Clinical trial NCT01606215
Conditions: Multiple Sclerosis
Keywords: multiple sclerosis mesenchymal stem cells bone marrow rapidly evolving
Sponsor: Imperial College London
Start date: 2013-01-01; Completion date: 2019-08-01
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a randomised, double-blind crossover study to study the effect of intravenous treatment with autologous (derived from the individuals themselves) mesenchymal stem cells (MSCs) in patients with multiple sclerosis (MS).

Detailed description:
Current treatments for MS target the immune system and are not curative. There is much interest in MSCs as they have the potential to not only affect the immune system but may also promote repair. This study will use MSCs that are harvested from the bone marrow and grown for up to 52 days before being given back to the person from whom they were harvested. This avoids any chemotherapy so is therefore safer than other types of stem cells. In this crossover study, everyone will receive their own stem cells back but in half of the patients it will be delayed by 24 weeks.

The primary outcomes are to check that the procedure is safe and to measure any changes on the MRI at 24 weeks. Other more exploratory measures will try to assess effects on repair in the central nervous system (CNS).

Arms: arm 1: 1-2 x106 MSCs/kg administered at Week 0 arm 2: Suspension media administered at Week 0
Interventions: intervention 1: Mesenchymal stem cells intervention 2: Placebo
Intervention descriptions: intervention 1: 1.0-2.0 million cells/kg body weight intervention 2: Placebo

Protocol documents:
Prot_SAP_ICF_000.pdf: 
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STREAMS 
 
Stem cells in Rapidly Evolving 
Active Multiple Sclerosis 
 
 
Version 6.0 – 18 December 2014 
 
MAIN SPONSOR: Imperial College London  
FUNDERS: UK MS Society and UK Stem Cell Foundation 
STUDY COORDINATION CENTRE: MS Group, Centre for Neuroscience 
NRES reference: GTAC192 
JRCO Reference number: CRO1959 
 
 
 
 
Protocol authorised by: 
 
Name & Role 
Date 
Signature 
 
Dr Paolo Muraro (CI) 
 
 
 
 
 
 
Clinical Reader in Neuroimmunology and Honorary Consultant Neurologist 
Centre for Neuroscience, Division of Experimental Medicine 
Faculty of Medicine, Imperial College 
Direct phone: +44 (0) 207 594 6670 
Fax: +44 (0) 207 594 6548 
E-mail address: p.muraro@imperial.ac.uk 
 
Mailing Address: 
Building 560/Burlington Danes, Room E415  
Imperial College London 
160 Du Cane Road 
London 
W12 0N


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1. STUDY MANAGEMENT  
 
 
Study Management Group 
 
Chief Investigator:  
Dr Paolo A. Muraro MD PhD 
Clinical Reader in Neuroimmunology and Honorary Consultant Neurologist 
Centre for Neuroscience, Division of Experimental Medicine 
Building 560/Burlington Danes, Room E415 Imperial College London 
160 Du Cane Road 
London W12 0NN  
Tel: +44 (0) 207 594 6670   Fax: +44 (0) 207 594 6548 
E-mail: p.muraro@imperial.ac.uk  
 
Co-Investigators:  
Professor Siddharthan Chandran FRCP PhD 
Centre for Multiple Sclerosis Research, University of Edinburgh 
Chancellor's Building, 49 Little France Crescent, Edinburgh 
Scotland EH16 4SB 
Tel: +44 (0) 131 242 7976   
Email: siddharthan.chandran@ed.ac.uk  
 
Professor Francesco Dazzi MD PhD 
Chair in Stem Cell Biology and Head Stem Cell Biology 
Department of Haematology, Faculty of Medicine 
Hammersmith Campus, Imperial College London 
London W12 0NN 
Tel: +44 (0) 208 383 2134    
Email: f.dazzi@imperial.ac.uk 
 
Professor David Miller MD FRACP FRCP 
Professor of Clinical Neurology,  
Department of Neuroinflammation, UCL Institute of Neurology  
Queen Square, University College London 
London WC1N 3BG 
Tel: +44 (0) 207 829 8771   Fax: + 44 (0) 207 278 5616 
     Email: david.h.miller@ucl.ac.uk  
 
Dr Richard Nicholas PhD FRCP 
Consultant Neurologist, West London Neurosciences Centre and Honorary  
Senior Lecturer Imperial College London 
Charing Cross Hospital, Fulham Palace Road 
London W6 8RF 
Tel: +44 (0) 208 846 1186   Fax: +44 (0) 208 846 7487 
E-mail: r.nicholas@imperial.ac.uk 
 
 


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Collaborators: 
 
Dr Omar Malik PhD FRCP 
Consultant Neurologist, West London Neurosciences Centre,  
Charing Cross Hospital, Fulham Palace Road,  
London W6 8RF 
Tel: +44 (0) 208 846 1186  Fax: +44 (0) 208 846 7487 
E-mail: omar.malik@imperial.nhs.uk 
 
Dr Mark W Lowdell PhD FRCPath 
Senior Lecturer in Haematology, UCL and Honorary Consultant Scientist at Royal Free 
Hampstead NHS Trust 
Director of Laboratory of Cellular Therapeutics  
Royal Free Hampstead NHS Trust 
London NW3 2PE 
Tel: +44 (0) 207 830 2183    
Email:  m.lowdell@ucl.ac.uk 
 
Clinical Research Fellow: 
 
Dr Rehiana Ali MB BChir (Cam) MA MRCP 
Centre for Neuroscience, Division of Experimental Medicine 
Imperial College London 
Burlington Danes Building 
160 Du Cane Road 
London W12 0NN 
Email: r.ali12@imperial.ac.uk  
 
Statistician: 
Dr Maria Pia Sormani PhD 
Department of Health Sciences (DISSAL) 
University of Genoa Via Pastore 1 
Genoa 16132 Italy 
Tel: +39 010-3538473    
Email: mariapia.sormani@unige.it 
 
 
Trial Management: 
 
Mr David Wilkie 
Coordinator, Imperial College London 
Room 11L14 (Lab Block) 
Charing Cross Hospital, Fulham Palace Road 
London W6 8RF 
Tel: +44 (0) 208 383 0675  Fax: +44 (0) 208 383 0584 
Email: d.wilkie@imperial.ac.uk  
 
 
 


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Study Coordination Centre 
 
For general queries, supply of study documentation, and collection of data, please contact: 
 
Study Coordinator: Mr David Wilkie 
Tel: +44 (0) 208 383 0675 
Fax: +44 (0) 208 383 0584 
 
 
CRO (study management, monitoring and data management) 
Centro Clinical Trials 
IRCCS Azienda Ospedaliera Universitaria San Martino – IST 
Istituto Nazionale per la Ricerca sul Cancro 
Largo Rosanna Benzi 
16132 Genova, Italy 
Tel +39 010.5558 – 471 (or 477 or 332 or 224) Fax: +39  010354103 
Email:  clinicaltrials@hsanmartino.it 
 
 
 
Clinical Queries 
 
Clinical queries should be directed to the Study Coordinator, Mr David Wilkie, who will direct the 
query to the most appropriate person.  
 
Urgent, out of hours clinical queries should use the 24 hour emergency telephone number: 
+44 (0) 7779106743. 
 
 
 
Sponsor 
 
Imperial College is the main research sponsor for this study.  For further information regarding 
the sponsorship conditions, please contact the Research Governance Manager at: 
 
 
 
Joint Research Compliance Office 
Imperial College London and Imperial Healthcare NHS Trust 
Room 5L10A 
5th Floor, Lab Block 
Charing Cross Hospital 
Fulham Palace Road 
London  W6 8RF 
 
Tel: 0203 311 0205 
Fax: 0203 311 0203 
 
 
 
 
 


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Funders 
 
UK MS Society and UK Stem Cell Foundation Reference  Number:  G088679 
 
This protocol describes the STREAMS study and provides information about procedures for 
entering participants.  Every care was taken in its drafting, but corrections or amendments may 
be necessary. These will be circulated to investigators in the study.  Problems relating to this 
study should be referred, in the first instance, to the Chief Investigator.  
 
