
Side effects of autologous HSCT 
There is a risk for serious side effects of HSCT, mainly due to the toxicity of the conditioning  regimens. The 
HSCTrelated mortality rate reported to The European Society for Blood and Marrow Transplantation (EBMT) from 
1995 to 2000  was 7.3 %, whereas from 2001 to 2007 it was significantly lower; 1.3 %. This change may be due 
to better patient selection and improved investigator experience, but could also be associated with a concomitant  
switch from high intensity conditioning to the use of medium intensity (BEAM) or low intensity, cyclophosphamide-
based conditioning regimens. In the 4 most recently reported MS patient series of non-myeloablative conditioning 
299 patients were treated, and there was no registered treatment related death17, 18, 22, 23. In  a recently reported 
MS patient material treated with a high intensity myeloablative conditioning regimen, consisting of busulfan, 
cyclophosphamide and anti-thymocyte globulin (ATG), one of the 24 patients died of transplantation-related 
complications21. Other frequent serious side effects of HSCT include, neutropenic fever, infectious diseases 
complicated with bacteremia/sepsis, hemorrhagic cystitis, liver toxicity and reactivation of varicella virus Epstein-
Barr virus (EBV) or cytomegalovirus (CMV).. Mucositis and diarrhea were more prevalent in early studies using 
medium and high intensity conditioning regimens.  Following the immediate post transplant period (which per 
definition extends to HSCT day +100), there is an increased risk of secondary autoimmune diseases, including 
thyroid disease and immunological thrombocytopenia (ITP). The incidence rate of autoimmunity has been 
reported to be lower in treatment protocols using ATG than in protocols including alemtuzumab17, and also lower 
than registered when treating with alemtuzumab alone16.   
1.3.3 
Autologous HSCT: Mechanisms of action 
In autoimmune diseases like MS, autologous HSCT is applied to eradicate the autoimmune immunological 
memory and to regenerate a naïve and self-tolerant immune system from hematopoietic precursors24 . However, 
the mechanisms of action of HSCT in MS patients still need to be clarified. The MS-disease process is believed to 
be driven by the adaptive immune system, comprising T cells and B cells. One hypothesis is that HSCT works by 
eradicating autoreactive T cells and B cells, replacing them with a non-autoimmune repertoire. One study using 
high-throughput sequencing of T cell receptor (TCR) beta-chains following HSCT showed that  the CD4+ T cell 
repertoire was replaced to a larger extent than the CD8+ T cell repertoire25. The B cell repertoire has so far not 
been investigated in HSCT. Another study has demonstrated that HSCT promotes anti-inflammatory T cell 
responses17. Distinct cytokine profiles may be associated with high MS activity and flares26. As recommended by 
the EBMT, a wide array of immunological parameters should thus be monitored in prospective HSCT-studies in 
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1.3.4 
Autologous HSCT: Markers of treatment response                                                                                      
 It is known from Systematic follow-up studies demonstrate that in 20-30 % of the patients new disease activity is 
observed 2-5 years after HSCT 17, 18. It is, however, not known why some patients relapse after treatment 
whereas others seem to respond very well. It has been shown that a less diverse post-treatment TCR repertoire 
is associated with a poor response 25. Thus, pre- and post-treatment characterization of the TCR and probably 
also the B cell receptor (BCR) repertoires, and post-treatment monitoring of possible pathogenic T and B cell 
clones may provide important clues to why the treatment fails in a subgroup of MS patients. Finally, it will be of 
interest to investigate whether the oligoclonal B cell response in the cerebrospinal fluid, which is a hallmark of the 
disease, remains after successful treatment with HSCT 28. Detection of other immunological biomarkers and pre- 
and post transplant cytokine levels may also be of value in reflecting treatment responses after HSCT in RRMS 
patients27. 
1.4 
Rationale and purpose for the study 
This study is a randomized multicentre treatment 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 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 
treatments16-18. This study will determine the relative role of HSCT versus alemtuzumab. 
The main hypothesis of the study:  
HSCT is superior to EMA–approved immunomodulatory drugs in preventing further inflammatory disease 
activity and/or development of disability in RRMS patients with recent breakthrough inflammatory 
disease activity.  
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, asimmunomodulatory treatment in MS may reach full effect after 3 months or 
more2.  
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 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 the USA17, 18. 

  
 
  
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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 15.  
 
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.  
1.5 
Benefit-risk assessment 
The risk to subjects in this trial will be minimized by compliance with eligibility criteria, close clinical monitoring, 
avoidance of prohibited treatments and adherence to protocol contraception requirements and Investigator 
guidance regarding specific safety areas. The inclusion of an active comparator arm ensures that all patients in 
the study will receive active therapy. 
 
The overall benefits and safety profile for autologous HSCT has been outlined in section 1.3.  
Data suggest that the treatment related mortality with HSCT can be decreased to 1–2 % in experienced centres 
using HSCT with mainly conditioning of high and medium intensities, and it has been even  lower (≤ 0.3 %) in MS 
patients treated with low intensity conditoning regimens17, 18, 21, 29-31. However, the mortality rate for HSCT has not 
been compared to that of other immunomodulatory MS treatments in a prospective randomized clinical study.  
 
MS is associated with an extensive loss of quality-adjusted life years32, 33 Despite the risk of treatment related 
mortality and serious side effects, the overall longterm benefits associated with HSCTthus support continued 
research on HSCT and treatment of RRMS29, 34.  
 
The comparator alemtuzumab is approved for the treatment of relapsing RRMS. In controlled clinical trials, 
treatment with alemtuzumab was associated with autoimmune thyroid disorders in 30-40 % of patients, serious 
events of idiopathic thrombocytopenic purpura in approximately 1 %, and nephropaties, including anti-glomerular 
basement membrane (anti-GBM) disease in 0.3 %  during a 48-53 months follow-up period  after an initial 
LEMTRADA exposure16. Treatment with alemtuzumab is associated with an increased risk of infections, including 
but not restricted to urinary tract infection, upper respiratory tract infection, sinusitis, oral herpes, influenza, and 
bronchitis. The most common adverse reactions with alemtuzumab (in ≥20% of patients) are rash, headache, 
pyrexia, and respiratory tract infections. The efficacy of alemtuzumab in reducing clinical (ARR and disability 
progression) and MRI disease activity as well as brain volume loss, has been demonstrated in Phase 3 clinical 
trials3, 35. 
Overall, the balance of benefits and risks support  a clinical study to evaluate the potential of HSCT as an 
effective and safe therapy in the target population. 
 
 
2 
STUDY OBJECTIVES AND RELATED ENDPOINTS 
2.1 
Study objective 
The objective of this prospective, randomized study is to investigate the efficacy and safety of HSCT compared to 
alemtuzumab in patients with aggressive relapsing remitting MS.  
In Norway, the clinical study is supplemented with a health economic evaluation.  

  
 
  
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2.2 
Primary endpoint  
The primary efficacy endpoint of this prospective, randomized study is to determine differences between patients 
in the 2 treatment arms according to the following criteria: 
 
Proportion of patients with no evidence of disease activity (NEDA, as defined per protocol) during a 2 
year (96 week) period 
 
Pre-planned study extension: Proportion of patients with NEDA (as defined per protocol) during a 5 year 
(240 week) period. 
NEDA is the absence of a protocol defined disease activity event. 
 
A protocol-defined disease activity event is the occurrence of at least one of the following:                                                                   
- A new T1 Gd-enhanced lesion on MRI of the brain and spinal cord                                                           
- A new T2 hyperintense lesion on MRI of brain and spinal cord                                                                                             
- A protocol-defined MS relapse (see below)                                                                                                               
- 24 week confirmed disability progression based on increases in Expanded Disability Status Scale 
(EDSS) (see below and Appendix C)  
MS relapse is defined as new or worsening neurological symptoms attributable to MS, lasting at least 48 hours, 
without pyrexia, with an objective change on neurological examination after at least 30 days of clinical stability. 
Disability progression is defined as an increase of one point in the EDSS score (or half a point if the baseline 
EDSS score was equal to 5.5), confirmed after 24 weeks, with an absence of relapse at the time of assessment. 
MRI imaging will be performed according to the Revised Consortium of Multiple Sclerosis Centers (CMSC) MRI 
Protocol and Guidelines4                                                                                                 
2.3 
Secondary endpoints 
The secondary efficacy endpoints for this study are to evaluate the efficacy of the study treatments on the basis 
of the following endpoints: 
 Proportion of patients with no evidence of disease activity, including atrophy (NEDA 4), as per protocol 
defined disease activity events (as defined in section 2.2) plus atrophy (measured yearly atrophy 
above threshold of 0, 4 %) during a 2 year (96 week) period5. 
o Pre-planned study extension: Proportion of patients who have NEDA 4 during a 5 year (240 
week) period.  
 Time to first protocol-defined disease activity event as defined in section 2.2  
 Change in EDSS from baseline (Visit 4.1) to Weeks 96 and 240 
 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 
 Annualized rate of protocol-defined relapses during 96 weeks 
 Time to onset of first protocol-defined relapse 
 Change in MRI T2-weighted hyperintense lesion volume from baseline to Weeks 48 and 96 (and 240) 
 Change in MRI T1-weighted hypointense lesion volume from baseline to Weeks 48 and 96 (and 240) 
 Change in brain volume from baseline to week 48 and week 96 (and week 240), and from week 48 to 
week 96 (and week 240)5  

  
 
  
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 Time to detection of a new MRI T2 lesion 
 Total number of MRI T1-weighted Gd-enhanced lesions at weeks 24, 48, 96 (and 240) 
 Proportion of patients free from T1 Gd-enhancing lesions at weeks 24, 48, 96 (and 240) 
 Change in Nine-hole-peg test (9-HPT) score from baseline to week 48, 96 (and 240) 
 Change in Timed 25 foot walk (T25FW) score from baseline to week 48, 96 (and 240) 
 Change in The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) score from  
baseline to week 96 (and 240) 
2.4 
Exploratory endpoints 
 
To further assess the efficacy of the study treatments over the study period, the following outcome data, 
including patient-reported outcomes (PROs) will be obtained at baseline and in week 96 (and 240):  
o 
EQ-5D-5L 
o 
Fatigue Severity Scale (FSS) 
o 
Multiple Sclerosis Impact Scale (MSIS) - 29  
o 
Severity of relapses (residual disability (EDSS) after relapses) 
 
 
To characterise immune repertoires and markers of therapeutic response in blood and in CSF, and in 
accordance with EBMT recommendations regarding immune monitoring after HSCT in autoimmune 
diseases24 and recent findings in MS research,  immunological analyses will include at a minimum;  
o Immunocytometric analyses (subsets of major cellular populations) 
o T cell receptor sequencing  
o B cell receptor sequencing 
o Isoelectric focusing  
o ELISA for levels of neurofilament light chain 
o Proteomic study for potential other biomarkers for therapeutic response 
o Detection of cytokine profiles    
 
 
Overall survival rate at week 96 (and week 240) 
 
Work productivity and activity impairment at week 96 (and 240) 
2.5 
Safety endpoints 
The safety objective for this study is to evaluate the tolerability of the study treatments usingthe following 
endpoints:  
 Rate and nature of adverse events 
 Frequency of serious adverse events 
 Clinical relevant changes in vital signs 
 Clinical relevant changes on physical examinations 
 Clinical relevant changes in clinical laboratory results. 
 Non-MS central nervous system (CNS) pathology 
 Use of concomitant medications, including pre-medications and medications used during the study 
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3 
OVERALL STUDY DESIGN 
3.1 
Overall study design and plan 
This study is a prospective, multicentre, interventional, unblinded, randomized, parallel group study to investigate 
the efficacy and safety of autologous HSCT compared to the current standard of treatment with alemtuzumab, in 
patients with relapsing remitting MS experiencing treatment failure in the preceeding year in spite of ongoing 
immunomodulatory treatment. If a new immunomodulatory MS treatment is registered during the study 
recruitment phase it will be evaluated if the new treatment should be added as comparator. 
The study design is chosen because it is expected to produce results which clarify the relative efficacy of HSCT 
versus the currently considered most efficient standard immunomodulatory drug used for RRMS.  This 
prospective, randomized study will provide data with impact on the possibility of HSCT to be accepted as a 
standard immunomodulatory treatment option for RRMS  19.  
 
The target group of this study is RRMS patients with breakthrough inflammatory disease activity while on other 
immunomodulatory MS treatment. The study will enroll approximately 100 patients. Patients will be assessed for 
primary and secondary efficacy endpoints and safety parameters following study treatments at predefined 
timepoints (scheduled study visits) and supplementing, unscheduled study visits, see section 6.1.5.  
 
 
 
 
 
 
 
 
 
Figure 3.1:1 Study design 
 
Patients are included in the trial once they have signed the informed consent form (ICF). All patients considered 
suitable after screening and meeting the inclusion criteria and none of the exclusion criteria will be randomized to 
one of the treatment arms. The randomization will be unblinded.The patients will be assigned at a ratio of 1:1 to 
either HSCT (arm A) or i the currently most efficient of currently registered immunomodulatory treatment (arm B). 
The patient assignment is stratified by age, sex and residency (country). 
Patient participation is concluded when they have completed the last planned study visit. The end of study is 
defined as “last patient out” (LPO), i.e. last visit completed by last patient after 2 year follow-up period, and for the 
planned study extension after 5 year follow-up period. Enrollment of patients into the study is competitive, 
however, if recruitment on country level exceeds agreed target this must be approved by the Sponsor. 
Randomization of required number of patients into the study is estimated to take 2 years. The estimated study 
    
 
 
 
2-3 weeks 
 
 
 
 
 
 
24 months 
 
 
 
 
+ 36 months 
Screening 
Arm B – Alemtuzumab 
Day “0” Cycle 1: 
5 days treatment 
Day “365”Cycle 2: 
3 days treatment 
Arm A – HSCT 
6-8 weeks 
2 year follow-up 
after Treatment 
day “0“ 
Randomization 
5 year follow-up 
after Treatment 
day “0“ 
Referral for fertility 
preserving measures 
2-4 weeks) 

  
 
  
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duration is expected to be maximum 4 years. If the pre-planned study extension to conduct a 5-years follow-up 
period receives financial funding, the total study duration will be maximum 7 years. 
3.2 
Administrative structure of the study 
This study is initiated by a team of collaborating physicians at the Department og Neurology, the Medical 
Department and the Department of Immunology and Transfusion Medicine at the central study site at Haukeland 
University Hospital (HUS) in Norway in close interaction with national and international PIs, co-PIs and research 
collaborators.  The Sponsor of this study  is Helse Bergen HF, Haukeland University Hospital (HUS), and the 
study will be conducted as a multicentre study in Norway, Sweden, Denmark and possibly other European 
countries.   
 The members of a Project Management Committee (PMC) and a Coordinating Investigator (CI) are assigned by 
the Sponsor.  The PMC has the overall responsibility for the planning, conduct and reporting in the study. Use of 
study data and biological material  for additional scientific substudies will be determined by the PMC.  The CI is 
responsible for coordination  of clinical investigators at defined study sites. . Medical Officers will be assigned and 
provide medical counselling to all participating study sites.  
Approval by Ethics Committees and Health Authorities must be available as applicable.   
An international Reference Group  (RG) consisting of independent experts will be established to provide clinical 
and/or scientific advice for the Sponsor, PMC and CI. The composition, tasks and responisibilities of the RG will 
be documented in the Trial Master File (TMF).  
The organization of the study at participating sites will be done according to agreed  responsibilities and tasks. A 
signed contract must be filed before the initiation of the clinical study. Tasks and functions assigned in order to 
organize, manage and evaluate the study will be defined per Norwegian Clinical Research Infrastructures 
Network (NorCRIN) SOPs. A list of responsible  clinicians (specialists in neurology and hematology comprising 
Principal investigators (PI) and co-PIs) at each study site will be given in the TMF. Any substantial amendments 
to the study protocol will be discussed and clarified with PIs and co-PIs, and with other research collaborators if 
applicable. follow-up GCP-training  conducted within the last 5 years is compulsory for all members of the PMC, 
as well as for all PIs and co-PIs. Neurologists performing EDSS-scorings at study visits also need to document 
recent EDSS certification. The Sponsor can provide formal training and certification in EDSS scoring for all 
relevant study personnel, see section 7.1.3. Curriculum vitae will be obtained from all formal clinical study 
personell as well as assigned research collaborators, and all documentation will be filed in the Investigator Site 
File (ISF).  
Data management will be handled by the Clnical Trial Unit at Oslo University Hospital, Norway, who will provide 
the eCRF and Randomization system. The study will use electronic CRF (eCRF) and randomization from 
ViedocTM, with role based access control, an interactive eCRF with in-data validation and signing, 
monitoring/locking functions, internal reporting of AEs and SAEs with notification to the Medical Officer, Monitor 
and representatives from the PMC as applicable, and data export.  ViedocTM will provide block randomization and 
will be provided with 50% of patients in each treatment group, stratified for age, sex and country.  The SOPs for 
Department for clinical research support will apply for these services.  
The Norwegian Clinical Infrastructures Network (NorCRIN), and NorCRIN’s SOPs will be used for planning and 
execution of study monitoring. 
Statistical evaluations will be performed by statistical expertise at HUS. 
Defined safety laboratory measurements will be analysed at each study site according to local procedures.. 
Reference ranges from local laboratories will be provided to the Data Management for programming into the 
eCRF. The central biobank involved in studyspecific sampling and long-term storage of biological material for 
future research will be Biobank Haukeland located at HUS. Details regarding biobanking are specified in a 
separate document available in the ISF and in section 7.4 of the protocol. 
 