This trial will adhere to the principles outlined in the Medicines for Human Use (Clinical Trials) 
Regulations 2 004 (SI 2004/1031), amended regulations (SI 2006/1928) and the International 
Conference on Harmonisation Good Clinical Practice (ICH GCP) guidelines. It will be conducted 
in compliance with the protocol, the Data Protection Act and other regulatory requirements as 
appropriate. 


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2. TABLE OF CONTENTS 
 
1. STUDY MANAGEMENT 
2 
2. TABLE OF CONTENTS 
6 
3. GLOSSARY OF ABBREVIATIONS 
8 
4. STUDY SUMMARY 
9 
5. INTRODUCTION 
10 
5.1 
BACKGROUND 
10 
5.2 
RATIONALE FOR CURRENT STUDY 
11 
6. STUDY OBJECTIVES 
14 
6.1 
PRIMARY STUDY OBJECTIVES 
14 
6.2 
SECONDARY STUDY OBJECTIVES 
14 
7. STUDY DESIGN 
14 
7.1 
STUDY OUTCOME MEASURES 
14 
7.2 
SUBJECT RECRUITMENT 
17 
8. PARTICIPANT ENTRY 
18 
8.1 
REFERRAL CRITERIA 
18 
8.2 
INCLUSION CRITERIA 
19 
8.3 
EXCLUSION CRITERIA 
19 
8.4 
CONCOMITANT MEDICATIONS 
20 
8.5 
WITHDRAWAL CRITERIA 
21 
9. RANDOMISATION AND ENROLMENT PROCEDURE 
21 
9.1 
ELIGIBILITY FOR RANDOMISATION 
21 
9.2 
RANDOMISATION PRACTICALITIES 
21 
9.3 
BLINDING PROCEDURES 
22 
9.4 
UNBLINDING 
22 
10. STUDY TREATMENTS 
22 
10.1 
BONE MARROW HARVEST 
22 
10.2 
ISOLATION AND EXPANSION OF AUTOLOGOUS MSCS 
23 
10.3 
RELEASE OF THE MSC PRODUCT FOR CLINICAL USE 
23 
10.4 
STUDY TREATMENT INFUSION OF AUTOLOGOUS MSCS OR PLACEBO 
23 
10.5 
POST-STUDY TREATMENT INFUSION EVALUATION 
24 
10.6 
TOXICITY ASSESSMENT 
24 
11. PHARMACOVIGILANCE 
24 
11.1 
DEFINITIONS 
24 
11.2 
CAUSALITY 
25 
11.3 
REPORTING PROCEDURES 
26 
12. ASSESSMENT AND FOLLOW-UP 
29 
12.1 
STUDY ASSESSMENTS 
29 
12.2 
SCHEDULE OF VISITS 
29 
12.3 
EVALUATION OF MS 
34 
12.4 
LOSS TO FOLLOW-UP 
35 
12.5 
TRIAL CLOSURE 
35 


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12.6 
CLINIC-BASED ASSESSMENTS 
35 
12.7 
OTHER STUDY EVALUATIONS 
36 
12.8 
MRI PROCEDURES 
37 
13. STATISTICS AND DATA ANALYSIS 
39 
13.1 
RATIONALE 
39 
13.2 
SAMPLE SIZE 
40 
13.3 
EVALUATION OF PRIMARY OUTCOME VARIABLES 
40 
13.4 
EVALUATION OF SECONDARY OUTCOME VARIABLES 
40 
13.5 
EVALUATION OF EXPLORATORY OUTCOMES 
41 
13.6 
DATA ANALYSIS 
41 
13.7 
RECORD RETENTION 
41 
14. MONITORING 
41 
14.1 
RISK ASSESSMENT 
41 
14.2 
MONITORING AT THE STUDY COORDINATION CENTRE 
42 
14.3 
MONITORING AT LOCAL SITE 
43 
15. DOCUMENTATION 
43 
15.1 
CASE REPORT FORMS 
43 
15.2 
SOURCE DOCUMENTATION 
43 
15.3 
SAFETY MONITORING COMMITTEE 
43 
15.4 
DATA RETENTION AND ARCHIVING 
43 
16. REGULATORY ISSUES 
44 
16.1 
CLINICAL TRIALS AUTHORISATION 
44 
16.2 
ETHICS APPROVAL 
44 
16.3 
CONSENT 
44 
16.4 
CONFIDENTIALITY 
44 
16.5 
INDEMNITY 
45 
16.6 
SPONSOR 
45 
16.7 
FUNDING 
45 
16.8 
AUDITS AND INSPECTIONS 
45 
17. TRIAL MANAGEMENT 
45 
18. PUBLICATION POLICY 
46 
19. REFERENCES 
47 
20. APPENDICES 
49 
APPENDIX 1: KURTZKE EXPANDED DISABILITY STATUS SCALE (EDSS) 
49 
APPENDIX 2: MULTIPLE SCLEROSIS IMPACT SCALE (MSIS-29) 
50 
APPENDIX 3: MULTIPLE SCLEROSIS FUNCTION COMPOSITE SCORE (MSFC) 
51 
APPENDIX 4: SF-36 ASSESSMENT (VERSION 2) 
52 
APPENDIX 5: PROTOCOL DEVIATION FORM 
56 
APPENDIX 6: DECLARATION OF HELSINKI 
58 
APPENDIX 7: STEM CELL REFERRALS STANDARD OPERATING PROCEDURE 
61 
APPENDIX 8: MRI PATIENT INFORMATION SHEET 
65 
APPENDIX 9: INFORMED CONSENT FOR MRI SCAN 
66 
 


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3. GLOSSARY OF ABBREVIATIONS 
 
AE 
Adverse event 
ATMP 
Advanced Therapy Medicinal Product 
BM 
Bone marrow 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CRF 
Case report form 
CRO 
Clinical Research Organisation 
CSF 
Cerebrospinal fluid 
ECG 
Electrocardiogram 
e-CRF 
Electronic case report form 
EDSS 
Extended Disability Status Scale 
FS 
Functional systems 
FSS 
Functional subscores 
GA 
Glatiramer acetate 
GCP 
Good Clinical Practice 
GEL 
Gadolinium enhancing lesion 
GP 
General Practitioner 
HIV 
Human Immunodeficiency Virus 
HTLV 
Human T-cell Lymphotropic Virus 
ICH-GCP 
International Conference on Harmonisation on Good Clinical Practice 
IFN-β 
Interferon β 
iPSP 
Induced pluripotent stem cells 
IV 
Intravenous 
LP 
Lumbar puncture 
MHRA 
Medicines and Healthcare Regulatory Agency 
MRI 
Magnetic resonance imaging 
MS 
Multiple sclerosis 
MSC 
Mesenchymal Stem/Stromal Cells 
MSFC 
Multiple Sclerosis Functional Composite 
MSIS-29 
Multiple Sclerosis Impact Scale-29 
NB 
Negative binomial 
NHS 
National Health Service 
PASAT 
Paced Auditory Serial Addition Test 
PBMC 
Peripheral blood mononuclear cell 
PIS 
Patient Information Sheet 
PPMS 
Primary progressive multiple sclerosis 
R&D 
Research and Development 
RRMS 
Relapsing remitting multiple sclerosis 
SAE 
Serious adverse event 
SF-36 
Short Form-36 
SOP 
Standard Operating Procedure 
SPMS 
Secondary progressive multiple sclerosis 
SSA 
Site Specific Assessment 
SUSAR 
Suspected unexpected serious adverse reaction 
T25-FW 
Timed 25-Foot Walk 
 
 
KEYWORDS: Multiple Sclerosis, rapidly evolving, mesenchymal stem cells, bone marrow 


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4. STUDY SUMMARY 
 
 
 
TREATMENT 
At week 0 and at week 24 a single infusion of either ex-vivo expanded 
autologous MSCs or suspension media will be administered intravenously. 
MSCs will be given at 1-2 x 106 MSC/Kg recipient body weight as at baseline.  
TITLE 
Stem cells in Rapidly Evolving Active Multiple Sclerosis (STREAMS) 
 
DESIGN 
 
Randomised double-blind crossover study 
 
AIMS 
 
To describe the safety and efficacy of intravenously administered autologous 
MSCs in patients with Multiple sclerosis (MS). 
 
OUTCOME MEASURES 
 
 
Primary outcome: To assess the safety of intravenous therapy with 
autologous MSCs in MS patients. The safety of MSCs infusion will be 
evaluated including frequency, timing and severity of any adverse events in 
both MSCs and placebo treatment groups. A statistical comparison of the 
number of adverse events between treatment groups will be carried out using 
a chi-square test.  
 
Co-Primary outcome: To assess the activity of autologous MSCs in MS 
patients. The total number of gadolinium-enhancing lesions (GEL) at MRI at 
weeks 4, 12 and 24 will be compared between treatment groups using a 
Negative Binomial (NB) regression analysis, adjusting for the number of GEL 
at baseline.  
    Secondary outcomes: To gather preliminary information about the efficacy of 
the experimental treatment in terms of combined MRI activity, incidence of 
relapses and disability progression. 
 
INCLUSION CRITERIA 
 
Patients with clinically and radiologically active multiple sclerosis as defined by: 
1. Diagnosis of MS: 
a. Relapsing remitting MS (RRMS): >1 moderate-severe relapse and >1 GEL 
in past 18 months or >1 moderate-severe relapse and >1 new T2 lesion in 
past 18 months. 
b. Secondary progressive MS (SPMS) with an increase of >1 EDSS point (if 
baseline EDSS < 5.0) or 0.5 EDSS point (if baseline EDSS >5.5), in the 
previous 18 months and >1 GEL in past 18 months or >1 moderate-severe 
relapse and >1 new T2 lesion in past 18 months. 
c. Primary progressive MS (PPMS) patients with positive oligoclonal bands in 
the cerebrospinal fluid (CSF) and an increase of >1 EDSS point (if baseline 
EDSS < 5.0) or 0.5 EDSS point (if baseline EDSS >5.5), or quantifiable, 
objective evidence of equivalent progression in the previous 18 months and 
>1 GEL in past 18 months or >1 new T2 lesion in past 18 months. 
 
2. Age 18 to 50 years. 
3. Disease duration 0 to 10 years from diagnosis (inclusive). 
4. EDSS 2.0 to 6.5 at screening evaluation. 
5. ≥1 GEL on MRI within 6 months prior to harvesting. 
6. Adequate culture of subject’s MSCs and their release for clinical use.  
DURATION 
4-year project with staggered recruitment of subjects. 


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5. INTRODUCTION  
 
5.1 
BACKGROUND 
 
5.1.1 The burden of MS 
Multiple sclerosis (MS) is an inflammatory demyelinating disease associated with neurological 
impairment and affects approximately 100,000 young adults in the UK alone. MS can cause severe 
neurological impairment and affects the quality of life of both the individual and their families. MS is 
also a major socio-economic burden for society; it costs the United Kingdom approximately 
£12,000 per patient per year in the early stages of the disease but this rises to nearly £60,000/year 
in the advanced stages [1].  
 
5.1.2. The challenges of MS 
Multiple sclerosis (MS) is a very complex disorder both clinically and pathologically [2]. It is a 
chronic inflammatory disease of the central nervous system (CNS), which ultimately leads to 
myelin damage and axonal loss. The cause is unknown.  Aetiology is multifactorial, but the key 
pathogenic event appears to be an uncontrolled response of components of the immune system (T 
and B lymphocytes) to myelin proteins.  
There are different forms of the disease. About 80% of the patients have a relapsing-remitting (RR) 
course that, in two-thirds of cases, will evolve into a secondary progressive (SP) course after about 
10-15 years of the disease. About 20% of the patients have a progressive course from onset, 
called “primary progressive MS” (PPMS) [3]. It is believed that, in MS, inflammation and irreversible 
neurodegeneration coexist, with inflammation causing relapses and neurodegeneration being 
responsible for the irreversible disability that characterises most patients with chronic disease. 
Clinical severity of MS ranges from benign disease, in which the patient remains fully functional in 
all neurological systems (15 years after disease onset) to malignant MS which is characterised by 
an aggressive course resulting in accumulation of severe disability or death within a short time. The 
majority of patients suffer from a disease course of intermediate severity between these two 
extremes.  
 
5.1.3. Current treatments for MS 
No curative therapies exist for MS.  As both the aetiology and pathogenesis underlying the disease 
are, as yet, unknown and due to the existing clinical heterogeneity in the MS population, treatments 
are suboptimal and have been challenging to develop.  
 
Current immunomodulatory therapies for MS - including the use of interferon β (IFN-β), glatiramer 
acetate (GA) or mitoxantrone - are only partially effective, do not abolish inflammation and have 
only modest effects on disease progression. Natalizumab, a humanised antibody against the 
cellular adhesion molecule (α-4 integrin), prevents the adhesion of lymphocytes and monocytes to 
endothelial cells of the blood brain barrier and therefore interferes with the entry of inflammatory 
cells into the CNS. It is more efficacious than the aforementioned immunomodulatory drugs, 
reducing the relapse rate by 68% and progression of disability by 54% when compared to placebo. 
There is a 1:1000 risk of developing progressive multifocal leukoencephalopathy (PML), an 
opportunistic infection of the CNS, in MS patients who have been treated with natalizumab for 
more than 2 years [4]. 
 
5.1.4. Development of new disease modifying treatments for MS 
Recently, there have been significant developments in new treatment strategies for MS, including 
monoclonal antibodies for targeted immunomodulation  (daclizumab, campath-1H, rituximab),  
limiting immune cell trafficking (e.g. fingolimod), or ‘resetting’ the immune system (through high-
dose cyclophosphamide or haematopoietic stem cell transplantation) [5]. These therapies,  
 


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however, are at different stages of clinical development and evaluation of their safety and efficacy 
in treating MS requires further investigation. 
 
5.1.5. Surrogate markers of disease in MS 
Increasing evidence suggests that Magnetic Resonance Imaging (MRI) measures may offer 
sensitive, objective biomarkers of disease phenotype.  MRI is the most widely utilised surrogate 
marker of disease activity in MS.  Among MR metrics, the number of gadolinium-enhancing lesions 
(GEL) provides a measure of new inflammatory activity [6] and a large number of clinical trials have 
used gadolinium-enhanced lesions as the outcome measure.  However, the relationship between 
such “conventional” MRI markers and the clinical evolution of disease is weak and MR metrics 
providing additional brain structural and metabolic information are expected to better predict clinical 
outcomes and capture important aspects of disease pathology [7]. 
 