  
 
  
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A Data Safety Monitoring Board (DSMB) independent of the Sponsor will assess the progress of the trial, 
including safety and efficacy assessments at specified intervals. The DSMB will  advice the Sponsor on whether 
to continue, modify, or stop the trial. The tasks and responsibilities of the DSMB will be specified in a separate 
charter filed in the TMF.  
 
A central study radiology reading centre will be appointed by the PMC. 
 
Spinal fluid proteomic analyses will be performed by the Proteomics group at the University of Bergen, 
Department of Biomedicine. Spinal fluid and blood immunological analyses will be performed at research 
laboratories at HUS and Akershus University Hospital. Other collaborating research institutes are Sahlgrenska 
Academy University of Gothenburg,Rigshospitalet Copenhagen, and the VUmc MS Center in Amsterdam. 
The users of this study  are RRMS patients. Representatives from  a national MS patient organization, The 
Norwegian MS Society (MS-Forbundet),have been included in planning this study. Their representatives will also 
be involved in the following tages of the study through representation in the RG, and in informing the MS patient 
population of the study progress,results, and about the implications of study results on the routine medical 
treatment of RRMS patients. This is to ensure that all aspects of the study  are in accordance with the best 
interest of the target group.  
 
 
4 
STUDY POPULATION 
4.1 
Selection of study population 
An appropriate number of RRMS-patients will be screened in Norway, Sweden, Denmark and possibly other 
European countries. . National/regional study sites will be assigned to ensure that approximately 100 patients are 
randomized within the estimated timeframe of 2 years. If enrollment is delayed or the enrollment rate is lower than 
anticipated, additional sites might be assigned by Sponsor. The number of patients included may be increased 
during the study period if study drop out or event rates differ from expected levels. 
Every patient who fulfils the inclusion criteria and does not fulfil any exclusion criteria will be randomized, and 
receive the allocated study treatment. 
Re-testing:  
Re-testing for eligibility criteria is only to be performed once for a laboratory result which is obviously received 
beyond stability or thought to be a spurious result based on earlier laboratory values for a patient. To avoid 
protocol violations, a re-test should be carried out as soon as possible to ensure that the result of the laboratory 
test is received within the next planned visit window. 
Re-screening: 
Re-screening of a patient is only allowed once. If failing, the patient should be declared as a screening failure in 
the eCRF with their originally allocated patient number, and a new patient number will be assigned at the time of 
re-screening. The patient must be re-consented using the currently approved versions of the Patient Information 
Sheet (PIS)  and Informed Consent Form (ICF). 
 
A log of all patients enrolled into the study (i.e. having signed the Informed Consent Form) must be maintained by 
the site staff in the ISF at the investigational site irrespective of whether they have been treated with an 
investigational  drug or not. This log should clearly identify any re-screened patient.  

  
 
  
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4.2 
Inclusion criteria 
All of the following conditions must apply to the prospective patient at screening visit prior to receiving study 
treatment:  
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.   
___________________________ 
* A woman is considered of childbearing potential (WOCBP) if; 
- 
having experienced menarche and 
- 
not postmenopausal (12 months with no menses without an alternative medical cause) and  
- 
not permanently sterilised (e.g., hysterectomy, bilateral oophorectomy or bilateral salpingectomy). 
¥  Highly effective birth control methods are; 
- 
combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) 
associated with inhibition of ovulation 
- 
progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation  
- 
intrauterine device (IUD) 
- 
intrauterine hormone-releasing system ( IUS) 
- 
bilateral tubal occlusion 
- 
vasectomised partner 
- 
sexual abstinence 
 
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. 

  
 
  
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4.3 
Exclusion criteria 
Patients will be excluded from the study if they meet any of the following criteria at screening visit (V1): 
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 CMV, EBV, HSV, VZV, hepatitis virus, toxoplasmosis, HTV, 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, cladribin and alemtuzumab 
6. Treatment with glucocorticoids or ACTH within one month prior to study inclusion 
7. Having experienced an MS relapse within one month prior to study inclusion 
8. Prior or current major depression 
9. 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. 
10. Prior or current alcohol or drug dependencies 
11. Cardiac insufficiency, cardiomyopathy, significant cardiac dysrhytmia, unstable or advanced ischemic 
heart disease (NYHA III or IV) 
12. Significant hypertension: BP > 180/110 
13. Prior history of malignancy except localized basal cell, squamous skin cancer or carcinoma in situ of the 
cervix.  
14. Known thyroid disease, and/or abnormal serum thyroid hormone status  
15. Failure to willingly accept or comprehend risk of irreversible sterility as a side effect of therapy 
16. WBC < 1,5 x 109/L 
17. Platelet (thrombocyte) count < 100 x 109/L  
18. ALAT and/or ASAT more than 2 times the upper normal reference limit (UNL) 
19. Serum creatinine > 200 µmol/L  

  
 
  
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20. Serum bilirubin > 20 µmol/L  
21. Presence of metallic objects implanted in the body that would preclude the ability of the patient to safely 
have MRI exams 
22. Diagnosis of primary progressive MS 
23. Diagnosis of secondary progressive MS 
24. Treatment with natalizumab, fingolimod and dimetylfumurat within the last 2 months (washout must be 
performed as specified in section 5.1) 
25. Use of teriflunomide (Aubagio®) within the previous 2 years unless cleared from the body (plasma 
concentration < 0.02mcg/ml following elimination from the body with cholestyramine or activated 
powdered charcoal)  as specified in section 5.1 
26. Any hereditary neurological disease such as Charcot-Marie-Tooth disease or Spinocerebellar ataxia 
27. Any disease that can influence the patient safety and compliance, or the evaluation of disability 
28. History of hypersensitivity reaction to rabbit  
29. Women who are pregnant, breast-feeding, or who plan to become pregnant within the timeframe of this 
study 
30. 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. 
4.4 
Removal of patients from therapy or assessments 
4.4.1 
Removal of individual patients 
This is a long-term study and all patients should be encouraged to stay compliant with the study protocol and 
remain in the study, if continued study participation is found  to be medically safe and in the best interest of the 
patient.  
Permanent study medication discontinuation is only justified when a clear and persistent contraindication arises, 
or if the patient request to stop study treatment (i.e. not to receive the second treatment cure with alemtuzumab at 
the 1 year visit (Visit 7)).  
An excessive withdrawal rate can severely impact the scientific value of the study. The “Intention to treat” (ITT) 
analysis requires that all randomized patients be followed until end of study. This includes careful patient 
selection and appropriate explanation of the study procedures and visit schedule prior to enrolment, including an 
explanation of the consequences of premature withdrawal. 
Withdrawal of informed consent 
A patient has the right to withdraw informed consent for participation at any time for any reason. However, 
withdrawal of consent should be very rare and unusual. Patients must be informed that they can withdraw from 
the study without withdrawing consent and perhaps agree to the collection of their vital status e.g. by phone. A 
true withdrawal of consent means that the patient cannot be contacted about the study again. Because of this, the 
Investigator must be involved in the discussion with the patient regarding a withdrawal of consent, and preferably 
discuss the withdrawal of consent with the Sponsor’s representative prior to study discontinuation.  

  
 
  
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If the patient withdraws informed consent for participation in the study, the study will end for the patient. The 
patient must stop receiving study medication, and should be asked to return to the clinic for the end of study visit 
and perform assessments as described in the Flow Chart.  
Patient lost to follow-up 
If a patient is lost to follow-up, every effort should be made by the investigator and site staff to contact and locate 
the patient before the patient is declared lost to follow-up. Investigators and site staff must use every possible 
means, according to local regulations, to locate patients who have missed visits.  
Pregnancy 
If a patient becomes pregnant during the study, the study medication will be stopped, and the patient will be 
followed according to the patient’s original scheduled study visits during the trial, and until birth or termination of 
the pregnancy. Due to the nature of the disease under study, patients who become pregnant during the course of 
the study will be removed from per protocol analysis.  
4.4.2 
Trial Discontinuation 
The overall study or a specific study site, or a patient may be discontinued at any time at the discretion of the 
Sponsor in the event of the following: 
 
Occurrence of AEs unknown to date in respect of their nature, severity and duration, invalidating the earlier 
positive benefit-risk-assessment  
 
Incorrect enrollment, i.e. the patient does not meet the inclusion/exclusion criteria  
 
Violation of GCP, the clinical study protocol, or the contract, affecting the continued performance of the trial 
 
Failure to reach required recruitment targets on trial level or at a specific study site 
 
The Sponsor, PMC and CI will inform all investigators, relevant Competent Authorities and Ethics Committees in 
case of a prescheduled termination of the study along with the reasons for such an action. If the study is 
terminated early on grounds of safety, the Competent Authorities and Ethics Committees will be informed within 
15 days. 

  
 
  
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5 
TREATMENTS 
In this study cyclophosphamide, anti-thymocyte globulin and alemtuzumab are defined as Investigational 
Medicinal Product(s) (IMPs):  
Cyclophosphamide (Sendoxan®), powder for iv injection fluid. For storage and preparation instructions see the 
SmPC. 
Anti-thymocyte globuline (Thymoglobuline®), powder for iv infusion fluid. For storage and preparation instructions 
see the SmPC. 
Alemtuzumab (Lemtrada®), concentrate for iv infusion fluid. For storage and preparation instructions see the 
SmPC. 
A schematic illustration of the treatments/patient flows is available in Appendix A. 
5.1 
Wash-out of immunomodulatory treatment(s)  
Patients with RRMS experiencing treatment failure on immunomodulatory treatments the previous year will need 
to follow the below timelines for wash out before start of study treatment. Wash out should start after eligibility 
and randomization is confirmed (i.e. at Visit 2).  
Tabell 5.1.1 Wash out duration 
Treatment 
Time until start of study treatment 
 
Study arm A:  
Study arm B:  
Natalizumab 
2 months 
2 months 
Fingolimod 
2 months 
2 months 
Dimetylfumurat 
2 months 
2 months 
Glatiramer 
acetate 
No wash-out required 
No wash-out required 
Beta interferons 
No wash-out required 
No wash-out required 
Teriflunomide* 
After 
stopping 
treatment 
with 
teriflunomide: 
• 
cholestyramine 8 g is administered 3 
times daily for a period of 11 days, or 
cholestyramine 4 g three times a day 
can be used, if cholestyramine 8 g 
three times a day is not well tolerated, 
• 
alternatively, 
50 g 
of activated 
powdered charcoal is administered 
every 12 hours for a period of 11 days. 
After 
stopping 
treatment 
with 
teriflunomide: 
• 
cholestyramine 8 g is administered 3 
times daily for a period of 11 days, or 
cholestyramine 4 g three times a day 
can be used, if cholestyramine 8 g 
three times a day is not well tolerated, 
• 
alternatively, 
50 
g 
of 
activated 
powdered charcoal is administered 
every 12 hours for a period of 11 days. 
* Accelerated elimination procedure: Teriflunomide is eliminated slowly from the plasma. Without an accelerated 
elimination procedure, it takes an average of 8 months to reach plasma concentrations less than 0.02 mg/l, 
although due to individual variation in substance clearance it may take up to 2 years. An accelerated elimination 
procedure can be used at any time after discontinuation of teriflunomide (see section 4.6 and 5.2 for procedural 
details). 

  
 
  
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5.2 
Dosage and drug administration (study treatments and supportive care) 
The study treatments and supportive care medication will be administered to the subject by authorized site 
personnel only.  
5.2.1 
Selection of doses 
Cyclophosphamide and anti-thymocyte globulin are approved drugs for treatment of various autoimmune 
diseases, including eradication of self-reactive immune response by the conditioning regime prior to autologous 
stem cell transplantation, as described in section 5.2.2. The conditioning regimens used for HSCT in MS can be 
separated into high, intermediate and low dose intensity.  In MS treatment studies using high intensity HSCT 
regimen treatment related mortality was approximately 4%, while the mortality rate was lower in MS patients   
treated with low or medium intensity conditioning regimens17, 18, 21, 29, 30 A recent meta analysis found no significant 
differences in 2-year rates of disability progression in patients treated with HSCT using high, intermediate and low 
regimen intensities34. The highest proportion of MS-patients with NEDA at 24 months was found in a serie of 145 
patients, using HSCT with low regimen intensity17, 34. Given these results regarding treament effect and treatment 
related mortality using high, intermediate and low intensity conditioning regimens, a low intensity regimen has 
been selected for use in this trial. 
Alemtuzumab is an approved treatment of adult patients with relapsing remitting multiple sclerosis, and is 
considered to be the most effective immunomodulating for treatment of MS. The selected dose is in accordance 
with literature recommendations and clinical practice.  
For more details see the current version of the SmPCs. 
5.2.2 
STUDY ARM A (HSCT): 
Mobilization and peripheral blood stem cell harvesting 
Priming chemotherapy (cyclophosphamide) is included in the standard study mobilization regimen to enhance 
mobilization while maintaining disease control and to prevent a potential flare, which may be a consequence of 
granulocyte colony stimulating factor therapy alone36.  
Day 1: Cyclophosphamide 2.0 g/m2 body surface area will be given iv in 1000 ml of standard glucose (glucose 
50mg/ml) over 60 minutes. The cyclophosphamide dose is highly emetogenic, and an appropriate, combined 
antiemetic regime should be used37-39. A forced diuresis with a desired minimum volume of 150 ml urine/hour is 
obtained by infusion of at least 3000 ml of normal saline iv supplemented with 20 ml furosemide/1000 ml fluid, 
and complementary doses of 20 mg furosemide iv to obtain the required urinary output. To further protect the 
urothelium (prevent hemorrhagic cystitis), uromitexan (Mesna®) 800 mg/m2 is applied 15 minutes prior to the 
cyclophosphamide infusion, as well as 3, 6 and 9 hours after start of the cyclophosphamide infusion. Since 
neurogenic bladder with delayed emptying is common, a foley catheter is placed in patients with a history of urine 
retention.  
Days 5-10: Granulocyte colony stimulating factor (filgrastim) 5 mcg/kg body weight/day sc in the evening. 
Acetaminophen (paracetamol) or mild oral opioids are acceptable as on demand medication against filgrastim-
associated pain in the skeleton and soft tissues. 
Day 11 and until apheresis is discontinued: Granulocyte colony stimulating factor (filgrastim) 5 mcg/kg body 
weight  x 2 sc/day. Daily measurements of CD34+ counts in peripheral blood. Apheresis begins according to local 
routines, and continues until a minimum of 2 x 3.0 x 106 CD 34+ cells/kg body weight is obtained. The stem cell 
graft is processed and stored in accordance with local routines and national regulations. Lymphocyte depletion of 
the stem cell graft is not yet recommended by the study officials. 