 
5.2 
RATIONALE FOR CURRENT STUDY 
 
5.2.1. Mesenchymal stem/stromal cells (MSCs) 
Mesenchymal stem/stromal cells (MSCs) are non-haematopoietic cells that reside in adult bone 
marrow and have the ability to self-renew and differentiate into tissues of mesodermal origin [8]. 
The relative ease by which MSCs can be expanded ex-vivo without significant manipulations has 
made them a potential candidate for use in regenerative medicine. They demonstrate extensive 
proliferative capacity in vitro and retain the ability to differentiate into several mesenchymal 
lineages, such as bone, cartilage, adipose tissue and muscle in lineage-specific cultures [9, 10]. 
Such multipotential capacity of MSCs appears to persist after transplantation - following intra-
uterine injection of human MSCs into sheep, these cells engrafted and differentiated along multiple 
mesenchymal lineages (which was site-specific) and were still detectable for up to 13 months after 
transplantation [11]. In vitro, MSCs proliferate to spindle-shaped cells in confluent cultures. The cell 
yield after expansion varies with the age and condition of the donor and with the harvesting 
technique [12, 13]. In the absence of an agreed standardised marker, it is difficult to characterise 
MSCs so they are typically defined by a combination of phenotypic and functional characteristics. 
By flow cytometry, MSCs are negative for the haematopoietic markers CD14, CD34 and CD45. 
The cells remain positive for a number of adhesion molecules, including CD73, CD90, CD105 and 
CD166. The hallmark of MSCs is tri-lineage potential in vitro; i.e. the ability to differentiate into 
bone, cartilage and fat upon appropriate induction. MSCs give rise to the supportive stroma that 
constitutes the haematopoietic microenvironment and so sustain haematopoiesis in vitro by 
expression of a variety of haematopoietic cytokines (including IL-6, IL-11, leukemia inhibitory 
factor, stem cell factor and flt3/flk2 ligand) and growth factors but also via direct physical 
association [14, 15]. Human MSCs express human leukocyte antigen (HLA) class I and can be 
induced by interferon-gamma (IFNγ) to express HLA class II which should allow recognition by 
alloreactive T cells. However, this does not happen suggesting that MSCs escape detection by the 
immune system. They have immunomodulatory effects demonstrated in co-culture experiments in 
which human MSCs (even after being pre-cultured with IFN-γ) fail to induce proliferation of 
allogeneic lymphocytes, as reviewed in [16]. MSCs also escape lysis by cytotoxic lymphocytes 
(CTLs) despite expression of HLA class 1, the usual targets for CTL lysis, and by Killer-cell 
Immunoglobulin-like Receptors (KIR) ligand-mismatched Natural Killer cells [17]. When MSCs are 
present in mixed lymphocyte cultures (MLC), T-cell proliferation is suppressed [18]. The 
suppression is independent of HLA and occurs when added MSCs are autologous to the 
stimulatory or responder lymphocytes, or derived from a third party donor. Lymphocyte proliferation 
induced by mitogens is also markedly reduced in the presence of autologous or allogeneic MSCs 
[18]. MSCs which have differentiated into adipocytes, osteoblasts and chondrocytes retain the  
capacity to reduce lymphocyte proliferation in MLC [19]. In fact, differentiation, particularly along 
the osteogenic lineage, enhances their immunosuppressive effect. 


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5.2.2. Preclinical work on MSCs as relevant to multiple sclerosis 
Uccelli and colleagues have extensively evaluated the effect of MSCs on experimental 
autoimmune encephalomyelitis (EAE), an experimental model of MS. They demonstrated that 
MSCs infused intravenously homed to lymphoid organs, ameliorated EAE and reduced infiltration 
of the CNS by T cells, B cells and macrophages [20]. More recently the same group demonstrated 
that MSCs migrate into the inflamed CNS and whilst they do not differentiate into neural cells, this 
is still associated with reduced demyelination and axonal loss [21]. These results suggest that 
MSCs exert their therapeutic activity on the inflamed CNS through the peripheral control of immune 
cells and a protective effect in situ [22]. In addition, MSCs could foster endogenous repair through 
the recruitment of local neural precursor cells leading to some degree of endogenous neurogenesis 
and remyelination [23]. Many other features are also likely to be relevant for exploitation of MSCs 
in MS and CNS related diseases. MSCs display a potent antioxidant effect in EAE affected mice 
[24] and this neuroprotective effect may result from the release of anti-apoptotic molecules [25] and 
of neurotrophins [26]. These results support the concept that MSCs are likely to foster CNS repair 
not only by acting as tolerogenic cells, but also as bioactive providers of trophic and anti-apoptotic 
factors leading to neuroprotection [27]. Autologous bone marrow-derived MSCs from MS patients 
exhibit the same properties as MSCs from healthy donors in terms of proliferation, phenotype, in 
vitro differentiation and immunosuppressive ability [28, 29].  
 
5.2.3. Clinical experience of MSC therapy in humans 
Safety: It has been estimated that at least 2000 patients in total have been treated with MSCs 
either within the clinical trial setting or as anecdotal cases. This includes a number of patients with 
stroke and MS with no reports of significant graft related complications such as induction of 
immunodeficiency and its attendant complications of opportunistic infections and malignancy. The 
procedure is simple, relatively cheap, potentially widely applicable and the autologous source is 
ethically acceptable to all patients. Recent studies have shown that MSCs from autoimmune 
patients display normal ability to support haematopoiesis [30], immunomodulatory activity [31] and 
surface and molecular phenotype [32], thus supporting the possibility of safely utilising autologous 
MSCs for transplantation purposes in these patients. 
 
Clinical experience in Graft-versus-host disease (GvHD) and Crohn’s disease: Pre-clinical 
experiments have shown that MSC infusions can be highly efficacious in GvHD but ineffective if 
administered before the onset of the disease or after permanent tissue damage has occurred, thus 
indicating that an acute inflammatory microenvironment is crucial to promote the therapeutic 
properties of MSCs [33]. The initial clinical experience with GvHD supports such a notion, because 
MSCs have no effect on the chronic form of the disease. Pre-clinical studies have extensively 
supported this notion [34-36] and more recently, a European Blood and Marrow Transplantation 
(EBMT) multicentre clinical trial has described the successful use of MSCs in severe steroid-
resistant acute graft-versus-host disease (GvHD), with 60% of patients obtaining complete durable 
remissions without toxicity [37]. MSCs are currently being tested for the treatment of Crohn’s 
disease based on the observation that transplanted bone marrow cells can repopulate the human 
gastrointestinal tract and that BM-derived epithelial cells are remarkably increased during the 
epithelial regeneration after GvHD and ulcer formation [38]. 
 
Clinical experience of MSC treatment in MS: There are reports of small numbers of patients with 
MS who received IV or intrathecal (IT) infusions of MSC cells with some reported benefit. The 
results of an early phase I/II study of MSCs in neurological diseases reported on the administration 
of autologous MSCs to 19 amyotrophic lateral sclerosis and 15 MS patients [39]. MSCs were given 
as a combination of IT and IV injections, at doses up to 60–70x106 cells per injection per patient 
and patients were followed for 6–28 months with the main purpose being to determine feasibility 
and safety. No patient experienced significant side effects except that of mild meningeal irritation, 
having symptoms of headache and fever, in those receiving IT injections of cells. Magnetic  
 
 


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resonance imaging (MRI) in 20 of the patients did not reveal any unexpected pathology 1 year after 
MSC transplantation. No injection-related (early or late) infections were reported. Additional data  
on the use of MSCs in MS included a small study in 10 patients with MS from Iran, which reported 
no significant adverse events [40]. A MRC funded phase IIa study (with MS Society addendum 
funding) by the applicants (SC & DHM) had also treated 10 patients. The importance of this latter 
study with regard to the current proposal is twofold: (1) it had established capability for cell 
expansion, validation, regulatory screening of autologous MSCs with successful intravenous 
delivery of autologous MSCs to 10 patients without any adverse events; and (2) the patients had 
progressive disease unlike the proposed study that is targeted at an “inflammatory-dominant” 
cohort with clinically and radiologically highly active disease. Thus we would regard the two studies 
as being complementary - with the MRC study providing significant added value, leverage and 
field-tested expertise and methodologies e.g. standard operating procedures (SOPs) to ensure that 
the desired outcomes are realistic. We are satisfied that sufficient information on the safety of 
autologous bone marrow-derived, intravenously administered MSCs exists to propose exploring 
such therapy in patients with active inflammatory MS. This position appears justified by the very 
latest publication which was a randomised, double-blind, placebo-controlled trial of autologous 
mesenchymal stem cells in multiple sclerosis [41]. A similar crossover trial design was employed 
and the results in 9 patients, whilst not powered to detect significance, showed a trend to lower 
mean cumulative number of GELs at 6 months in those patients treated with MSCs. No serious 
adverse events were identified. 
 
5.2.4. Rationale for this study 
Evidence from preclinical studies suggested that MSCs were an effective cell therapy for 
experimental autoimmune encephalomyelitis (EAE). In EAE, the IV injection of MSCs ameliorates 
the clinical course of acute disease and decreases demyelination, immune infiltrates and axonal 
loss, but has little or no effect in later stages of EAE. These results led to the conclusion that MSC 
administration should focus on individuals with on-going inflammation and before they develop 
irreversible disability. Pioneer small clinical studies in MS have already suggested their safety, thus 
paving the road from their clinical exploitation into larger phase II studies addressing their biological 
effect on markers of disease activity [39]. An international panel of MS neurology and stem cell 
experts, as well as immunologists formed an “International Mesenchymal Stem Cells 
Transplantation” (MSCT) Study Group with the aim to derive a consensus on the utilisation of 
MSCs for the treatment of MS along with protocols for the culture of the cells and the treatment of 
patients. This international consensus, based on the efforts of Dr. Uccelli (University of Genoa) and 
Dr. Freedman (University of Ottawa), has been achieved and was published in 2010 [42]. In the 
consensus paper, the authors devised the synopsis of a phase I/II clinical trial, which will be fully 
adopted by scientists and clinicians belonging to the MSCT Study Group and presented to the 
respective national regulatory and funding agencies as single nation studies. This approach will 
enable the running of a series of parallel, independent but related, national studies adopting 
identical protocols, inclusion and exclusion criteria, primary and secondary outcomes collected on 
identical forms. The opportunity to pool the results of these studies will overcome the limitations of 
small phase I/II studies and provide enough statistical power to draw conclusions on the safety and 
efficacy of autologous MSCs transplantation in MS [42]. Our study will be conducted following the 
guidelines of the aforementioned consensus and utilise a protocol identical to the one adopted in 
other European countries and North America participating in this international collaborative effort. 
Identical, parallel but independent national trials will be conducted in Spain, Sweden, Denmark, 
France, Germany and Canada in order to assess the efficacy, safety and the toxicity of MSC 
infusion, as administered within this specific treatment protocol, in active MS. Evaluation of primary 
and secondary outcomes as well as exploratory outcomes will be carried out at the single national 
trial level but, more importantly, also on the entire data set obtained by pooling the results of all 
national trials, for an expected total of 160 randomised patients. 
 
 


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6. STUDY OBJECTIVES 
 
6.1 
PRIMARY STUDY OBJECTIVES 
 
There are two co-primary objectives: 
 
 
To assess the safety of IV therapy with autologous MSCs in MS patients.  
 
To evaluate the activity of autologous MSCs in MS patients, quantified by the reduction in 
the number of new contrast-enhancing lesions (GEL) on MRI scans over a 24 week period. 
 
 
6.2 
SECONDARY STUDY OBJECTIVES 
 
To gather preliminary information about the efficacy of the experimental treatment in terms of: 
 
 
combined MRI activity including MRI measures of remyelination 
 
clinical activity including incidence of relapses and disability progression and  
 
effect on immunological markers (for patients in the first phase of recruitment). 
 
 
 
7. STUDY DESIGN 
 
STREAMS is a randomised, double-blind crossover study comparing IV treatment with autologous 
MSCs vs. suspension media in MS patients with regards to the number of adverse events and new 
MRI activity (measured as GEL) at 24 weeks. A secondary analysis will compare the number of 
adverse events and GEL at weeks 0-23 and 24-48 within each treatment group (see Figure 1). 
 
7.1 
STUDY OUTCOME MEASURES 
 
Primary endpoints:  
 
number, timing and severity of adverse events in the MSC treatment group will be 
compared to the placebo group; 
 
total number of GEL counted over month 1, 3 and 6 will be compared between treatment 
groups. 
 
Secondary endpoints:  
 
volume of GEL identified over months 1, 3 and 6 will be compared between treatment 
groups. 
 
number of GEL counted over months 7, 9 and 12 (crossover re-treatment) compared 
between treatment periods (placebo vs. active treatment) for each patient. 
 
combined unique MRI activity (number of new or enlarging T2, or enhancing or re-
enhancing lesions). 
 
number of relapses in MSC treatment group vs. placebo group in the first 6 months and 
after crossover re-treatment in the two groups (see below for the definition of a relapse). 
 
time to sustained progression of disability (RRMS group) (see below for definition of 
sustained EDSS progression) and proportion of progression-free patients.  
 


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 
proportion of disease-free patients (i.e. patients without relapses) and progression of MRI 
activity in the two groups.  
 
changes in the Multiple Sclerosis Functional Composite (MSFC) score in MSC treatment 
group compared to the placebo group. 
 
effect of MSCs on the peripheral immune responses (for patients in the first phase of 
recruitment). 
 
effect of MSCs on delayed type hypersensitivity (Type 1V hypersensitivity) reaction as 
measured by the Mantoux test. 
 
Given the exploratory nature of MSC use, no specific quantitative assumptions have been made 
about the outcomes measures. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 1:  Patient flow and study outline 
 
 


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7.2 
SUBJECT RECRUITMENT 
 
 
Patients recruited will have been seen by the Imperial College Healthcare NHS Trust MS 
service (Figure 2).  
 
Interested parties who enquired about the trial have been directed to an email address to 
register their interest: stemcellms@imperial.ac.uk. Patients have been sent a response 
described in the ‘Stem Cell referrals’ standard operating procedure (Appendix 7) to prevent 
subjects delaying appropriate therapies recommended by their current medical 
professional. 
 
When ethical approval is given, subjects will be contacted to determine: 
o Whether they are they still interested in taking part 
o Whether they fit the inclusion criteria that can be assessed over the phone  
o Whether they would be able to be referred to Imperial College Healthcare NHS 
Trust MS service for further evaluation if needed. 
 
On receipt of a NHS referral letter, the patient will be seen in the NHS clinic for an 
assessment of their MS. Prior to clinical review by Imperial College Healthcare NHS Trust 
MS service, subjects will be contacted to provide further details of their MS diagnosis, if not 
already provided, to consider the likelihood of there being further management options -  
including all ongoing trials – available to them as a consequence of that review. 
 
The review by the Imperial College Healthcare NHS Trust MS service will ensure that 
appropriate investigations have been performed to confirm the diagnosis of MS. 
Management options – including all available clinical trials – will be discussed with the 
patient. If appropriate, it will be confirmed that their MS care will be under Imperial College 
Healthcare NHS Trust otherwise their care will revert solely to their usual medical 
practitioner.  
      
      
 
     Figure 2: Patient eligibility selection and flow 
 
Interested enquiry directed to:
stemcellms@imperial.ac.uk
Potential subject 
seen in clinic
Standard email response (see Appendix 7)
NHS clinic – diagnosis and management 
options including clinical trials discussed
Contact interested subject 
Request NHS GP referral
Study approved
Study screening visit to assess eligibility
Contact appropriate healthcare 
professional to obtain further information
NHS GP referral 
received
Further information 
received
PIS sent to patient
R
EFER
R
A
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PR
O
CESS
STU
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Eligibility for the STREAMS study will only be considered at the study screening visit. The inclusion 
criteria will need to be fulfilled (see section 8.2).  
At this visit, they will have a full discussion of the Patient Information Sheet (PIS) and if they 
consent, will proceed to undergo all study assessments and procedures including bone marrow 
harvesting (see Figure 4). 
 