  
 
  
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The Medical Officer appointed by the official central study site should be consulted in an unexpected case of a 
poor stem cell mobilizer..  
Interval between mobilization and conditioning 
In order to avoid cumulative cardiac toxicity from cyclophosphamide, a minimum of three weeks should separate 
administration of cyclophosphamide for mobilization and for conditioning. A maximum interval of eight weeks is 
recommended. 
Conditioning regime (HSCT days -5 to -1) and reinfusion of the stem cell 
product (HSCT day 0) 
HSCT days -5 to -2: Cyclophosphamide 50 mg/kg/day will be given iv in 1000 ml of standard glucose (glucose 
50mg/ml) over 4 hours. The cyclophosphamide dose is highly emetogenic, and an appropriate, combined 
antiemetic regime should be used37-39.  A forced diuresis of minimum 150 ml urine/hour should be obtained by 
infusion of at least 3000 ml normal saline iv supplemented with 20 mg of furosemide per 1000 ml fluid, and 
complementary doses of 20 mg furosemide iv to obtain the required urinary output to preserve the kidney 
function. To prevent hemorrhagic cystitis, repeated doses of uromitexan (Mesna®) 30mg/kg over 30 minutes in 
100 ml normal saline (NaCl 9%) are given 30 minutes prior to cyclophosphamide infusion, as well as 4, 8, 12, 16 
and 20 hours after start of each cyclophosphamide infusion, respectively. A foley catheter should be placed in 
patients with a history of urine retention. 
HSCT days -5 to -1: Anti-thymocyte globulin (ATG-rabbit, Thymoglobuline®) 0.5 mg/kg body weight will be given 
iv on day –5, 1.0 mg ATG-rabbit/kg will be given iv on day -4, and 1.5 mg ATG-rabbit /kg will be given iv on days -
3,-2 and -1 over 10 hours in 500 ml of normal saline (NaCl 0.9%). Due to the risk of an anaphylactic reaction, 
premedicate with methylprednisolone 500 mg iv and an oral antihistamine of local choice 60 minutes prior to each 
ATG test dose and subsequent ATG infusion. An ATG test dose (1 ml of the ATG infusion) should always be 
administered at least 10 minutes before initiating the ATG infusions. Patients are instructed to remain in the ward 
during the entire infusion period, and an available anaphylaxis emergency kit is mandatory. An in-line 0.22 m filter 
should be applied for the ATG administration. Ulcus prophylaxis should also be applied during high dose steroid 
therapy.                                                                                                               
HSCT day 0: Reinfusion of a minimum of 3,0 x 106 CD 34+ cells/kg body weight. Premedication according to 
local routines; oral acetoaminophen 1000 mg po and an oral antihistamine are recommended. 
 
Additional compulsory supportive therapy: 
Prednisolone: 
Declining doses of Prednisolone are used to prevent ATG-associated serum sickness: 
• 
HSCT days 0, +1 and +2: Prednisolone 60 mg x 1 po 
• 
HSCT days +3 and +4: Prednisolone 40 mg x 1 po 
• 
HSCT days +5 and +6: Prednisolone 20 mg x 1 po 
• 
HSCT days +7 and +8: Prednisolone 10 mg x 1 po. 
• 
If fever or other signs of serum sickness: A supplement of metylpredisolone (Solu-medrol) 250 mg iv 
(followed by 125 mg iv/day for 2 days) is considered in addition to broad spectrum antibiotics if 
consistent fever >380C. Fever or other reactions may also result in neurological deteriation in MS-
patients, and thus should be immediately addressed according to site routines36. 
 
Antibiotic prophylaxis36:  
• 
Gram-negative prophylaxis according to local standard, starting the latest 2 days after stem cell 
reinfusion (HSCT Day +2)  
 
• 
HSCT day -5 and until 6 months after transplantation: Valaciclovir 500 mg x 2 po. 
• 
HSCT day +2 and until 3 months after transplantation: Flukonazol 200 mg x 1 po. 

  
 
  
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• 
After granulocyte recovery: trimetoprim-sulpha 500 mg 2 tabl. x 2 po on Saturdays and Sundays for 3-
6 months or 1 tabl.x 2 po three times a week for 3-6 months according to local routines. 
 
Therapy of fever and suspected or documented infections: 
Microbiological specimens (blood cultures, urine and nasopharyngeal aspiration viral tests) should immediately 
be obtained if fever or other signs of infection (may be subtle in neutropenia), followed by prompt inititation of 
broad-spectrum iv antibiotic medication according to site routines. CMV and/or EBV reactivations (indicated by 
PCR results and/or clinical signs) should also be preemptively treated according to national/local/study site 
policies and protocols36. 
 
ATG-associated serum sickness (see above) or emerging bone marrow regeneration should also be considered 
and dealt with in febrile episodes, but should not exclude or replace broad spectrum iv antibiiotics for suspected 
or documented infections.  
 
Blood product transfusions: 
Platelets and erythrocyte transfusions should be administered according to study site policies and protocols. 
Blood products should be irradiated36. 
Cyclophosphamide-associated hemorrhagic cystitis: 
Hemorrhagic cystitis should be suspected if hematuria and/or painful miction (urination) during or following 
cyclophosphamide infusions. Suspected hemorrhagic cystitis should be investigated and treated according to 
transplant study site procedures.  
 
Revaccination schedule: 
Revaccinations should be performed after HSCT. Recommendations provided in Appendix B should be adjusted 
at each study site according to national guidelines. 
5.2.3 
STUDY ARM B (alemtuzumab): 
Premedication (prior to every alemtuzumab infusion): 
a. Cetirizine 10 mg po or similar oral antihistamine 
b. Methylprednisolone 1000mg iv in 100ml 0.9% saline prior to alemtuzumab infusion 
c. Acetaminophen 1000 mg po prior to alemtuzumab infusion 
 
Alemtuzumab 12 mg iv daily on 5 consecutive days at first alemtuzumab treatment cycle, followed by 3 
consecutive days at the second alemtuzumab treatment cycle 12 months later. 
 
Around 3% of patients treated with alemtuzumab experience serious infusion reactions. The patient should be 
monitored with measurement of blood pressure and pulse every hour during infusion. After each infusion with 
alemtuzumab, the patient should be observed for 2 hours for infusion associated reactions. Resources for the 
management of anaphylaxis or serious reactions should be available. The infusion should be stopped if any of the 
following occur: Hypotension (systolic blood pressure <90 or a decrease of >10mmHg from baseline if baseline 
systolic blood pressure <90), Persistent high grade fever, oxygen desaturation, dyspnoea, back pain, pruritus, 
restlessness, or other subjective complaints). The most common infusion reactions could be treated as follows: 
Hypotension: Isoplex 500mls followed by 0.9% sodium chloride IV bolus 1L IV over 30 minutes. Rigors: 
chlorphenamine 10mg IV. Fever: paracetamol 1g by mouth. Dyspnoea, back pain, pruritus, O2 desaturation: 
100% Oxygen through a non-rebreathing mask followed by hydrocortisone 100mg IV and chlorphenamine 10mg 
IV. Consider 0.5ml epinephrine (adrenaline) 1:1000 intramuscularly. If infusion reaction symptoms completely 
resolve and the patient is back to baseline, re-challenge with alemtuzumab but at a slower infusion rate, doubling 
the infusion time. 
 
Antiviral prophylaxis:  
Acyclovir 200mg po twice daily, beginning at the first day of alemtuzumab infusion and continuing for 1 
month after each alemtuzumab treatment cycle.  

  
 
  
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Discharge if stable after a 2-hour monitoring period: Vital signs, heart rate and blood pressure.  Extended 
monitoring duration when indicated. 
 
5.3 
Duration of therapy 
The planned duration of therapy is stated in section 5.2  
Duration of therapy may deviate from what is planned if an intercurrent illness effects the safety of the patient, the 
ability to administer treatment, or the primary study endpoints. Fertility measures implemented for women of 
childbearing potential may postpone initiation of stem cell mobilization for up to 2-4 weeks.  
5.4 
Premedication and monitoring 
Premedication and washout will be performed as indicated in section 5.1 
5.5 
Concomitant medication, restrictions and rescue therapy 
Concomitant medication related to MS study treatment is stated in section 5.2.  
All other concomitant medication (incl. vitamins, herbal preparation and other “over-the-counter” drugs) used by 
the patient will be recorded by the Investigator in the patient’s medical record and eCRF. Herbal preparations 
should be avoided for the last month before start of treatment procedures (uncertainties regarding possible side 
effects on  treatment medications and stem cells). Pain medication other than acetaminophen and po opioids 
should not be used 2 weeks prior to stem cell mobilization due to possible adverse effects on stem cell function 
by a variety of “pain killers”. 
5.5.1 
Restricted therapy 
Prohibited therapy in both study treatment arms:  Natalizumab, fingolimod, dimetylfumurat, glatiramer acetate, 
interferon beta medications, teriflunomide, and alemtuzumab if administered outside the study.  
In Arm A which includes cyclophosphamide, concomitant administration and dosages of agents inhibiting or 
inducing CYP450 may alter the treatment effect. The risk for CYP450 induction or inhibition must be carefully 
considered prior to or during concomitant administration of known inducing and inhibiting agents, including; 
amiodarone, aprepitant, bupropion, ciprofloksacin, azoles (including flukonazol in daily doses >150 mg), 
klaritromycin, prasugrel, sulfonamides, telitromycin, rifampicin, fenobarbital, karbamazepin, fenytoin, St. John’s 
Wort and systemic corticosteroids.  
 
MS-relapse treatment with a 5-day course of iv or per oral methylprednisolone is permitted by the study protocol. 
Apart from immunomodulatory MS treatment (see section 5.1 for wash out), no cytotoxic or immunosuppressive 
treatments or drugs other than the study medications can be used during the last six months prior to entry or 
during the trial, and the patient starting such medication will be excluded. 
5.5.2 
Rescue medication, emergency procedures and additional treatments 
During the study period, and in particular after recent discharge from hospital, the patient should without 
hesitation contact the study site or a local emergency ward if signs of infections or any other sign of altered 
general condition. 
It is essential for optimal interpretation of the study results that the patients are informed  to contact their regular 
neurologist or their study PI/co-PI within three days in the case of a suspected relapse (MS attack).- The patient 

  
 
  
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must undergo a neurological evaluation within 7 days from the onset of relapse symptoms. If the treating 
physician decides that the patient has a possible relapse, the patient should without undue delay be referred for 
an unscheduled relapse visit at a defined study site including  a quantitative neurological examination, EDSS 
scoring and MRI. If the relapse is considered to impede neurological function, the patient is treated with iv or oral 
methylprednisolone 500 or 1000 mg daily for 3 or 5 consecutive days according to local routines.Patients with 
aggressive attacks should be discussed with the CI/NC/PI before local initiation of high dose steroid treatment. 
5.6 
Drug compliance and accountability 
All study treatments are administered as intravenous therapy. The study drug is administered by health care 
personnel and the patient is admitted to hospital during treatment. Compliance is therefore expected to be close 
to 100%.  
Distribution, return, accountability, batch numbers and destruction of the study drug must be logged and filed in 
the ISF. Internal procedures at the hospital may be followed if fulfilling GCP/GMP requirements.  
5.7 
Drug labeling, storage and supply 
 
The investigational product will have a label permanently affixed to the outside and will be labeled according with 
ICH GMP and national regulations, stating that the material is for clinical trial / investigational use only and should 
be kept out of reach of children. For detailed description of the label, please refer to the ISF. 
Study medication must be stored under recommended storage conditions indicated on the label. A temperature 
log must be maintained by the investigator/pharmacist to make certain that the drug supplies are stored at the 
correct temperature.  
The products have a marketing authorization, is routinely ordered by the pharmacy and will be dispensed from 
the pharmacy's own stock. 
 
5.8 
Subject numbering and assignment to treatment groups 
Each subject is identified in the study by a unique subject number that is assigned through the eCRF system. 
When a subject signs the Informed Consent Form he/she is considered enrolled into the study as a screened 
patient. Patients not eligible for randomization after screening will be registered as Screening Failures in the 
eCRF. Once assigned the subject number cannot be reused for any other subject.  
5.9 
Fertility related procedures 
Due to the chemotoxicity of cyclophosphamide, counselling regarding fertility conserving measures (at Visit 3) is 
recommended for both females and males randomized to the study. Fertility conserving measures (i.e. sperm, 
oocyte and/or ovarian storage) are performed according to national guidelines and must be completed prior to 
start of stem cell mobilization at Visit 4.1.  
 

  
 
  
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6 
STUDY PROCEDURES 
6.1 
Details of trial procedures by visits 
The patient information and informed consent procedures may take place prior to the screening visit (but within 
study window), or at the day of screening visit.  The patient should be given ample time to ready through and 
consider participation in the study before signing the Informed Consent Form. No trial procedures should be done 
unless the patient has in writing consented to taking part in the trial.  
The study will consist of the following periods; screening, pre-transplantation/evaluation, randomization, 
treatment, and follow-up phases. All trial related procedures at selected visits will be done according to the Flow 
Chart with footnotes, and per details provided in the sections below.  
All patients are to adhere to the visit schedule as specified in the Flow Chart, and if a visit is re-scheduled, 
subsequent visits should follow the original visit date schedule (one month is defined as 28 calendar days). 
6.1.1 
Screening  
No trial procedures should be done unless the patient has consented to taking part in the trial. 
Screening (Visit 1) of the patients will take place at participating study sites. Once the patient has consented to 
trial participation, he/she is considered to be enrolled in the trial and have started screening. The patient should 
be registered in the enrollment log and in the eCRF as a screened patient.  
All eligibility criteria should be assessed together with relevant baseline parameters prior to study inclusion 
(inclusion/exclusion criteria). If the patient meets the entry criteria, Visit 2 should occur as soon as possible once 
it has been confirmed that the patient is eligible to continue.  
Patients who fail screening (i.e. fail to meet one or more of the inclusion criteria, and/or meet one or more of the 
exclusion criteria) following Visit 1 procedures should be registered as a screening failure in ViedocTM. If the 
patient does not meet the entry criteria, the patient will be followed and treated according to national/local clinical 
treatment guidelines. 
6.1.2 
Randomization visit  
Randomization will occur at Visit 2 using eCRF after confirming that all inclusion criteria are still fulfilled, but no 
exclusion criteria are fulfilled. The randomization visit (Visit 2) can be performed as a Phone Visit if there are no 
clinical relevant changes for the patient since the screening visit (Visit 1). Adverse events and concomitant 
medication should be documented and registered in the eCRF.  
For patients currently being treated with natalizumab, fingolimod, dimetylfumurat, glatiramer acetate, interferon 
beta-1a/1b, teriflunomide, or alemtuzumab, please refer to section 5.1 for details regarding washout of the 
immunomodulatory treatments. 
6.1.3 
Pre-transplantation evaluation  
Arm A - Patients randomized to HSCT 
All patients should have a full physical examination at both pre-treatment visits (Visit 3). Comorbidities, 
concomitant medication, and any adverse events must be reported (see section 8). 
Pre-transplantation evaluation: Before start of stem cell mobilization and harvesting, pre-transplantation 
information (oral and written) and clinical evaluation should be performed by a transplant specialist/hematologist 

  
 
  
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in order to ensure that the patient is physically and mentally eligible for HSCT. Critical organ tolerabilities for 
HSCT are evaluated by blood tests (hematology, clinical biochemistry, liver tests, thyroid status, viral serology), 
chest X-ray, lung function tests (spirometry incl. DLCO), echo cardiography, and dental examination (to exclude 
or eradicate potentially infectious oral foci prior to start of treatment). Also, the patients should be offered fertility 
counselling  to decide whether fertility measures should be performed before start of stem cell mobilization. 
Minimum criteria for respiratory and cardiac functions36 must be fulfilled;   
 
FEV1/FVC > 60% of predicted after bronchodilator therapy  
 
DLCO > 50% of predicted  
 
Resting LVEF > 50 % 
 
If the transplant specialist/hematologist finds that the patient is eligible for autologous HSCT preparations for stem 
cell mobilization/harvesting can start. Patients not found eligible for HSCT after the pre-transplantation evaluation 
will be discontinued from study treatment and treated according to standard guidelines. 
Fertility related procedures: Before start of treatment and/or treatment related procedures, all patients (men and 
female) should have blood samples collected for fertility hormone status for long-term storage in Biobank 
Haukeland for future research. Fertility conserving measures according to individual preferences and in line with 
national guidelines must be completed prior to start of stem cell mobilization (Visit 4.1). For male patients: 
collection of sperm for storage. For most female patients: start of hormone therapy for fertility conserving 
measures, followed by harvesting and storage 2-4 weeks later.  
Arm B - Patients randomized to alemtuzumab 
Patients randomized to alemtuzumab will not undergo supplementing clinical pre-treatment visits after 
randomization (Visit 3 will therefore be omitted), before returning for Visit 4.1 to start study treatment. 
6.1.4 
Treatment and follow-up period 
Patient reported outcome forms (PROs) should be filled in at the start of the visit, physical examination and 
laboratory assessments must be done prior to administration of any study drugs or start of study treatment. PROs 
will be available both in paper and electronic format.  
If any additional treatment is considered necessary for the patient’s welfare during the treatment period it may be 
given at the investigators discretion (see section 5.5 for restricted medication). 
Arm A - Patients randomized to HSCT 
If the patient is considererd eligible for autologous HSCT (by pretransplantation evaluation), procedures for stem 
cell mobilization/harvesting, conditioning and HSCT are initiated.  
 