 
 
8. PARTICIPANT ENTRY 
 
8.1 
REFERRAL CRITERIA 
 
All potential study patients need to be referred by a clinician and the referral should include: 
1. A current diagnosis of MS. 
2. Age 18-50. 
3. An assessment of mobility level (preferably EDSS score) documenting EDSS 2.0-6.5 or 
equivalent mobility. 
4. MRI brain and/or spinal cord performed within the last 18 months with findings consistent 
with MS and showing at least one gadolinium-enhancing lesion (GEL) or one new lesion 
compared to previous imaging. 
 
 
Justification for the referral criteria 
 
Criterion 1  
Given the experimental nature of the intervention, patients with only one symptomatic episode 
(diagnosed MS on grounds of paraclinical support) will not be considered.  
All patients with clinically defined MS will need to satisfy the revised McDonald criteria.  
 
Criterion 2  
The lower limit of age has been set because MS in children is rare and differs significantly from MS 
in the adult population, and because the study will be carried out in adult (not paediatric) hospital 
facilities. The upper limit of age has been specified for safety of the experimental cell therapy 
intervention and to limit the confounding effect of age-related differences in spontaneous lesion 
repair in the study population. 
 
Criterion 3  
A lower Expanded Kurtzke Disability Status Score (EDSS) limit has been specified to ensure that 
recruited patients have acquired sufficient disability to merit experimental therapeutic approaches.  
An upper Expanded Kurtzke Disability Status Score (EDSS) limit has been specified to ensure that 
recruited patients are able to tolerate the trial procedures and assessments.  
 
Criterion 4  
This provides a group which will reduce the chance of unnecessary patient testing to meet MRI 
requirements for the inclusion criteria.  
 
 
 


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8.2 
INCLUSION CRITERIA 
 
Patients with clinically and radiologically active multiple sclerosis as defined by: 
 
1. Diagnosis of MS: 
a. Relapsing remitting MS (RRMS): >1 moderate-severe relapse and >1 GEL in past  
18 months or >1 moderate-severe relapse and >1 new T2 lesion in past 18 months. 
b. Secondary progressive MS (SPMS) with an increase of >1 EDSS point (if baseline  
EDSS < 5.0) or 0.5 EDSS point (if baseline EDSS >5.5), in the previous 18 months  
and >1 GEL in past 18 months or >1 moderate-severe relapse and >1 new T2 lesion  
in past 18 months. 
c. Primary progressive MS (PPMS) patients with positive oligoclonal bands (OCBs)  
in the cerebrospinal fluid (CSF) and an increase of >1 EDSS point (if base-line  
EDSS < 5.0) or 0.5 EDSS point (if baseline EDSS >5.5), or quantifiable,  
objective evidence of equivalent progression in the previous 18 months and >1 GEL 
in past 18 months or >1 new T2 lesion in past 18 months. 
2. Age 18 to 50 years. 
3. Disease duration 0 to 10 years from diagnosis (inclusive). 
4. EDSS 2.0 to 6.5 at screening evaluation. 
5. >1 GEL on MRI within 6 months prior to harvesting. 
6. Adequate culture of a subject’s MSCs and their release for clinical use. 
 
 
Justification for the inclusion criteria 
Working definitions for active MS emphasise accumulation of disability, occurrence of relapses or a 
combination of both. Our aim is to identify a patient population who is at increased risk of continued 
progression and loss of function but has not accumulated advanced levels of neuronal injury or 
degeneration which could fail to show a treatment effect even if it exists. We have therefore 
formulated criteria to recruit patients with mild to moderate disability and evidence of ongoing 
inflammation (gadolinium-enhancing lesions) relatively early in the disease.  
Each subject must generate MSCs suitable for clinical use otherwise the procedure will have no 
chance of benefit (section 10.3). 
 
 
8.3 
EXCLUSION CRITERIA 
 
1. RRMS without at least one severe relapse in the previous 18 months or without at least one 
GEL or one new T2 in the previous 18 months. 
2. SPMS without relapses and without new lesions (GEL or T2 positive) on MRI in the last 18 
months. 
3. PPMS without positive CSF OCBs or without a GEL or new T2 lesion in the previous 18 
months. 
4. No gadolinium enhancing lesion(s) in the 6 months prior to bone marrow harvesting. 
5. A previously ineligible patient who failed to meet the MRI requirements of the inclusion 
criteria will not be reviewed unless further imaging, revealing ≥1 GEL, becomes available. 
6. Failure of BM sample to generate MSCs suitable for clinical use within a specified time 
frame. 
7. Treatment with any immunosuppressive therapy, including natalizumab and fingolimod, 
within the last 3 months. 
8. Treatment with interferon-beta or glatiramer acetate within the last 1 month. 
9. Treatment with alemtuzumab (campath-1H) within the last 2 years. 


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10. Prior treatment with total lymphoid irradiation and autologous or allogeneic hematopoietic 
stem cell transplantation. 
11. Participation in clinical trials of any experimental drugs in the 6 months before study entry. 
12. Corticosteroid treatment in the previous 30 days. 
13. Presence of any active or chronic infection. 
14. Previous history of a malignancy other than basal cell carcinoma of the skin and carcinoma 
in situ that has been in remission for more than one year. 
15. Severely limited life expectancy by any other co-morbid illness. 
16. Abnormal blood counts, a history of myelodysplasia or other cytopenia. 
17. Known pregnancy, positive urine pregnancy test at screening or risk or pregnancy (this 
includes patients who are unwilling to practice active contraception for the duration of the 
study). 
18. Any breastfeeding woman. 
19. Contraindication to MRI including but not limited to intracranial aneurysm clips (except 
Sugita), history of intra-orbital metal fragments that have not been removed by an MD (as 
confirmed by orbital X-Ray), pacemaker and non-MR compatible devices (e.g. heart valves, 
inner ear implants), history of claustrophobia or the inability of the subject to lie still on their 
back for a period of 1.5 hours in the MRI scanner.  
20. An estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 or history or presence of 
renal impairment (e.g. serum creatinine clearance less than 30ml/min). 
21. Inability to give written informed consent/comply with study procedures. 
22. Any significant organ dysfunction or co-morbidity that the Investigators consider would put 
the subject at unacceptable risk by participating in the study or that would interfere with the 
functional assessments. 
 
Justification for the exclusion criteria 
These criteria are used to exclude MS patients without an active, inflammatory disease and to 
exclude patients with medical problems or those who are receiving or have received treatments 
that could increase their risk of serious morbidity or mortality from MSCT or any other facet of this 
protocol.  
 
 
8.4 
CONCOMITANT MEDICATIONS 
 
All concomitant medications will be recorded at every study visit. Treatment with disease-modifying 
therapies is not permitted throughout the study – and appropriate wash-out periods are required 
(see section 8.3) prior to enrolment. Use of corticosteroids will be permitted for relapses that occur 
during the study although patients cannot have received corticosteroids in the 30 days prior to 
enrolment. In addition, in the event of a relapse occurring either between randomisation and the 
first infusion (Week 0) or before the second infusion (Week 24), the infusion will be delayed if the 
relapse requires the use of corticosteroids, so ensuring that there will be at least 30 days between 
the methylprednisolone and the infusion. Relapses and the corticosteroids received will be 
documented on the electronic case report forms. 
Symptomatic treatments for MS can be continued throughout the study and may also be initiated if 
appropriate and at the usual doses. If a patient is already being treated with Fampridine 
(Fampyra®) at the screening visit, this can be continued but this treatment cannot be initiated  
during the course of the trial because the effects on walking will affect some clinical endpoints 
being measured.  
 