Hospital stays I and II (outward setting in some study hospitals): For stem cell mobilization most patients will be 
hospitalized for 2(-3) days while receiving cyclophosphamide and standard supportive medication for mobilization 
of stem cells. This is followed by daily subcutaneous injections of granulocyte colony stimulating factor 
(Filgrastim®)from Day 5 until finalized stem cell harvesting.  On Day 10 or 11 the patient returns to the study 
hospital for stem cell harvesting. Details regarding dosing and administration of the mobilization regime are 
provided in Section 5.2. Mobilization and harvesting procedures and any events that occur are registered on Visit 
4.1 in the eCRF.  
 
In order to avoid cumulative cardiac toxicity from cyclophosphamide, a minimum of 3 weeks should separate 
administration of cyclophosphamide for mobilization and conditioning. A maximum interval of 8 weeks is 
recommended.  
 

  
 
  
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Hospital stay III: Three to six weeks after harvesting, the patient is hospitalized for about 3 weeks to perform 
conditioning, stem cell reinfusion (HSCT) and a protective isolation period. Detailed instructions on administration 
of study treatments during this stay are provided in Section 5.2 and in Appendix A (a schematic overview of the 
patient flow). The isolation period usually lasts for 5-10 days. Routine blood sampling will be performed daily as 
part of the patient monitoring during the hospital stay III for conditioning, reinfusion and isolate period (3 weeks). 
Daily tests: Hgb, leucocyte count with differentials, thrombocyte count (2 times daily for 5 days while receiving 
ATG), CRP, creatinine, sodium, kalium. Three times a weeks: blood cross-match, ALP, GT, ASAT, ALAT. 
bilirubin (and supplementing liver tests on demand if suspected liver toxicity). Once a week: p-CMV and p-EBV 
PCRs. The patient is discharged from hospital according to local routines, but the patient should as a minimum 
have a reconstituted bone marrow function, be off parenteral antibiotics and other supplementary iv therapy and 
be capable of performing adequate daily activities of life.  Procedures and any events that occur are registered on 
Visit 4.2 in the eCRF.    
 
 
Short term follow-up after HSCT (post-transplantation control visits): After discharge from hospital, weekly follow-
up is required until Day +100 after HSCT for safety monitoring (blood test and consultation) and clinical care (see 
also section 7.1.8). Weekly blood tests and consultations should be under the direct control of a transplant 
specialist or combined care between transplant specialist/hematologist and referring neurologist or a general 
practitioner when a patient is considered clinically stable by the transplant specialist (intervals may be extended 
by the transplant specialist after the first 6 weeks). Monthly blood pregnancy tests are required. 
The first post-transplant study visit is performed at day +100 after HSCT at designated HSCT-study sites. 
According to the study design the HSCT day +100 visit is considered to “parallel” the 3 months study visit in arm 
B (Visit 5). 
 
Long-term follow-up (study visits at HSCT/central study site(s)):  All patients will return for study follow-up visits, 
endpoint evaluation and collection of study data according to Flow Chart at 6, 12, 18, and 24  
months after Treatment day “0” (and after 30,36, 42,48, 54 and 60 months during the study extension).   
Between study visits patients should have the following safety laboratory tests analyzed locally  
-  Every third month (at least):  
- Hematology: HgB, leucocytes with cell differentials, thrombocytes 
- Clinical chemistry: serum sodium, potassium, bilirubin, CRP, creatinine 
- Thyroid gland: TSH, free T4 
- Urine strip analysis  
- Monthly: 
- Serum human chorionic gonadotropin (hCG) pregnancy test (required only until 12 
months after last administration of alemtuzumab 
An unscheduled visit should be performed in case of abnormal findings indicating MS relapse or disability 
progression (as per protocol definitions, see section 2.2), suspected treatment complication, any acute illness of 
undetermined cause, or at the discretion of the Investigator. Close communication between the patients and local 
hospital staff involved in weekly/quarterly safety follow-up is crucial for timely identification and reporting of events 
in the study. 
 
Fertility measures: For women with fertility conserving measures prior to HSCT treatment, transvaginal ultrasound 
of ovaries will be performed at 1 year and 2 year follow-up visits (Visit 7 and 9) to investigate potential impact of 
cyclophosphamide on fertility. For men, sperm sampling will be performed at 1 year and 2 year follow-up visits 
(Visit 7 and 9) to investigate potential impact of cyclophosphamide on fertility. 
 

  
 
  
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Arm B - Patients randomized to alemtuzumab 
After randomization to arm B, patients will start alemtuzumab treatment course 1 at Visit 4.1 (Treatment day “0”), 
followed by study visits at 3 and 6 months (Visits 5 and 6, respectively). 
At 12 months (Visit 7), the patient receives alemtuzumab treatment course 2. See section 5.2 for dosages and 
administration of alemtuzumab and standard supportive therapy.  
Short and long term study visits after discharge:   
All patients will return for study follow-up, endpoint evaluation and collection of study data according to Flow 
Chart at 6, 12, 18 and 24 months after Treatment day “0” (and after 30, 36, 42, 48, 54 and 60 months during the 
extension study).   
Between study visits patients should have the following safety laboratory tests analyzed locally:  
Monthly laboratory tests until 60 months after the last alemtuzumab treatment cycle: 
- Hematology: HgB, leucocytes with cell differentials, thrombocytes 
- Clinical chemistry: serum sodium, potassium, bilirubin, CRP, creatinine 
- Urine strip analysis  
- Serum human chorionic gonadotropin (hCG) pregnancy test (required only until 4 
months after last administration of alemtuzumab)   
 
Thyroid gland function (every 3 months until 60 months): TSH, free T4. 
Gynecological examination including HPV/cervical dysplasia screening annually. 
 
An unscheduled visit should be performed in case of abnormal findings indicating MS relapse, suspected 
treatment complication, any acute illness of undetermined cause, or at the discretion of the Investigator. Close 
communication between the patients and local hospital staff involved in weekly/quarterly safety follow-up is 
crucial for timely identification and reporting of events in the study. 
In case the study extension will not be performed, patients in both study arms should be followed up long-term 
according to  standard of care by their treating neurologist. For arm B this also includes the monthly laboratory 
tests until 48 months after the last alemtuzumab treatment cycle, as specified above in this section. 
 
6.1.5 
Unscheduled visits 
In addition to the scheduled study visits, patients may have unscheduled study visits due to a new, confirmed MS 
activity event (clinical relapse, disability progression or MRI findings per protocol definitions, see section 2.2), a 
suspected treatment complication, any acute illness of undetermined cause, for other reasons, or at the discretion 
of the Investigator. Data collected during unscheduled study visits will be recorded in the unscheduled visit 
eCRFs. Additional procedures and investigations should be performed as indicated by the clinical situation. 
Patients must be instructed to immediately report new neurological symptoms, re-occurring or worsening of 
previous symptoms to the Investigator. If a patient reports symptoms that may be consistent with relapse, an 
unscheduled study visit must be performed as soon as possible (whenever possible within 7 days of onset of the 
symptoms). 
 
6.1.6 
Withdrawal and early study discontinuation 
If a patient refuses to attend all originally planned study visits, but agrees with vital status assessment, the latter 
will be conducted preferably according to visit schedule as in the Flow Chart, but as a minimum at the 2 year visit 
(Visit 9), and at the 5 year visit (Visit 15) for the planned study extension. 

  
 
  
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6.1.7 
End of study period 
If a patient discontinues study participation early (prior to Visit 7 or Visit 9) for whatever reason, he/she should 
return to the study site for the End of Study assessments.  
For patients completing study per protocol, the last scheduled visit will be at 2 years follow-up, and for the 
extension study 5 years follow-up.  
6.1.8 
Switch to other therapy   
Patients may be  offered treatment  corresponding to the opposite study treatment arm  or start other MS 
medication if they experience significant new inflammatory disease activity (see Section 2.2) during the study 
treatment period. Significant inflammatory disease activity during the treatment period is a protocol-defined 
disease activity event (refer to section 2.2), but must include both a relapse and protocol defined MRI activity 
and/or disability progression. Start of  therapy corresponding to the treatment offered in the opposite study 
treatment arm  will need to wait for 12 months after the latest alemtuzumab treatment or 12 months after 
conditioning in the HSCT treatment arm.Earlier rescue treatment should be discussed with the CI. 
A follow-up study visit (scheduled or unscheduled) prior to cross-over is required to assess the patients clinical 
status and safety parameters.  
6.2 
Procedures for discontinuation 
For patients who stop study treatment after Visit 4.1 (only applicable for arm B), or who wishes to withdraw from 
further study participation, the following should be performed whenever possible: 
End of Study (EOS/EOXS) visit procedures including completion of PROs,  physical examination, vital signs, 
neurological examination, MRI, recording of adverse events and concomitant medication, sampling of blood for 
safety laboratory parameters and biobanking, CSF and stool sample. 
Patients discontinuing study treatment should continue to follow the original visit schedule. 
6.3 
Laboratory tests 
Collection of biological material must be done at timepoints as specified in the Flow Chart. The local study site 
laboratory will be used for the analyses of hematology, biochemistry and serology specimens collected, sperm 
analysis (at selected sites only and according to WHO standard) and for serum hCG pregnancy test.  
 
Biological material for biobanking will be collected and shipped to Biobank Haukeland for long-term storage. 
Details describing collection, processing, shipment and storage of samples are available in the ISF. 
 
 

  
 
  
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7 
ASSESSMENTS  
7.1 
Assessment of efficacy  
In order to confirm NEDA or evidence of new disease activity events during the study treatment and 
observation periods, the following clinical and radiological parameters and examinations should be 
performed at scheduled and unschedules study visits): 
7.1.1 
Lesions and atrophy 
MRI will be performed at timepoints indicated in the Flow Chart. Measures of new lesions, enlargement of existing 
lesions, the total lesion load, and changes in brain volume will be done at a central MRI reading site. Procedures 
for obtaining and reading of MRI images will be filed int the ISF. 
7.1.2 
Clinical MS relapse 
A relapse should without undue delay be confirmed by an assigned neurologist (PI or co-PI at a study site at a 
scheduled study visit (if a suspected relapse occurs within a few days before a scheduled visit) or at a 
supplementing, unscheduled study visit, including a full clinical neurological examination with EDSS scoring 
followed by MRI, preferably within 7 days from onset of symptoms. 
7.1.3 
Expanded Disability  Status Scale (EDSS) 
Disability progression will be assessed using EDSS at timepoints indicated in the Flow Chart40. For assessment 
of EDSS, see Appendix  C.  
7.1.4 
For individual patients EDSS scores should preferably be assessed by the same 
neurologist  (PI or co-PI) throughout the study. EDSS certification is compulsory for all 
study personnel performing EDSS scorings at defined study visits, and  copies of 
relevant certificates should be placed in the ISF.Patient reported outcomes (PROs) 
 Assigned investigators or other designated site-personnel should ensure that the patient has access to a quiet 
area at the study site where  the patient can record her/his  answers in the questionnaires. If a patient cannot give 
or decide upon a response to a specific questions no response should be recorded. The study site investigator or 
designated site-personnel should check that all items have been completed by the patient, but the patient 
response to each item should not be scrutinized . Instructions to patients are included in the questionnaires.  
EQ-5D-5L 
Health related quality of life will be assessed using the EQ-5D-5L (see Appendix D) according to the Flow Chart41. 
EQ-5D-5L is a standardised instrument to measure of health outcome. It is designed for self-completion by the 
patients41.  
The EQ-5D-5L self-report questionnaire essentially consists of 2 pages comprising: 
 
the descriptive system (five dimensions of health; namely mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression). 
Each 
dimension 
comprises 
three 
levels 
(no 
problems, 
some/moderate 
problems/extreme problems).  
 
the EQ-VAS (visual analogue scale) which records the patient’s self-rated health status on a vertical 
graduated (0 – 100) VAS.   
 

  
 
  
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In Norway, as a part of an extended QoL assessment and a health economic evaluation, the EQ-5D-5L 
questionnaire will be supplemented with questionnaires regarding the overall contentment of the patient, 
employment status and participation in social life.  
Multiple Sclerosis Impact Scale (MSIS) 
The Multiple Sclerosis Impact Scale (MSIS-29) is a 29-item self-report measure comprising 20 items associated 
with a physical scale and 9 items associated with a psychological scale. 
Patients (or their proxies) are asked about the impact of MS on day-to-day life in the last 2 weeks. All items have 
5 response options from 1 (not at all) to 5 (extremely). Each of the 2 scales are scored by adding up the 
responses across items, then converting to a 0 to 100 scale, where 100 indicates greater impact of disease on 
daily function (worse health).  
Reliability and validity evidence have been obtained in multiple samples of people with MS from disability levels of 
0 to 9.5 on the Expanded Disability Status Scale. The MSIS-29 is responsive to intervention, with a change score 
of about 8 on the physical scale or about 6 on the psychological scale having moderate to high sensitivity and 
specificity for patients, indicating whether they had improved or not42. 
Fatigue Severity Scale (FSS) 
The Fatigue Severity Scale (FSS) is a method for evaluating fatigue in multiple sclerosis and other neurological 
conditions.  
The Fatigue Severity Scale (FSS) is designed to differentiate fatigue from clinical depression, since both share 
same symptoms. Essentially, the FSS involves answering a short questionaire that requests a rating of the 
patients’ subjective level of fatigue.  
7.1.5 
9-Hole Peg Test  and Timed 25-foot walk  
9-HPT and T25FW  are two out of three variables recommended as primary measures in the Multiple Sclerosis 
Functional Composite (MSFC)43. 9-HPT is a quantitative measure for upper extremity function, whereas the 
T25FW is a quantitative measure for lower extremity function44. 
 
7.1.6 
The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) 
The BICAMS is a brief cognitive assessment that can be used also in study sites with staff members with no 
neuropsychological training45 The tests address specific cognitive deficits that are common in MS patients, and 
the scales were chosen also for their psychometric qualities (reliability, validity and sensitivity)46. Tests must be 
administered during daytime, in a standardized manner, and in a quiet room. The order of tests will be fixed: the 
Symbol Digit Modalities Test (SDMT),Brief Visuospatial Memory Test-Revised (BVMT-R), and California Verbal 
Learning Test-II (CVLT-II). 
7.2 
Assessment of safety and tolerability  
Safety will be monitored by the assessments described below and reported AEs. Significant findings present prior 
to the signing of informed consents must be included in the relevant medical history/ current medical condition 
page of the eCRF. For details on AE collection and reporting, see Section 8.  
For the assessment schedule see Flow chart.  

  
 
  
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7.2.1 
Physical examination 
A full physical examination will be performed by the investigator and includes the following; skin (colour, rash, 
lesions, oedema), lymph nodes, blood pressures, heart rate, body temperature, body height/weight, oral 
inspection, lung/heart/abdominal examination, peripheral pulse. Documentation of clinical parameters obtained by 
physical examinations must be part of the source documents available at each study site. 
7.2.2 
Vital signs 
Vital signs including body temperature, blood pressure and heart rate will be measured at all study visits after the 
patient has rested for five minutes in seated position. The recordings should be performed on the same arm, 
preferably using a mercury sphygmomanometer or a validated certified blood pressure recording instrument. The 
recordings should be documented in source documents and entered into the eCRF.  
7.2.3 
Body height and  weight 
Body height and  weight will be measured at the screening visit (Visit 1) according to the following restrictions: 
• 
weight is registered after bladder voiding 
• 
shoes and coat/jackets should be taken off  
• 
pockets should be emptied of heavy objects (i.e. keys, coins etc.) 
Registrations of body weight are repeated with the same restrictions before ordering the mobilization and 
conditioning regimens in order to facilitate adequate adjustments of doses of all relevant  medications (study 
drugs and weigth-dependet supportive care) of the mobilization and conditioning regimens in study arm A. 
7.2.4 
Safety laboratory parameters 
All safety laboratory parameters will be collected at the timepoints as indicated in the Flow Chart, and include 
hematology, liver enzymes/parameters, clinical chemistry, thyroid status and serology. All safety parameters 
evaluated during the study are listed in Table 7.2.2:1 below. The samples will be analysed at the local laboratory 
at each study site. The respective reference ranges must be provided to the central study administration for 
uploading into the eCRF.  
Table 7.2.4:1 Safety laboratory parameters – blood, serum, plasma 
Hematology 
 
 
Hemoglobin 
 
WBC/leukocytes 
 
 
Platelet count / thrombocytes  
 
Differentials: neutrophils, eosinophils, 
basophils, monocytes, lymphocytes 
Liver enzymes/parameters 
 
 
ALAT (alanine transaminase, SGPT) 
 
ASAT (aspartate transaminase, SGOT) 
 
 
Alkaline phosphatase  
 
GT (glutamyl transferase) 
 
Bilirubin total, fractionated if increased 
Clinical chemistry 
 
 
Albumin 
 
Calcium 
 
Creatinine  
 
CRP  
 
Magnesium  
 
Potassium 
 
Sodium 
 
Thyroid status 
 
 
TSH (thyroid stimulating hormone) 
 

  
 
  
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 
Free T4 
 
Pregnancy testing will be performed in serum in female patients of child-bearing potential only. For patients in 
study treatment arm A, pregnancy testing will be performed monthly from start of conditioning and until 12 months 
after last administration of cyclophosphamide. For patients in study treatment arm B pregnancy testing will be 
performed monthly from start of treatment with alemtuzumab until 4 months after the last study administration of 
alemtuzumab.  
The safety measurement schedules differ somewhat in arm A and arm B. See section 6.1.4 for detailed 
information about study and non-study safety follow-up.  
7.2.5 
Serology laboratory parameters 
Serology parameters are analyzed at Visit 1 to rule out active or chronic viral infections as part of the 
eligibility evaluation. EBV and CMV should be checked weekly until Day +100.  
Table 7.2.5:1 Serology laboratory parameters – serum 
Serology 
 
 
Quantiferone 
 
Hepatitis Bs-virus ag 
 
Hepatitis Bs-virus ab 
 
Hepatitis Bc-virus ab 
 
Hepatitis C virus ab 
 
HIV ab 
 
Herpes simplex virus ag/ab 
 
 
Varicella zoster virus IgM/IgG 
 
CMV ab 
 
EBV ab 
 
Toxoplasmosis ab 
 
HTLV ab 
 
Syphilis TP ab 
 
7.2.6 
Chest X-ray  
Chest X-ray is performed at the screening visit (Visit 1) to rule out presence of tuberculosis or other relevant 
pulmonary diseases. 
7.2.7 
Arm A: Pretransplant tolerability investigations 
Ecco cardiography, lung spirometry with DLCO and dental/oral examination will be performed as part of the 
pretransplantation evaluation in arm A in order to rule out ciritical organ dysfunctions and identify and eradicate or 
diminish potenicially infectious foci before start of HSCT-associated chemotherapy regimens. 
7.2.8 
Karnofsky Performance Status 
The Karnofsky Performance Status will be completed by patients in the study arm A to describe  general physical 
performance. The Karnofsky score is not linked to a study endpoint, but is a requested score when updating the 
European Bone Marrow Transplantation (EBMT) register.  
All study sites are requested to report relevant registrations in study arm A to the EBMT. 
7.3 
Research assessments 
A wide array of immunological parameters and other biomarkers will be performed in various patient samples. 

  
 
  
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7.3.1 
Biobanking  
Participation in sampling of whole blood, serum, and plasma for biobanking is mandatory and a prerequisite for 
participation in the study. Information concerning biobanking of these samples are included in the main ICF for 
the study. Detailed instructions on sampling, sample handling, shipment and storage of samples are provided in 
the ISF. 
Biobanking of CSF, DNA, stool and sperm samples (the latter applicable for male patients in treatment arm A 
only) and the transvaginal ultrasound procedure (applicable for female patients in treatment arm A only) are 
voluntary and not a prerequisite for study participation. A separate informed consent form will be provided, and in 
accordance with ethical and regulatory requirements, this must be signed before sampling is executed..  
Biological samples  will be stored in the Biobank Haukeland at HUS, and will only be used as decided by the 
PMC for research related to MS pathogenesis and effects of  the study treatments.   
Measures are implemented to  comply with applicable rules for collection, biobanking, and in particular for future 
use of biological samples and clinical data obtained during this study.  
7.3.2 
Methods and timing of sample collections 
Sampling will be performed at time-points indicated in the Flow Chart. Some of the samples will only be collected 
from patients at selected sites indicated with an “*” in the text below. Details for sample collection, processing and 
storage are provided in the laboratory manual. 
Whole blood:  
From less than 10 mL to a maximum of 120 mL blood will be drawn for preparation of PBMC, buffy coat, serum 
and plasma at each timepoint for sample collection as described in Flow Chart.  
Preparation of serum: 
Approximately 12 mL whole blood will be drawn into untreated serum separator tubes allowed to clot for 50-
60 min, and thereafter centrifuged. The serum will be split into 8 x 500 µL . The will be  stored at -80⁰C in 
Biobank Haukeland.  
Preparation of plasma: 
Approximately 12 mL blood will be drawn into EDTA collection tubes, centrifuged and the plasma split into 8 
x 500 µL aliquots,   and stored at -80⁰C in Biobank Haukeland.  
Cells from blood:  
8 mL whole blood will be drawn into anticoagulant collection tubes, split in 8 x 1 mL aliquots, fixed and stored 
at -80⁰C.  
 
DNA banking:  
Approximately 12 mL blood will be drawn into an EDTA tube as described for “Preparation of Plasma”. The 
buffy coat will be aliquoted into 2 x 500 µL and stored at -80⁰C in Biobank Haukeland. Donation of buffy coat 
for DNA analyses is optional and will be done only at one visit.  
* Preparation of PBMC:  
At different study visits approximately 60 mL (Visit 4.1 and Visit 5), 40 mL (Visit 4.2) and 70 mL (Visit 3.1, 
Visit 7, and thereafter biannually), 90 mL (Visit 6) whole blood will be drawn into anti-coagulant tubes, 
processed and aliquots of approximately 15-20 million cells per mL will be cryopreserved.  These cells will be 
cryopreserved at -196⁰C.  
CSF: 

  
 
  
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Approximately 12 mL CSF will be collected in sterile tubes and centrifuged at low speed to preserve the cells. The 
first 2 mL will be used for routine analysis. The supernatant will be aliquoted into 8 x 500 µL and stored in -80⁰C 
in Biobank Haukeland. The cells will be fixed and stored at -80⁰C.   
Stool: 
A portion (approximately 10 g) of the first stool of the day will be collected, processed, split into 8 x 800 µL 
aliquotes  and frozen at -80 °C in the biobank.  
 
*Sperm: 
Participants will be asked to abstain from ejaculation for 2 consecutive days and then to masturbate without 
lubricant into a glass specimen container.  
 
* Stem cell product: 
Approximately 1 mL of the stem cell product will be collected from patients treated at HUS.  
7.3.3 
Cerebrospinal fluid  
CSF analyses will include, but are not limited to, T cell receptor sequencing, B cell receptor sequencing, 
isoelectric focusing, quantification of neurofilament light chain levels (ELISA) and cytokines, proteomic study for 
potential other biomarkers for therapeutic response, but also other analyses in the future for upcoming scientific 
purposes to better understand the nature of the MS disease and/or the human responses to the applied study 
treatments. 
7.3.4 
Fertility measures 
Sperm sampling will be performed at  the 1 year and 2 year follow-up visits (Visit 7 and 9) to investigate potential 
impact of study treatment on male fertility. Specimen volume, consentration and pH will be measured. Specimens 
will also be inspected for motility and morphology.  
Transvaginal ultra sound will be performed to investigate potential impact of study treatment on female fertility. 
Fertility related hormones will be analyzed in male and female patients.  
 
7.3.5 
Microbiota analysis 
The microbiota of stools will be analysed by DNA extraction and purification, library preparation, 16S rRNA gene 
sequence analysis. Other analyses might also be performed if new knowledge indicates scientific interest to 
better understand the nature of the MS disease and/or the human responses to the applied study treatments. 
7.3.6 
Blood cells  
To investigate characteristics of the treatment mechanisms and identify markers of therapeutic response, cells 
from whole blood will be collected pre- and post-treatment. Mass cytometry will be used to study immune 
reconstitution and immune ablation during treatment. Further, these cells will be used to sequence T-cell  and B-
cell receptors. 
Immune monitoring will be performed in PBMCs, serum and CSF as recommended by EBMT24. Cytokine profiles 
will be detected by flow cytometric analyses of patient serum and CSF before start of treatment and at regular 
intervals after treatment, and before start of other immunomodulatory MS-treatment in patients with (new) 
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Additionally blood for PBMC with separation of CD4 and CD8 will be analyzed immediately using antibody-
covered magnetic beads.  
7.3.7 
Cells from graft samples and blood during apheresis procedure  
During mobilization 16 mL whole blood will be drawn from patients treated at the central study site (HUS) to 
perform cell analyses. An aliquot of the graft sample will also be analyzed with various immunological analyses. 
7.3.8 
Analyses of plasma for virus activation of IgG response 
Several studies have shown an association between first appearence (or relapse) of MS and high levels of 
humoral immune activation against Epstein-Barr virus  (EBV) - in particular titers of EBV nuclear antigen-147; 
EBNA47. A putative mechanism for this relationship is ”molecular mimicry”, i.e. a cross activation of EBV peptides 
and human cellular epitopes. However, the role of EBV in MS is not confirmed, and an enhanced IgG reactivity 
could alternatively reflect EBV-specific antigenic exposure. 
EBV antibodies in serum from both groups of patients will be analyzed retrospectively. Plasma, routinely stored in 
the biobank at regular intervals (and at relapse), will be used for analyses of EBV antibodies. As controls, 
antibody titers against other viruses with or without connection to CNS diseases will be analysed. 
7.3.9 
MRI  
MRI will be performed at regular intervals as part of the clinical effect evaluation as specified in the primary and 
secondary endpoints. Other MRI endpoints related to treatment effect may be added.  
7.3.10 Proteomics 
Proteomics analyses are planned for the CSF samples in this project, and partially also for the plasma/serum 
samples (only targeted analyses). Global quantitative proteomics where as many as possible of the proteins in 
the CSF of all samples to be compared are identified and quantified will be used to get an overview of the 
proteins affected by the treatment. For the proteins of interest from these analyses, those affected by the 
treatment given, we will develop or establish targeted proteomics assays to enable absolute accurate 
quantification of up to 40 proteins in a multiplexed manner. These assays will be used to analyze new samples for 
verifying the initial findings and when verified they will serve as measurement of the affected biological processes 
in larger cohorts of various disease states and treatments to reflect patient disease status and potentially predict 
prognosis and treatment effect. 
8 
SAFETY MONITORING AND REPORTING  
The investigator is responsible for the detection and documentation of events meeting the criteria and definition of 
an adverse event (AE) or serious adverse event (SAE). Each patient will be instructed to contact the investigator 
immediately should they manifest any signs or symptoms perceived as potentially serious. 
The methods for collection of safety data are described below. 

  
 
  
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8.1 
Definitions 
8.1.1 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product and which does 
not necessarily have a causal relationship with this treatment.  
An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether 
or not related to the medicinal (investigational) product.  
The term AE is used to include both serious and non-serious AEs. 
An adverse reaction is defined as a response to a medicinal product or treatment which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal product or treatment 
and an adverse event is at least a reasonable possibility. Adverse reactions may arise from use of the medicinal 
product or treatment within or outside the terms of the marketing authorisation or from occupational exposure. 
Conditions of use outside the marketing authorisation include off-label use, overdose, misuse and abuse. 
If an abnormal laboratory value/vital sign are associated with clinical signs and symptoms, the sign/symptom 
should be reported as an AE and the associated laboratory result/vital sign should be considered additional 
information that must be collected on the relevant eCRF. 
8.1.2 
Serious Adverse Event (SAE) 
A serious adverse evente (SAE) is defined as any untoward medical occurrence that:  
 
Results in death 
 
Is immediately life-threatening 
 
Requires in-patient hospitalization or prolongation of existing hospitalization  
 
Results in persistent or significant disability or incapacity 
 
Is a congenital abnormality or birth defect 
Is an important medical event that may jeopardize the subject or may require medical intervention to prevent one 
of the outcomes listed above. Medical and scientific judgment is to be exercised in deciding on the seriousness of 
a case. Important medical events may not be immediately life-threatening or result in death or hospitalization, but 
may jeopardize the subject or may require intervention to prevent one of the listed outcomes in the definitions 
above. In such situations, or in doubtful cases, the case should be considered as serious. Hospitalization for 
administrative reason (for observation or social reasons) is allowed at the investigator’s discretion and will not 
qualify as serious unless there is an associated adverse event warranting hospitalization. 
A pre-planned hospitalization admission (i.e. elective or scheduled surgery arranged prior to the start of 
treatment) for pre-existing condition, or hospitalization due to a MS-relapse is not considered to be a serious 
adverse event. 
8.1.3 
Suspected Unexpected Serious Adverse Reaction (SUSAR)  
 
Suspected Unexpected Serious Adverse Reactions are SAEs  that are unexpected as defined in section 8.2 and 
possibly related to the investigational medicinal product(s). 
 

  
 
  
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8.2 
Expected adverse events 
To fulfill the regulatory requirement for expedited safety reporting, the Medical Officer appointed by the Sponsor 
evaluates whether a particular adverse event is a known side effect of the treatment or not. Reference documents 
for known side effects are the current versions of the SmPCs for alemtuzumab (Lemtrada®), cyclophosphamide 
(Sendoxan®), anti-thymocyte globuline (ATG-rabbit, Thymoglobulin®), uromitexan (Mesna®). 
8.3 
Time Period for Reporting AE and SAE  
For each patient the standard time period for collecting and recording AE and SAEs will begin at signature of 
informed consent and continue until the day of the 2 year follow-up visit (and until year 5 for the planned 
extension visit). If future funding allows the study extension to be performed, then AE reporting should be limited 
to SAEs and AEs related to study treatment during the extension period.  
During the course of the study, all AEs and SAEs will be proactively registered for each patient; events should be 
followed up to resolution, unless the event is considered by the investigator to be unlikely to resolve due to the 
underlying disease. Every effort should be made to obtain a resolution for all events, even if the events continue 
after study discontinuation/ completion. 
8.4 
Recording of adverse events 
If the patient has experienced adverse event(s), the investigator will record the following information in the eCRF: 
 
The nature of the event(s) described by the investigator in precise standard medical terminology (i.e. not 
necessarily the exact words used by the patient). 
 
The duration of the event described in terms of event onset date and event ended data. 
 
The intensity of the adverse event (mild, moderate, severe) 
 
The Causal relationship of the event to the study medication, which should be assessed as one of the 
following: 
Unrelated: 
There is not a temporal relationship to investigational product administration (too early, or late, or 
investigational product not taken), or there is a reasonable causal relationship between non-investigational 
product, concurrent disease, or circumstance and the AE. 
 
Unlikely:  
There is a temporal relationship to investigational product administration, but there is not a reasonable causal 
relationship between the investigational product and the AE. 
 
Possible:  
There is reasonable causal relationship between the investigational product and the AE. Dechallenge 
information is lacking or unclear. 
 
Probable:  
There is a reasonable causal relationship between the investigational product and the AE. The event 
responds to dechallenge. Rechallenge is not required. 
 
Definite:  

  
 
  
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There is a reasonable causal relationship between the investigational product and the AE.  
 