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Symptomatic treatments for MS permitted in the STREAMS trial (this list may not be exhaustive): 
 
 
Common Symptoms in MS 
Examples of drugs used to treat symptom 
Fatigue  
Modafinil, amantadine 
Depression 
Tricyclic antidepressants, monamine-oxidase 
inhibitors, selective serotonin reuptake 
inhibitors, other antidepressant drugs. 
Spasticity 
Baclofen, tizanidine, dantrolene, diazepam, 
gabapentin, botulinum toxin 
Reduced walking ability 
Fampridine (Fampyra®)* 
Bladder – urinary urgency, frequency and 
incontinence  
Anti-cholinergics (e.g oxybutynin, tolterodine, 
darifenacin, solifenacin) 
Constipation 
All types of laxatives 
Oscillopsia  
Gabapentin, baclofen, clonazepam 
Erectile dysfunction 
Phosphodiesterase type 5 inhibitors (e.g. 
sildenafil) 
 
*Fampridine can be continued if it was prescribed before enrolment into the trial but cannot be 
initiated during the study.  
 
 
8.5 
WITHDRAWAL CRITERIA 
 
Subjects can voluntarily withdraw at any time from the study and follow-up assessments. All data 
collected up to that point will be retained. Any collected biological specimens will be kept and used 
for research unless subjects request that these unused samples are destroyed. 
A patient’s participation in the study may also be discontinued at any time at the discretion of the 
investigator, and justifiable reasons include Suspected Unexpected Serious Adverse Reactions 
(SUSAR) or deterioration in the disease activity requiring immunomodulatory treatment but their 
data until that point will be included in the analysis. 
 
 
 
9. RANDOMISATION AND ENROLMENT PROCEDURE 
 
9.1 
ELIGIBILITY FOR RANDOMISATION  
 
To be eligible for randomisation a subject must have fulfilled all the entry criteria. 
 
 
9.2 
RANDOMISATION PRACTICALITIES 
 
 
All subjects will be randomised after the investigator has verified that they are eligible by the criteria 
(section 8). Randomisation will be carried out within a web-based system, made available to 
authorised researchers, by the Clinical Research Organisation (CRO) in charge: Centro Clinical 
Trials, Fax +39/010354103  Email: clinicaltrials@hsanmartino.it 


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Eligible patients will be randomised to receive immediate vs. delayed treatment with either 
autologous MSCs or equivalent volume of suspension media at baseline. At 6 months, patients and 
investigators will continue to be blinded to therapy, but treatments will be reversed (i.e. those who 
received initial MSCs will receive suspension media and vice versa). 
 
 
9.3 
BLINDING PROCEDURES 
 
The patient, assessor team (EDSS, MSFC, MSIS-29, SF36) and MRI team will be blinded to the 
treatment assignments. 
The treating team will not be blinded to treatment assignments. For details about roles, see the 
Delegation Log. 
 
 
9.4 
UNBLINDING 
 
Unblinding is restricted to clinically relevant needs impacting patient safety. It should be used only 
under circumstances where the knowledge of the treatment is necessary for the proper care of 
the patient. If the treatment code is broken, the reason and date should be recorded and signed 
by the investigator.  If treatment is discontinued prematurely for any reason other than disease 
progression the study data centre (Centro Clinical Trials) should be informed immediately.  All 
patients will continue to be followed-up, irrespective of whether they have discontinued treatment 
prematurely. 
 
9.4.1. Reasons for unblinding 
Clinical events: This includes the occurrence of fatal or life-threatening SAE, or any 
circumstances wherein the judgment of the treating neurologist, blind to the treatment modality, 
may compromise patient safety or where the patient is unable to provide informed consent to 
clinically necessary investigations, procedures or treatments as a consequence of the blinding. 
MRI findings: Any radiological evidence suggestive of anomalous disease exacerbation or 
adverse event. This refers to an increase of ≥5 number of lesions above the number of lesions on 
the baseline scan, or the appearance of atypical lesions as assessed by the reviewing radiologist 
(section 14.1.1). The treating team will be informed as soon as possible. 
 
 
 
10. STUDY TREATMENTS 
 
10.1 BONE MARROW HARVEST 
 
Pre sampling checks: 
Coagulation studies will be performed at the Week -10 and Week 0 visit (screening and pre-
treatment, respectively). In accordance with JACIE (Joint Accreditation Committee International  
Society for Cellular Therapy – the European Group for Blood & Marrow Transplantation) 
requirements, participants will be tested at a maximum of 30 days before bone marrow and skin 
sampling for HIV 1, HIV 2, Hepatitis B, Hepatitis C, HTLV 1, HTLV 2, CMV, and Syphilis. These 
latter tests will be done at the Week -10 visit. 
 
 


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Bone marrow sampling: 
Bone marrow (BM) will be harvested at week -8 according to the Trust policy. The principle is to 
collect only the BM rich in stroma and early precursors which are contained in the first part of the 
aspirate. Therefore, the procedure consists of repetitive extractions of 2 ml of BM aliquots. The 
procedure will require local anaesthesia and intravenous sedation may be required in selected 
cases. The procedure can be done as an outpatient in the haematology day-care unit. The entire 
methodology and SOPs have been established and validated in ten MS patients in Cambridge and 
in 15 patients with GvHD at Hammersmith Hospital. 
The bone marrow aspiration will be performed by the registrar in charge of aspirates according to 
the SOP for mesenchymal stem cell preparation.  
 
 
10.2 ISOLATION AND EXPANSION OF AUTOLOGOUS MSCS 
 
The Haematology Laboratory (based at Imperial College London), will receive the bone marrow 
and will act as the manufacturing site for the trial. It will produce the MSCs under the existing GMP 
license and according to the manufacturing protocol as described in the IMP dossier submitted to 
the MHRA. 
 
Briefly, MSCs are isolated from bone marrow harvests and ex-vivo expanded in the presence of 
Modified Eagles Medium supplemented with 5% human platelet lysate according to a Standard 
Operating Procedure included in the MHRA IMP dossier. The final product is tested to exclude 
growth of aerobic and anaerobic bacteria and defined as adherent cells positive for CD73, CD90 
and CD105 and negative for CD45. 
 
Adequate expansion in culture to obtain sufficient number of MSC to achieve the treatment dose is 
a prerequisite for continuation in the trial. MSC preparations that have not expanded to confluency 
(to reach a target of 1-2 million cells/kg body weight) within 52 days from the start of culture will be 
aborted and the subject will be withdrawn from the study. If the expansion is <1 million cells/kg 
body weight, then these cells will be stored in the biobank at Imperial College London. Consent for 
these actions will have been sought at the screening visit. 
 
 
10.3 RELEASE OF THE MSC PRODUCT FOR CLINICAL USE 
 
MSCs may be released from the laboratory for clinical use if they fulfill the provisions of the 
advanced therapy medicinal products (ATMP) license described in the dossier approved by the 
MHRA. 
MSC preparations that have not passed the release criteria will be disqualified for trial clinical use 
and the subject will be withdrawn from the study. 
 
10.4 STUDY TREATMENT INFUSION OF AUTOLOGOUS MSCS OR PLACEBO 
 
At week 0 and at week 24, a single infusion of either ex-vivo expanded autologous MSCs or 
suspension media will be administered intravenously. For MSCs, we will give a dose of 1-2 x 106 
MSC/Kg recipient body weight (as measured at baseline).  
 
 


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10.5 POST-STUDY TREATMENT INFUSION EVALUATION  
Following the study treatment, patients will be monitored for infusion-related toxicity for three hours. 
Temperature, blood pressure, pulse and oxygen saturation will be measured at baseline and after 
15 minutes, 60 minutes and 3 hours. Any toxicity will be treated at the discretion of the attending 
physician. 
 
 
10.6 TOXICITY ASSESSMENT  
 
Infusion-related toxicity is defined as any of the following within three hours post-treatment infusion: 
 
Systolic blood pressure (mmHg) <90 or >180, or >33% decrease or increase from 
baseline. 
 
Diastolic blood pressure (mmHg) <50 or >100, or >33% decrease or increase from 
baseline. 
 
Heart rate: <60 or >110 or >33% decrease or increase from baseline. 
 
Body temperature (°C) >38.5 or >1°C increase. 
 
Any other toxic side effect. 
 