 
Action taken 
 
The outcome of the adverse event – whether the event is resolved or still ongoing. 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity, whereas 
seriousness is defined by the criteria in Section 8.1.2. An AE of severe intensity need not necessarily be 
considered serious. For example, nausea that persists for several hours may be considered as severe nausea, 
but is not an SAE. On the other hand, a stroke that results in only a limited degree of disability may be considered 
a mild stroke, but would be an SAE. 
8.5 
Reporting procedures 
8.5.1 
AEs and SAEs 
All adverse events and serious adverse events defined in section 8.1 will be registered in the patient's eCRF. 
SAEs must be reported within 24 hours after the site has become aware of the SAE. Every SAE must be 
documented by the investigator. By filling in seriousness criteria on the AE page in the eCRF the SAE form is 
recorded in the database, and notification sent to the Medical Officer (at Sponsor). The initial report shall promptly 
be followed by detailed, written reports if necessary. The initial and follow-up reports shall identify the individual 
subjects by unique code numbers assigned to the latter.  
The Sponsor keeps detailed records of all SAEs reported by investigators, and performs an evaluation with 
respect to causality and expectedness. Based on, among other, SAE reports, the Sponsor will evaluate whether 
the study risk/benefit ratio associated with the study is changed. All participating study sites will be informed 
bimonthly of serious adverse events. 
8.5.2 
SUSARs 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be reported to the Competent Authority and 
Ethics Committee according to national regulations. The following timelines should be followed: 
The sponsor will ensure that all relevant information about SUSARs that are fatal or life-threatening is recorded 
and reported as soon as possible to the Competent Authority and Ethics Committee in any case no later than 
seven (7) days after knowledge by the sponsor of such a case, and that relevant follow-up information is 
subsequently communicated within an additional eight (8) days. 
All other SUSARs will be reported to the Competent Authority and the Ethics Committee as soon as possible but 
within a maximum of fifteen (15) days of first knowledge by the sponsor. 
SUSARs will be reported using the Danish Medicines Agency’s e-form  for electronic reporting to the European 
Union (EU) medicines regulatory network. The e-form is available via the web-site www.laegemiddelstyrelsen.dk. 
8.5.3 
Exemptions to SAE reporting 
A list of serious adverse events that commonly occur in the trial population or are components of a trial endpoint 
are exempted from expedited reporting to regulatory agencies or ethics committees. These events are known 
consequences of the underlying disease, and it is not possible, based on a single case to conclude that there is a 
reasonable possibility that these events are caused by the study treatment. Refer to current version of SmPCs for 
a list of SAEs exempted from expedited reporting to authorities. 

  
 
  
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Fatal and life-threatening serious adverse reactions are NOT exempted from expedited reporting, although they 
are mentioned in the SmPC.  
8.5.4 
Annual safety report 
Once a year during the study period, the Sponsor will provide Competent Authorities with an annual safety report 
according to national guidelines. The format will comply with national requirements.  
8.5.5 
Clinical study report 
The adverse events and serious adverse events occurring within the study period will be discussed in the safety 
evaluation part of the Clinical Study Report. 
8.6 
Procedures in case of emergency  
The investigator is responsible for assuring that procedures and expertise are available to cope with 
emergencies. A Medical Officer is available for clinical guidance. Contact details are provided in the ISF. 
 
9 
DATA MANAGEMENT AND MONITORING   
9.1 
Case report forms 
The Clinical Data Management System (CDMS) used for the eCRF in this study is ViedocTM. The setup of the 
study specific eCRF in the CDMS will be performed by the Department of clinical research support at Oslo 
Univerity Hospital. The eCRF system will be FDA Code of Federal Regulations 21 Part 11 compliant. 
The designated investigator staff will enter the data required by the protocol into the eCase report forms (eCRF). 
The Investigator is responsible for assuring that data entered into the eCRF is complete, accurate, and that entry 
is performed in a timely manner. The electronic signature of the investigator will attest the accuracy of the data on 
each eCRF. If any assessments are omitted, the reason for such omissions will be noted on the eCRFs. 
Corrections, with the reason for the corrections will also be recorded.  
An online eLearning with detailed instructions incorporated is included in the CDMS. After database lock, the 
investigator will receive a digital copy of the subject data for archiving at the investigational site. 
9.2 
Source data  
In accordance with regulatory requirements the Investigator should prepare and maintain adequate and accurate 
source documents and study records. Source data are all information in original records and certified copies of 
original records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents (original records or 
certified copies). Changes to the data should be traceable (audit trail). 
Data reported on the eCRF must be consistent with the source data or the discrepancies must be explained. 
The medical records for each patient should contain information which is important for the patient’s safety and 
continued care, and to fulfill the requirement that critical study data should be verifiable.  

  
 
  
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To achieve this, the medical records of each patient should clearly describe at least: 
 
That the patient is participating in the study, e.g. by including the enrollment number and the study code or 
other study identification 
 
Date when Informed Consent was obtained from the patient and statement that patient received a copy of 
the signed and dated Informed Consent 
 
Results of all assessments confirming a patient’s eligibility for the study 
 
Diseases (past and current; both the disease studied and others, if relevant) 
 
Surgical history, as relevant 
 
Treatments withdrawn/withheld due to participation in the study 
 
Results of assessments performed during the study 
 
WHO performance status assessments conducted as part of the study, if applicable 
 
Treatments given, changes in treatments during the study and the time points for the changes  
 
Visits to the clinic / telephone contacts during the study, including those for study purposes only 
 
Non-Serious Adverse Events and Serious Adverse Events (if any) including causality assessments  
 
Date of, and reason for, discontinuation from study treatment  
 
Date of, and reason for, withdrawal from study 
 
Date of death and cause of death, if available 
 
Additional information according to local regulations and practice 
A source data list will be agreed upon for each site specifying the source at a module or a variable level.  
The current medical history of the subject may not be sufficient to confirm eligibility for the study and the 
Investigator may need to request previous medical histories and evidence of any diagnostic tests. In this case the 
Investigator must retrieve previous medical records.  
Before providing any copy of patients’ source documents to the Sponsor the Investigator must ensure that all 
patient identifiers (e.g. patients name, initials, address, phone number, social security number) have been 
properly removed  or redacted to ensure patient confidentiality. 
9.3 
Study monitoring  
The Sponsor will monitor the conduct of the study by regular visits to study sites and by in-house data quality 
review. The Clinical Study Monitor will check the following: 
 
Informed consent process 
 
Reporting of adverse events and all other safety data 
 
Adherence to protocol and treatment compliance 

  
 
  
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 
Maintenance of required regulatory documents 
 
Drug  accountability 
 
Facilities and equipments 
 
Data completion on the eCRFs including source data verification (SDV). 
The Study Monitor will review the relevant eCRFs for accuracy and completeness and will ask the site staff to 
adjust any discrepancies as required. A combination of on-site, remote and central monitoring will be 
implemented to direct focus and resources to the areas of greatest risk, which have the most potential impact on 
patient safety and data quality.  
Sponsor representatives (e.g. monitors, auditors) and/or competent authorities will be allowed access to source 
data for source data verification in which case a review of those parts of the hospital records relevant to the study 
will be required.  
9.4 
Confidentiality 
The investigator shall arrange for the secure retention of patient identification and code list. Patient files shall be 
kept for the maximum period of time permitted by each hospital. The study documentation (CRFs, Site Files, etc) 
shall be retained and stored during the study and for at least 15 years after study closure, according to current 
legislation. All documentation regarding study drugs and the subject code list must be kept for 30 years after 
expiry date.  All information concerning the study must be stored in a safe place inaccessible to unauthorized 
personnel. 
9.5 
Database management 
Data management will be performed by the Department of clinical research support at Oslo University Hospital. 
The Data management procedures will be performed in accordance with the department’s SOPs and ICH 
guidelines. The data management process will be described in the study specific data handling plan and the 
study specific data handling report after database closure. 
Data entered into the eCRF will be validated as defined in the data validation plan. Validation includes, but is not 
limited to, validity checks (e.g. range checks), consistency checks and customised checks (logical checks 
between variables to ensure that study data are accurately reported) for eCRF data. A majority of edit checks will 
be triggered during data entry and will therefore facilitate efficient ‘point of entry’ data cleaning. 
Data management personnel will perform both manual eCRF review and review of additional electronic edit 
checks to ensure that the data are complete, consistent and reasonable. The electronic edit checks will run 
continually throughout the course of the study and the issues will be reviewed manually online to determine what 
action needs to be taken. 
Manual queries may be added to the system by clinical data management or study monitor. Clinical data 
managers and study monitors are able to remotely and proactively monitor the patient eCRFs to improve data 
quality. 
All updates to queried data will be made by authorised study site personnel only, and all modifications to the 
database will be recorded in an audit trail. Once the queries have been resolved, eCRFs will be signed by 
electronic signature Any changes to signed eCRFs will be approved and resigned by the Investigator. 
Adverse events and medical history will be coded from the verbatim description (Investigator term) using the 
Medical Dictionary for Regulatory Activities MedDRA. Prior and concomitant medications and therapies will be 
coded according to the always latest version of ATC/DDD Index. 

  
 
  
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Once the full set of eCRFs have been completed and locked, the Sponsor will authorise database lock and all 
electronic data will be sent to the designated statistician for analyses. Subsequent changes in the database will 
be restricted to written agreement between HUS and Department for clinical research support at Oslo University 
Hospital, Norway. 
The data will be stored in a dedicated and secured area at HUS. Data will be stored in a de-identified manner, 
where each study participant is recognisable by his/her unique trial subject number. The data will be stored until 
30 years after archiving of the Clinical Study Report.  
 
10 
STATISTICAL METHODS AND DATA ANALYSIS 
10.1 
Determination of sample size 
The sample size for the study was estimated on the basis of previous studies on the comparators. After two years 
of follow-up, the proportion of NEDA after HSCT was 80 % in an observational study17, while it was 32 % in a 
randomized trial after treatment with alemtuzumab3. The proportion of NEDA after HSCT is in this study 
conservatively predicted to be 64 %, representing a double percentage of NEDA compared to 32 % for 
alemtuzumab. A χ2 test was used to determine the sample size using a type 1 error rate of 0.05. A sample size of 
50 patients per treatment group would give a 87 % power to detect this predicted difference while assuming a 
dropout rate of 10 %. In a randomized RRMS treatment trial, the dropout rate was < 10 % in the alemtuzumab 
treatment group3. If there, for any reason, is a dropout rate of more than 10% in one of the treatment arms after 
randomization, but before first treatment, 10 additional patients will be recruited to the study and randomized in a 
1:1 ratio to the two treatment arms. 
 
This volume of patients is expected to be reached within 2 years after start of patient inclusion, based on the 
incidence rate of RRMS in Sweden/Denmark/Norway, which is approximately 1500 patients per year, and the 
current yearly rate of HSCT treatment of RRMS in Scandinavia using current (more narrow) indication criteria: 
approximately 50 patients6 
10.2 
Randomization  
10.2.1 Allocation- sequence generation 
Eligible patients will be allocated in a 1:1 ratio between the two treatment arms, using a computer randomisation 
procedure stratified by age, sex and country. The randomisation will be blocked within each stratum.  
Details of block size and allocation sequence generation will be provided in a separate document unavailable to 
those enrolling patients or assigning treatments.   
10.2.2 Allocation- procedure to randomize a patient 
The computer-generated randomized allocation sequence will be imported into the eCRF system and made 
available to the investigator (and sub-investigator if authorized by the principal investigator). The allocation will 
not be available until the patient has signed the informed consent form and deemed eligible to participate in the 
study. That is, authorized personnel will only know the allocation of included patients, but not for future patients.  

  
 
  
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10.3 
Population for analysis 
- 
Intention to treat (ITT) population: All randomized patients, regardless of protocol adherence. Patients 
that withdraw from the study for any reason at any stage after randomization will still be included in the 
ITT analyses. 
- 
Per-protocol (PP) population: Includes all patients who adhere to the protocol. Only subjects with 
important protocol violations (IPVs) for efficacy will be excluded from the PP population. These IPV  
definitions will include consideration of important violation criteria, treatment non-compliance, treatment 
dispensing errors and prohibited concomitant medication.  
- 
Safety population: Includes all subjects who have received at least one dose of study medication. 
Subjects who withdraw from the study will be included in the safety analysis. A list of withdrawn subjects, 
preferably with the reasons for withdrawal, will be made. 
All efficacy analyses will be performed using the ITT population. In addition, the PP population will be used in 
sensitivity analyses to evaluate the influence of protocol violations on the results from the ITT analyses.  
10.4 
Planned analyses 
Prior to the main statistical analysis, the data base will be locked for further entering or altering of data. A 
separate statistical analysis plan (SAP) will provide further details on the planned statistical analyses. The SAP 
will be finalized, signed and dated prior to database lock. The treatment allocation will be revealed after the 
database lock and used in the statistical analysis.  
There is no formally planned interim analysis. 
Deviation from the original statistical plan will be described and justified in the Clinical Study Report. Amendments 
to plan can be done until day of Database lock. 
10.5 
Statistical analysis 
10.5.1 Primary analysis 
NEDA will be defined as no protocol defined disease activity events during follow-up, as specified in section 2.2. 
The proportion of NEDA after 96 weeks in the HSCT group and the alemtuzumab group will be compared using a 
univariable logistic regression model, conducted as an ITT analysis. The proportion of NEDA in each treatment 
arm with corresponding 95% confidence intervals (CI), the p-value for the difference in proportions and the odds 
ratio (OR) and 95% confidence interval (CI) for NEDA according to treatment with HSCT compared to 
alemtuzumab will be presented. If the odds of NEDA in the HSCT group is signicantly higher compared to the 
odds of NEDA in the alemtuzumab group in this model, it will be concluded that HSCT has demonstrated a 
superior effect on NEDA compared to alemtuzumab. The statistical test used will be based on a two-sided 
hypothesis. Patients lost to follow-up will be excluded from the analysis of primary outcome. 
To assess the robustness of the ITT analysis, two sensitivity analyses will be conducted. First, the analysis above  
will be repeated in the PP population to evaluate the influence of protocol violations. Secondly, if there is 
imbalance in any of the stratification variables  in the treatment arms, these covariates will be include in separate 
multivariable logistic regression models as independent variables to evaluate the influence of these on the 
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10.5.2 Secondary analyses 
The secondary efficacy endpoints will be tested in a hierarchal order, corresponding to the order listed below, to 
account for multiple comparisons. The secondary endpoints will only be tested and interpreted as confirmatory if 
the primary efficacy endpoint reach a significance level of 0.05. Further, subsequent secondary endpoints will 
only be tested and interpreted as confirmatory if the endpoint listed ahead reaches a significance level of 0.05. 
Otherwise, the endpoints will be interpreted as non-confirmatory (i.e. descriptive only) independent of the p-
values. The statistical tests for all secondary endpoints will be based on two-sided hypotheses. Patients lost to 
follow-up will be excluded from all analyses except for endpoints defined by time to event (10.5.2.2, 10.5.2.9, and 
10.5.2.10). For these endpoints, the patients lost to follow-up up will be included in the analysis and censored at 
time of last visit. 
10.5.2.1 Annualized rate of protocol-defined relapses (ARR) at week 96 
The number of protocol-defined relapses in each treatment arm will be counted, and divided on the total time at 
risk in the study to estimate the ARR. Patients will contribute to time at risk from baseline to end of follow-up or 
withdrawal from the study, whichever occur first. The ARR in the two treatment arms will be compared using a 
negative binomial regression model, conducted as an ITT analysis.  The ARR for each treatment arm with 
corresponding 95% CIs, the rate ratio with corresponding 95% CIs and p-value will be presented. The robustness 
of the ITT analysis will be tested using the two sensitivity analyses as specificed for the primary analysis. 
10.5.2.2  Time to onset of first protocol-defined relapse 
Time to first protocol-defined relapse after HSCT or alemtuzumab will be compared using a Kaplan-Meier plot 
and an univariable Cox proportional hazards regression model, conducted as a ITT analysis. The median time to 
first relapse with 95% CIs, the overall hazard ratio with corresponding 95% CIs and p-values will be presented. 
The robustness of the ITT analysis will be tested using the two sensitivity analyses as specificed for the primary 
analysis. 
10.5.2.3  Cumulative combined unique activity (CUA) at week 96 
Combined unique activity will be defined as the presence of Gd-enhancing T1-lesions or new T2-lesions. 
Cumulative CUA will be defined as the total number of new Gd-enhancing T1-lesions and new T2-lesions at week 
24, 48 and 96. The total number of lesions after HSCT or alemtuzumab will be compared using a negative 
binomial regression model, conducted as an ITT analysis. Rate ratio with corresponding 95% CIs and p-value will 
be presented. The robustness of the ITT analysis will be tested using the two sensitivity analyses as specificed 
for the primary analysis. 
10.5.2.4 Proportion with confirmed disability improvement (CDI) at week 96 
CDI will be defined as ≥ 1-point EDSS decrease from baseline that is sustained for a minimum of 24 weeks 
among those with a baseline EDSS of ≥ 2. The proportion of patients with CDI in the two treatment arms will be 
compared using an univariable logistic regression model, conducted as an ITT analysis. The proportion of 
participants with CDI in each treatment arm with corresponding 95% CIs, the p-value for the difference in 
proportions and the OR and corresponding 95% CIs for CDI according to treatment with HSCT compared to 
alemtuzumab will be presented. The robustness of the ITT analysis will be tested using the two sensitivity 
analyses as specificed for the primary analysis. 
10.5.2.6  Proportion with confirmed disability progression (CDP) at week 96 
CDP will be defined as as ≥ 1-point EDSS increase from baseline that is sustained for a minimum of 24 weeks. 
The proportion of patients with CDP in the two treatment arms will be compared using an univariable logistic 
regression model, conducted as an ITT analysis. The proportion of patients with CDP progression in each 
treatment arm with corresponding 95% CIs, the p-value for the difference in proportions and the odds rate and 
corresponding 95% CIs for CDP according to treatment with HSCT compared to alemtuzumab will be presented. 
The robustness of the ITT analysis will be tested using the two sensitivity analyses as specificed for the primary 
analysis. 

  
 
  
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10.5.2.6  Proportion with increased T2-lesion burden at week 96 
Increased T2-lesion burden at week 96 will be defined as the the proportion of patients with presence of new T2-
lesions at week 24, 48 or 96. The proportion of patients with new T2-lesions in the two treatment arms will be 
compared using an univariable logistic regression model, conducted as an ITT analysis. The proportion of 
participants with new T2 lesions in each treatment arm, the p-value for the difference in proportions and the odds 
ratio and corresponding 95% CIs for new T2 lesions according to treatment with HSCT compared to alemtuzumab 
will be presented. The robustness of the ITT analysis will be tested using the two sensitivity analyses as 
specificed for the primary analysis. 
10.5.2.7  Proportion with increased Gd-enhancing lesion burden at week 96 
Increased Gd-enhancing lesion burden at week 96 will be defined as the the proportion of patients with presence 
of Gd-enhancing T1-lesions at week 24, 48 or 96. The proportion of patients with Gd-enhancing lesions in the two 
treatment arms will be compared using an univariable logistic regression model, conducted as an ITT analysis. 
The proportion of participants with Gd-enhancing lesions in each treatment arm, the p-value for the difference in 
proportions and the odds ratio and corresponding 95% CIs for Gd-enhancing lesions according to treatment with 
HSCT compared to alemtuzumab will be presented. The robustness of the ITT analysis will be tested using the 
two sensitivity analyses as specificed for the primary analysis. 
10.5.2.8  Brain atrophy at week 96 compared to week 48 
The difference in brain volume between week 48 and week 96 will be used to estimate the annual change in brain 
volume for each patient, as a measure of brain atrophy betweent two time points. Week 48 will be used as 
comparison instead of baseline to avoid the influence of intital pseudoatrophy related to initiation of 
immunomoduly treatment or HSCT. Annualized change in brain volume in the two treatment arms will be 
compared using a multivariable linear regression model including brain volume at week 48 as a covariate, 
conducted as an ITT analysis. The mean change in annualized brain volume in each treatment arm with 
corresponding standard deviation and the difference in mean change in annualized brain volume between the two 
treatment arms with corresponding 95% CIs and a p-value will be presented. The findings will also be presented 
as percentage change in annualized brain volume.The robustness of the ITT analysis will be tested using the two 
sensitivity analyses as specificed for the primary analysis.  
10.5.2.9  Time to first protocol-defined disease activity event 
Time to first protocol-defined disease activity event after HSCT or alemtuzumab will be compared using a Kaplan-
Meier plot and an univariable Cox proportional hazards regression model, conducted as a ITT analysis. The 
median time to first relapse with 95% CIs, the overall hazard ratio with corresponding 95% CIs and p-values will 
be presented. The robustness of the ITT analysis will be tested using the two sensitivity analyses as specificed 
for the primary analysis. 
10.5.2.10  Time to onset of first new T2 lesion 
Time to first new T2 lesion after HSCT or alemtuzumab will be compared using a Kaplan-Meier plot and an 
univariable Cox proportional hazards regression model, conducted as a ITT analysis. The median time to first 
relapse with 95% CIs, the overall hazard ratio with corresponding 95% CIs and p-values will be presented. The 
robustness of the ITT analysis will be tested using the two sensitivity analyses as specificed for the primary 
analysis. 
10.5.2.11  Total number of Gd-enhancing lesions detected by T1-weighted MRI at 
week 24, 48 and 96. 
The total number of Gd-enhancing at week 96 will be calculated as the sum of lesions detected by brain MRI at 
week 24, 48 and 96. The total number of lesions after HSCT or alemtuzumab will be compared using a negative 
binomial regression model, conducted as an ITT analysis. Rate ratio with corresponding 95% CIs and p-value will 
be presented. The robustness of the ITT analysis will be tested using the two sensitivity analyses as specificed 
for the primary analysis. 

  
 
  
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10.5.2.12  Proportion of patients with NEDA-4 at week 96 
NEDA-4 will be defined as no protocol defined disease activity events during follow-up, as specified in section 
2.2, and without a measured yearly atrophy above 0.4%. The proportion of patients with NEDA-4 in the two 
treatment arms will be compared using an univariable logistic regression model, conducted as an ITT analysis. 
The proportion of with NEDA-4 in each treatment arm with corresponding 95% CIs, the p-value for the difference 
in proportions and the odds ratio and corresponding 95% CIs for NEDA-4 according to treatment with HSCT 
compared to alemtuzumab will be presented. The robustness of the ITT analysis will be tested using the two 
sensitivity analyses as specificed for the primary analysis. 
10.5.2.13 Volumes of hyperintense lesions on T2-weighted scans and hypointense 
lesions on T1-weighed scans at week 48 and 96. 
The change in volumes of T2-lesions and T1-lesions from week 48 to 96 will be compared in the two treatment 
arms using multivariable linear regression models, including lesion volume at week 48 as a covariate, conducted 
as a ITT analysis. The mean change in volume with corresponding 95% CIs will be presented. 
10.5.2.14 Nine Hole Peg Test  and Timed 25-foot walk from baseline to week 96 
Each of the 9-hole peg test (9-HPT) and Timed 25-foot walk (T25FW) test will be conducted twice, and the 
average score for the two recordings will be converted to a Z-score. We will compare the score in the two 
treatment arms using a multivariable mixed effects linear regression model, conducted as an ITT analysis. The 
mean difference in change of T25FW and 9-HPT during follow-up between the treatment arms with 
corresponding CIs and p-value will be presented. The robustness of the ITT analysis will be tested using the two 
sensitivity analyses as specificed for the primary analysis. 
10.5.2.15 The Brief International Cognitive Assessment for Multiple Sclerosis 
(BICAMS) at week 96 
The change in BICAMS test score from baseline to week 96 will be estimated, and compared in the two treatment 
arms using linear regression, including baseline BICAMS test score as a covariate, conducted as an ITT 
analyses. The robustness of the ITT analysis will be tested using the two sensitivity analyses as specificed for the 
primary analysis. 
10.5.3 Safety analyses 
The safety analyses will include descriptive statistics of treatment data, laboratory data, adverse events, MRI 
data, withdrawal data, death  data and vital signs. 
10.5.4 Exploratory analyses 
The following exploratory efficacy endpoints will be analyzed:  
 
EQ-5D-5L 
 
Fatigue Severity Scale (FSS) 
 
Multiple Sclerosis Impact Scale (MSIS) - 29  
 
Severity of relapses (residual disability after relapses) 
 
In addition, exploratory subgroup analyses will be conducted of the primary and secondary efficacy endpoints 
within strata of sex, age at screening (<35 years vs ≥35 years ), EDSS (<4 vs ≥4), disease duration (<5 years vs 
≥5 years), and previous immunomodulatory treatment (< 3 drugs vs ≥3 drugs). 

  
 
  
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10.5.5 Other analyses (eg health economics, patient reported outcomes etc) 
An economic evaluation will be conducted in the Norwegian part of the study comparing the interventions in arms 
A and B. HRQoL scores and incremental cost-effectiveness ratios (ICERs) will be calculated. 
10.5.6 Descriptive statistics 
Information on the following variables will be provided as descriptive statistics: Age, sex, race, time since MS 
diagnosis, time since first clinical event, baseline EDSS, Gd-enhancing lesions (no. and volume), T2-lesions (no. 
and volume), normalized brain volume, number of relapses in past year, number of previous MS 
immunomodulatory treatment s, duration of previous MS immunomodulatory treatment use and generic name of 
previous MS immunomodulatory treatment s. 
Normally distributed continuous variable will be presented as mean with standard deviation. Skewed variables will 
be presented as median with corresponding interquartile range (IQR). Categorical variables will be presented as 
frequencies and percentages.  
 
11 
STUDY MANAGEMENT 
11.1 
Investigator-delegation procedure 
The principal investigator is responsible for making and updating a “delegation of tasks” listing all the involved co-
workers and their role in the project. The PI will ensure that appropriate training relevant to the study is given to 
all of the relevant staff, and that any new information of relevance to the performance of this study is forwarded to 
the staff involved. 
11.2 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations.  
All significant protocol deviations will be recorded and reported in the Clinical Study Report (CSR). 
11.3 
Study amendments 
If it is necessary for the study protocol to be amended, the amendment and/or a new version of the study protocol 
(Amended Protocol) must be notified to and approved by the Competent Authority and the Ethics Committee 
according to EU and national regulations. 
11.4 
Audits and inspections 
Authorized representatives of a Competent Authority and Ethics Committee may visit the site to perform 
inspections, including source data verification. Likewise the representatives from sponsor may visit the site to 
perform an audit. The purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, Good Clinical Practice (ICH GCP), and any 
applicable regulatory requirements. The principal investigator will ensure that the inspectors and auditors will be 
provided with access to source data/documents. 
 

  
 
  
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12 
ETHICAL AND REGULATORY REQUIREMENTS 
The study will be conducted in accordance with the protocol, with the latest version of  the Declaration of Helsinki, 
with ICH-GCP E6(R1) and applicable regulatory requirements. Registration of patient data will be carried out in 
accordance with national personal data laws. 
12.1 
Ethics committee approval 
The study protocol, including the patient information and informed consent form to be used, must be approved by 
the regional ethics committee before enrolment of any patients into the study. 
The investigator is responsible for informing the ethics committee of any serious and unexpected adverse events 
and/or major amendments to the protocol as per national requirements. 
12.2 
Other regulatory approvals 
The protocol will be submitted and approved by the applicable competent authorities before commencement of 
the study. 
The protocol will also be registered in www.clinicaltrials.gov before inclusion of the first patient. 
12.3 
Informed consent procedure 
The investigator is responsible for giving the patients full and adequate verbal and written information about the 
nature, purpose, possible risk and benefit of the study. They will be informed as to the strict confidentiality of their 
patient data, but that their medical records may be reviewed for trial purposes by authorized individuals other than 
their treating physician.  
It will be emphasized that the participation is voluntary and that the patient is allowed to refuse further 
participation in the protocol whenever she/he wants. This will not prejudice the patient’s subsequent care. 
Documented informed consent must be obtained for all patients included in the study before they are registered in 
the study. This will be done in accordance with the national and local regulatory requirements. The investigator is 
responsible for obtaining signed informed consent. 
A copy of the patient information and consent will be given to the patients. The signed and dated patient consent 
forms will be filed in the Investigator Site File binder and also scanned to be part of the patient’s electronic 
medical record at the hospital. 
12.4 
Subject identification 
The investigator is responsible for keeping a list of all patients (who have received study treatment or undergone 
any study specific procedure) including patient’s date of birth and personal number, full names and last known 
addresses.  
The patients will be identified in the eCRFs by patient number, initials and date of birth (not applicable for the 
Netherlands). 
 

  
 
  
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13 
TRIAL SPONSORSHIP AND FINANCING 
The study is sponsored by Helse Bergen HF, Haukeland University Hospital in Bergen, Norway, with funds from 
the Clinical therapy research in the specialist health services (Klinbeforsk). The funds are assigned the Clinic of 
Neurology at Haukeland University Hospital.  
 
14 
TRIAL INSURANCE 
Patients will be covered by the hospital’s insurance in accordance with requirements of the law in the different 
countries. 
 
 
15 
PUBLICATION POLICY 
Upon study completion and finalization of the study report the results of this study will either be submitted for 
publication and/or posted in a publicly assessable database of clinical study results.  
The results of this study will also be submitted to the Competent Authority and the Ethics Committee according to 
EU and national regulations. 
Personnel who have contributed significantly in study planning, study performance and interpretation of study 
results may be included by the PMC in the list of authors (ref. Vancouver convention 1988).  
 
16 
REFERENCES 
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10. Vasconcelos CC, Aurencao JC, Thuler LC, Camargo S, Alvarenga MP, Alvarenga RM. Prognostic factors 
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11. Fisniku LK, Brex PA, Altmann DR, et al. Disability and T2 MRI lesions: a 20-year follow-up of patients with 
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treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, 
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14. Rotstein DL, Healy BC, Malik MT, Chitnis T, Weiner HL. Evaluation of no evidence of disease activity in a 7-
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18. Burman J, Iacobaeus E, Svenningsson A, et al. Autologous haematopoietic stem cell transplantation for 
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19. Sormani MP, Muraro P. Updated views on autologous hematopoietic stem cell transplantation for treatment 
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20. Capello E, Saccardi R, Murialdo A, et al. Intense immunosuppression followed by autologous stem cell 
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21. Atkins HL, Bowman M, Allan D, et al. Immunoablation and autologous haemopoietic stem-cell transplantation 
for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet 2016;388:576-585. 
22. Nash RA, Hutton GJ, Racke MK, et al. High-dose immunosuppressive therapy and autologous hematopoietic 
cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3-year interim report. JAMA neurology 
2015;72:159-169. 
23. Shevchenko JL, Kuznetsov AN, Ionova TI, et al. Long-term outcomes of autologous hematopoietic stem cell 
transplantation with reduced-intensity conditioning in multiple sclerosis: physician's and patient's perspectives. 
Annals of hematology 2015;94:1149-1157. 
24. Alexander T, Bondanza A, Muraro PA, et al. SCT for severe autoimmune diseases: consensus guidelines of 
the European Society for Blood and Marrow Transplantation for immune monitoring and biobanking. Bone 
marrow transplantation 2015;50:173-180. 
25. Muraro PA, Robins H, Malhotra S, et al. T cell repertoire following autologous stem cell transplantation for 
multiple sclerosis. The Journal of clinical investigation 2014;124:1168-1172. 
26. Martins TB, Rose JW, Jaskowski TD, et al. Analysis of proinflammatory and anti-inflammatory cytokine 
serum concentrations in patients with multiple sclerosis by using a multiplexed immunoassay. American journal of 
clinical pathology 2011;136:696-704. 
27. Dsikowitzky L, Schwarzbauer J, Kronimus A, Littke R. The anthropogenic contribution to the organic load of 
the Lippe River (Germany). Part I: Qualitative characterisation of low-molecular weight organic compounds. 
Chemosphere 2004;57:1275-1288. 
28. Hauser SL. Hematopoietic stem cell transplantation for MS: extraordinary evidence still needed. Jama 
2015;313:251-252. 
29. Atkins HL, Freedman MS. Five Questions Answered: A Review of Autologous Hematopoietic Stem Cell 
Transplantation for the Treatment of Multiple Sclerosis. Neurotherapeutics : the journal of the American Society 
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30. Mancardi GL, Sormani MP, Di Gioia M, et al. Autologous haematopoietic stem cell transplantation with an 
intermediate intensity conditioning regimen in multiple sclerosis: the Italian multi-centre experience. Multiple 
sclerosis 2012;18:835-842. 
31. Muraro PA, Martin R, Mancardi GL, Nicholas R, Sormani MP, Saccardi R. Autologous haematopoietic stem 
cell transplantation for treatment of multiple sclerosis. Nature reviews Neurology 2017;13:391-405. 
32. NICE. Illustrative technology appraisal list and QALY shortfall. National Institute for Health and Care 
Excellence 2014. 
33. utredninger No. Stortingsmelding. 34 (2015–2016) Verdier i pasientens helsetjeneste - Melding om 
prioritering 2016. 
34. Sormani MP, Muraro PA, Schiavetti I, et al. Autologous hematopoietic stem cell transplantation in multiple 
sclerosis: A meta-analysis. Neurology 2017;88:2115-2122. 
35. Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for 
patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 2012;380:1819-
1828. 
36. Snowden JA, Saccardi R, Allez M, et al. Haematopoietic SCT in severe autoimmune diseases: updated 
guidelines of the European Group for Blood and Marrow Transplantation. Bone marrow transplantation 
2012;47:770-790. 
37. Hesketh PJ, Bohlke K, Lyman GH, et al. Antiemetics: American Society of Clinical Oncology Focused 
Guideline Update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
2016;34:381-386. 
38. Roila F, Molassiotis A, Herrstedt J, et al. 2016 MASCC and ESMO guideline update for the prevention of 
chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer 
patients. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 
2016;27:v119-v133. 
39. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice 
guideline update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
2011;29:4189-4198. 
40. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). 
Neurology 1983;33:1444-1452. 
41. Arroyo Gonzalez R, Kita M, Crayton H, et al. Alemtuzumab improves quality-of-life outcomes compared with 
subcutaneous interferon beta-1a in patients with active relapsing-remitting multiple sclerosis. Multiple sclerosis 
2016:1352458516677589. 
42. Smedal T, Johansen HH, Myhr KM, Strand LI. Psychometric properties of a Norwegian version of Multiple 
Sclerosis Impact Scale (MSIS-29). Acta neurologica Scandinavica 2010;122:244-251. 
43. Cutter GR, Baier ML, Rudick RA, et al. Development of a multiple sclerosis functional composite as a clinical 
trial outcome measure. Brain : a journal of neurology 1999;122 ( Pt 5):871-882. 
44. Goodkin DE, Hertsgaard D, Seminary J. Upper extremity function in multiple sclerosis: improving assessment 
sensitivity with box-and-block and nine-hole peg tests. Archives of physical medicine and rehabilitation 
1988;69:850-854. 
45. Walker LA, Osman L, Berard JA, et al. Brief International Cognitive Assessment for Multiple Sclerosis 
(BICAMS): Canadian contribution to the international validation project. Journal of the neurological sciences 
2016;362:147-152. 
46. Langdon DW, Amato MP, Boringa J, et al. Recommendations for a Brief International Cognitive Assessment 
for Multiple Sclerosis (BICAMS). Multiple sclerosis 2012;18:891-898. 
47. Ascherio A, Munger KL. Epstein-barr virus infection and multiple sclerosis: a review. Journal of neuroimmune 
pharmacology : the official journal of the Society on NeuroImmune Pharmacology 2010;5:271-277. 
 

  
 
  
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17 
LIST OF APPENDICES 
APPENDIX A – Patient Flow  
 
 

  
 
  
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APPENDIX B – Vaccination programme 
RECOMMENDED VACCINATION PROGRAMME after autologous stem cell transplantation (HSCT) in the RAM-
MS study  
Vaccines 
 
Time after HSCT 
Combination 
vaccine: 
tetanus, 
diphteria, 
pertussis, 
inactivated 
polio virus 
   with 
or 
without 
Hemophilus influenza B 
and/or Hepatitis B virus 
components 
 
 
 
All 
6 mths 
7 mths 
               12 mths 
Influenza virus 
(seasonal vaccine) 
All 
At 4-6 mths, followed by annual vaccination 
Pneumococcus  
(Prevenar 13® or 
corresponding vaccine) 
All 
3 mths 
4 mths 
5 mths 
   
 
Pneumococcus  
(Pneumovax® or 
corresponding vaccine) 
 
 
 
 
12 mths 
 
Human papilloma virus 
(HPV) 
Women according to EBMT* and National vaccine programmes; 
3 doses starting 6-12 mths after HSCT  
 
 
 
 
Supplementary vaccines (only if indicated): 
Measles, mumps and 
red pox (MMR)  
(note: live vaccine) 
Individual 
indication 
After 24 mths if seronegativity against measles and 
no ongoing immunosuppressive medication 
Chicken pox (varicella)  
(note: live vaccine) 
Individual 
indication  
After 24 mths if seronegativity against varicella and 
no ongoing immunosuppressive medication 
Hepatitis B  
Individual 
indication 
After 
6 
mths 
if 
increased 
risk 
of 
infection 
(work/travel) 
Hepatitis A  
Individual 
indication  
For travelers to certain countries, and for people at high 
risk of infection  
 
. 
 
* EBMT: European Society for Blood and Marrow Transplantation 
 
 

  
 
  
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APPENDIX C –  Expanded disability status scale (EDSS) 
 

  
 
  
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APPENDIX D - Patient Reported Outcomes 
D.1 EQ-5D-5L 
 

  
 
  
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D.2 Fatigue Severity Scale 
 
 
 
 

  
 
  
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D.3 Multiple Sclerosis Impact Scale (MSIS) 
 

  
 
  
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APPENDIX E - Karnofsky Performance Status 
 
Karnofsky 
Performance 
Status 
scale
 
 
 

  
 
  
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APPENDIX F - Timed 25 Foot Walk 
 
 

  
 
  
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APPENDIX G - Nine-Hole-Peg Test 
 
  

  
 
  
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APPENDIX H - The Brief International Cognitive Assessment for Multiple 
Sclerosis (BICAMS) 
 
Symbol Digit Modalities test (SDMT)  
 
 

  
 
  
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California Verbal Learning Test 2. Edition (CVLT-II) 
 
 
 

  
 
  
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 Brief Visuopatial Memory Test (BVMT-R, 1-3) -  Faux Stimuli 
 
 
 
 

  
 
  
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Brief Visiopatial Memory Test – revised (BMVT-R, 1-3) Form 1 
T-1 
 
 
 
 
 

  
 
  
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Brief Visiopatial Memory Test – revised (BMVT-R, 1-3) Form 2 
T-2 
 
 
 
 
 

  
 
  
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Brief Visiopatial Memory Test – revised (BMVT-R, 1-3) Form 3 
T-3 
 
 
 
 
 

  
 
  
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California Verbal Learning Test 2. Edition (CVLT-II) 
 
 

  
 
  
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18 
DESCRIPTION OF GLOBAL AMENDMENT(S) 
 
Number of global amendment 
 
2.0 
Date of CTP revision 
 
10-Jul-2017 
EudraCT number 
 
2017-001362-25 
Trial number 
 
- 
Investigational Product(s) 
 
- 
Title of protocol 
 
Randomized Autologous heMatopoietic stem cell transplantation 
versus Alemtuzumab  
for patients with relapsing remitting Multiple Sclerosis 
To be implemented only after approval of 
the IRB / IEC / Competent Authorities 
 
NA 
To be implemented immediately in order 
to eliminate hazard –  
IRB / IEC / Competent Authority to be 
notified of change with request for 
approval 
 
NA 
Can be implemented without IRB / IEC / 
Competent 
Authority 
approval 
as 
changes 
involve 
logistical 
or 
administrative aspects only 
 
NA 
 
Section to be changed 
 
Version 1.0 of the study protocol is re-written using a new 
template (NORCRIN) to ensure all requirements are met with 
regards to guidelines and quality. 
Description of change 
 
Substantial changes. Please refer to the document. 
Rationale for change 
 
Compliance and quality. 
 
 
Number of global amendment 
 
3.0 
Date of CTP revision 
 
22-Aug-2017 
EudraCT number 
 
2017-001362-25 
Trial number 
 
- 
Investigational Product(s) 
 
- 

  
 
  
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Title of protocol 
 
Randomized Autologous heMatopoietic stem cell transplantation 
versus Alemtuzumab  
for patients with relapsing remitting Multiple Sclerosis 
To be implemented only after approval of 
the IRB / IEC / Competent Authorities 
 
NA 
To be implemented immediately in order 
to eliminate hazard –  
IRB / IEC / Competent Authority to be 
notified of change with request for 
approval 
 
NA 
Can be implemented without IRB / IEC / 
Competent 
Authority 
approval 
as 
changes 
involve 
logistical 
or 
administrative aspects only 
 
NA 
 
Section to be changed 
 
 Flow chart 
 Section 1.5 Benefit-risk assessment 
 Section 4.2 In/ex criteria  
 5.2.1 Selection of doses 
 5.2.2 HSCT regimen 
 5.5.1 Restricted therapy 
 6.1.4 Treatment and follow-up  
 7.2.4 Safety laboratory parameters 
Description of change 
 
 Flow chart – correction made 
 Section 1.5 Benefit-risk assessment – description added 
 Section 4.2 In/ex criteria – correction made 
 5.2.1 Selection of doses – clarifications added 
 5.2.2 HSCT regimen – clarifications added 
 5.5.1 Restricted therapy – clarifications re. use of CYP450 
inducing agents in arm A added. 
 6.1.4 Treatment and follow-up – clarifications re. preganancy 
testing in both study arm added. 
7.2.4 Safety laboratory parameters - clarifications re. preganancy 
testing in both study arm added. 
Rationale for change 
 
Changes requested by NOMA after initial application submitted. 
 
Number of global amendment 
 
4.0 
Date of CTP revision 
 
30-Nov-2017 
EudraCT number 
 
2017-001362-25 
Trial number 
 
- 
Investigational Product(s) 
 
- 

  
 
  
Study: RAM-MS  
CLINICAL STUDY PROTOCOL 
20-Dec-2017 
RAMMS Version no. 4.2 – 20Dec2017 
Page 93 of 96 
Title of protocol 
 
Randomized Autologous heMatopoietic stem cell transplantation 
versus Alemtuzumab  
for patients with relapsing remitting Multiple Sclerosis 
To be implemented only after approval of 
the IRB / IEC / Competent Authorities 
 
NA 
To be implemented immediately in order 
to eliminate hazard –  
IRB / IEC / Competent Authority to be 
notified of change with request for 
approval 
 
NA 
Can be implemented without IRB / IEC / 
Competent 
Authority 
approval 
as 
changes 
involve 
logistical 
or 
administrative aspects only 
 
NA 
 
Section to be changed 
 
 Flow chart 
 Section 2 Study objective 
 Section 3 Study design 
 Section 4.2 and 4.3 In/ex criteria 
 Section 5.2.2 HSCT regimen 
 Section 5.2.3 Alemtuzumab – safety monitoring and emergency 
procedures 
 Section 5.5.2 Rescue medication, emergency procedures,.. 
 Section 6.1.4 Treatment and follow-up – Switch to other therapy 
 Section 6.1.8 Switch to other therapy 
 Section 7.1 Assessment of efficacy 
 Section 7.2 Assessment fo safety and tolerability 
 Section 7.3 Research assessments 
 Section 8.5.3 Exemption to SAE reporting 
 Section 10.5 
 Section 12 Ethical and regulatory requirements 

  
 
  
Study: RAM-MS  
CLINICAL STUDY PROTOCOL 
20-Dec-2017 
RAMMS Version no. 4.2 – 20Dec2017 
Page 94 of 96 
Description of change 
 
 Flow chart – minor adjustments and corrections 
 Section 2 Study objective – clarifications 
 Section 3 Study design – clarifications  
 Section 4.2 and 4.3 In/ex criteria – clarification in inclusion 
criteria #5. Exclusion criteria #4 added on request from MPA, 
other minor corrections/clarifications. 
 Section 5.2.2 HSCT regimen – minor clarifications made on 
request from MPA. 
 Section 5.2.3 Alemtuzumab – clarification regarding safety 
monitoring and emergency procedures added on request from 
MPA. 
 Section 5.5.2 Rescue medication, emergency procedures,.. – 
clarifications added to increase patients safety and at the 
same time ensure data quality. 
 Section 6.1.4 Treatment and follow-up – Switch to other therapy 
– details regading daily bloodsampling for safety monitoring 
after stem cell reinfusion, and a statement concerning long-
term follow up in case the planned extension period is not 
done, added on request from MPA.  
 Section 6.1.8 Switch to other therapy – clarification added. 
 Section 7.1 Assessment of efficacy – clarification added 
 Section 7.2 Assessment of safety and tolerability – weekly  
monitoring of EBV and CMV added, and pre-transplant 
tolerability investigations in arm A added in 7.2.7  
 Section 7.3 Research assessments – clarifications and details 
added in section 7.3.1 for biobanking, details regarding MRI 
and proteomics are added. 
 Section 8.5.3 Exemption to SAE reporting – it is added a 
statement to emphasize that fatal and life-threatening SAEs 
are NOT exempted from expedited reporting, on request from 
MPA. 
 Section 10.5 – clarifications re. two-sided hypothesis and 
sensitivity analysis added on request from MPA. 
 Section 12 Ethical and regulatory requirements – paragraph 
rephrased to include compliance with the protocol, on request 
from MPA. 
Rationale for change 
 
Most changes requested by MPA (Swedish Medicines Agency) 
 
Number of global amendment 
 
4.1 
Date of CTP revision 
 
08-Dec-2017 
EudraCT number 
 
2017-001362-25 
Trial number 
 
- 
Investigational Product(s) 
 
- 
Title of protocol 
 
Randomized Autologous heMatopoietic stem cell transplantation 
versus Alemtuzumab  
for patients with relapsing remitting Multiple Sclerosis 

  
 
  
Study: RAM-MS  
CLINICAL STUDY PROTOCOL 
20-Dec-2017 
RAMMS Version no. 4.2 – 20Dec2017 
Page 95 of 96 
To be implemented only after approval of 
the IRB / IEC / Competent Authorities 
 
NA 
To be implemented immediately in order 
to eliminate hazard –  
IRB / IEC / Competent Authority to be 
notified of change with request for 
approval 
 
NA 
Can be implemented without IRB / IEC / 
Competent 
Authority 
approval 
as 
changes 
involve 
logistical 
or 
administrative aspects only 
 
NA 
 
Section to be changed 
 
 Section 2.2 Primary endpoint – a correction made to the 
definition for MS relapse 
 Section 4.2 Exclusion criteria – correction made to criteria #24. 
 Section  7.3.4 Fertility measures – minor correction with regards 
to which parameters will be investigated. 
  
Description of change 
 
Minor non-substantial changes. 
Rationale for change 
 
To avoid misunderstandings and avoid inconsistencies in the 
protocol.  
 
Number of global amendment 
 
4.2 
Date of CTP revision 
 
20-Dec-2017 
EudraCT number 
 
2017-001362-25 
BI Trial number 
 
- 
BI Investigational Product(s) 
 
- 
Title of protocol 
 
Randomized Autologous heMatopoietic stem cell transplantation 
versus Alemtuzumab  
for patients with relapsing remitting Multiple Sclerosis 
To be implemented only after approval of 
the IRB / IEC / Competent Authorities 
 
NO 
To be implemented immediately in order 
to eliminate hazard –  
IRB / IEC / Competent Authority to be 
notified of change with request for 
approval 
 
NO 

  
 
  
Study: RAM-MS  
CLINICAL STUDY PROTOCOL 
20-Dec-2017 
RAMMS Version no. 4.2 – 20Dec2017 
Page 96 of 96 
Can be implemented without IRB / IEC / 
Competent 
Authority 
approval 
as 
changes 
involve 
logistical 
or 
administrative aspects only 
 
YES 
 
Section to be changed 
 
 Flow chart  
Description of change 
 
 Flow chart – Visit 5 in Arm B is moved from 3 months to 4 
months after start of treatment (V4.1) to correspond with V5 in 
arm A (HSCT Day +100). 
 Flow chart – SHBG added in footnote to list of hormones to be 
analysed for fertility status. 
Rationale for change 
 
Change made to V5 in arm B to align timing of 
sampling/assessements with Arm B.