 
 
11. PHARMACOVIGILANCE 
 
11.1 DEFINITIONS 
 
Adverse  Event  (AE):  Any untoward  medical  occurrence  in  a  patient  or  clinical  trial  
subject, administered a medicinal product and, which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational medicinal product (IMP), whether or not considered related to the IMP. 
 
Adverse Reaction (AR): All untoward and unintended responses to an IMP related to any dose 
administered. All AEs judged by either the reporting investigator or the sponsor as having 
reasonable causal  relationship  to  a  medicinal  product  qualify  as  adverse  reactions.    The 
expression ‘reasonable causal relationship’ means to convey, in general, that there is evidence or 
argument to suggest a causal relationship. 
 
Unexpected Adverse Reaction: An AR, the nature or severity of which is not consistent with the 
applicable product information (e.g. Investigator’s brochure for an unapproved investigational 
product or summary of product characteristics (SmPC) for an authorised product). When the 
outcome of the adverse reaction is not consistent with the applicable product information, this  
 
adverse reaction should be considered as unexpected. Side effects documented in the SmPC 
which occur in a more severe form than anticipated are also considered to be unexpected. 
 
Serious Adverse Event (SAE) or Serious Adverse Reaction: Any untoward medical 
occurrence or effect that at any dose: 
 
Results in death 
 
 


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 
 Is life-threatening – refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe 
 
 Requires hospitalisation, or prolongation of an existing inpatient hospitalisation 
 
 Results in persistent or significant disability or incapacity 
 
 Is a congenital anomaly or birth defect 
 
Medical judgement  should  be  exercised  in  deciding  whether  an  AE/AR  is  serious  in  
other situations.  Important AE/ARs that are not immediately life-threatening or do not result in 
death or hospitalisation but may jeopardise the subject or may require intervention to prevent 
one of the other outcomes listed in the definition above, should also be considered serious. 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR): any suspected adverse 
reaction related to an IMP that is both unexpected and serious. 
 
 
11.2 CAUSALITY  
Most adverse events and adverse drug reactions that occur in this study, whether they are 
serious or not, will be expected treatment-related toxicities due to the drugs used in this study.  
The assignment of the causality should be made by the investigator responsible for the 
care of the participant using the definitions in the table below. If any doubt about the causality 
exists, the local investigator should inform the study coordination centre which will notify the 
Chief Investigator. Other clinicians may be asked to advise in some cases. In the case of 
discrepant views on causality between the investigator and others, all parties will discuss the 
case.  In the event that no agreement is made, the MHRA will be informed of both points of 
view. 
 
 
 
 
Relationship 
Description 
Unrelated 
There is no evidence of any causal relationship. 
Unlikely 
There is little evidence to suggest there is a causal relationship (e.g. the event 
did not occur within a reasonable time after administration of the trial 
medication). There is another reasonable explanation for the event (e.g. the 
participant’s clinical condition, other concomitant treatment). 
Possible 
There is some evidence to suggest a causal relationship (e.g. because the 
event occurs within a reasonable time after administration of the trial 
medication).  However, the influence of other factors may have contributed to 
the event (e.g. the participant’s clinical condition, other concomitant 
treatments). 
Probable 
There is evidence to suggest a causal relationship and the influence of other 
factors is unlikely. 
Definitely 
There is clear evidence to suggest a causal relationship and other possible 
contributing factors can be ruled out. 
Not assessable 
There is insufficient or incomplete evidence to make a clinical judgement of the 
causal relationship. 
 
 


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11.3 REPORTING PROCEDURES 
 
All adverse events should be reported (Figure 3). Depending on the nature of the event, the 
reporting procedures below should be followed.  Any questions concerning adverse event 
reporting should be directed to the study coordination centre in the first instance.  A flowchart is 
given below to aid with the reporting procedures. 
 
11.3.1. Non-serious AR/AEs 
All such toxicities, whether expected or not, should be recorded in the toxicity section of the 
relevant case report form and sent to the study coordination centre within one month of the 
relevant AR/AE. 
 
11.3.2. Serious AR/AEs 
Fatal or life threatening SAEs and SUSARs should be reported on the day that the local site is 
aware of the event. The SAE form requests the following  information on any event: 
the nature of the SAE, the date of onset, the severity, corrective therapies given, the 
outcome and causality (i.e. unrelated, unlikely, possible, probably, definitely). The responsible 
investigator should sign the causality of the event. Additional information should be sent within 5 
days if the reaction has not resolved at the time of reporting.  
 
SAEs 
An SAE form should be completed and faxed to the study coordination centre for all SAEs within 
24 hours.   However, death from an unrelated cause (e.g. road traffic accident), MS relapses 
and hospitalisations for elective treatment of a pre-existing condition do not need reporting as 
SAEs. 
 
SUSARs 
In the case of suspected unexpected serious adverse reactions, the staff at the site should: 
 
 
Complete the SAE case report form & send it as soon as possible (within 24 hours and 
preferably by fax), signed and dated to the study coordination centre together with 
relevant treatment forms and anonymised copies of all relevant investigations. 
Or 
 
Contact the study coordination centre by phone and then send the completed SAE 
form to the study coordination centre within the following 24 hours as above. 
 
The  study  coordination  centre  will  notify  the  MHRA,  REC  and  the  Sponsor  of  all  SUSARs 
occurring during the study according to the following timelines; fatal and life-threatening within 7 
days of notification and non-life threatening within 15 days.   All investigators will be informed of all 
SUSARs occurring throughout the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 


Joint Research Compliance Office 
 
    
 
 
 
 
  
 
 
 
 
 
  
VERSION 6.0 18 DECEMBER 2014  
 
 
 
 
 
Page 27 of 66 
 
Figure 3. Safety reporting overview
 
 
 
Contact details for reporting SAEs and SUSARs 
Fax: xxx , attention xxx 
Please send SAE forms to: 
xxx 
Tel: xxx (Mon to Fri 09.00 – 17.00) 
 


Joint Research Compliance Office 
 
    
 
 
 
 
  
 
 
 
 
 
  
VERSION 6.0 18 DECEMBER 2014  
 
 
 
 
 
Page 28 of 66 
 
Figure 4. Schedule of study assessments and treatments 
 
Screening 
- 10 weeks 
(±7 days) 
 
- 8 
weeks 
(±7 
days) 
 
- 8 
weeks 
(±7 
days) 
 
 
- 2 
weeks 
(±14 
days) 
Week 0 
Week 0 
Week 4 
(±7 
days) 
Week 8 
(±7 
days) 
Week 
12 (±7 
days) 
Week 
16 (±7 
days) 
Week 
20 (±7 
days) 
Week 
24 (±7 
days) 
 
Week 
24 (±7 
days) 
 
Week 
28 (±7 
days) 
Week 
32 (±7 
days) 
Week 
36 (±7 
days) 
Week 
40 (±7 
days) 
Week 
44 (±7 
days) 
Week 
48 (±7 
days) 
Week 
48 (±7 
days) 
Informed Consent 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
review 
x 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
record 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical exam 
x 
x 
 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
 
x 
 
x 
x 
 
Study treatment (MSC) 
infusion 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
Adverse events record 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Release of MSC product 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lumbar puncture 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
Skin biopsy* 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow harvest 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EDSS 
x 
x 
 
 
x 
x 
x 
 
x 
 
 
x 
x 
x 
 
x 
 
 
x 
 
MSIS29 
x 
 
 
 
x 
 
x 
 
x 
 
 
x 
 
x 
 
x 
 
 
x 
 
MSFC 
x 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
T25-FW 
x 
 
 
 
x 
 
x 
 
x 
 
 
x 
 
x 
 
x 
 
 
x 
 
Quality of life/Fatigue 
impact scale  
x 
 
 
 
x 
 
x 
 
x 
 
 
x 
 
x 
 
x 
 
 
x 
 
Hematology, Blood 
Chemistry 
x 
 
 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
 
x 
 
x 
x 
 
Blood tests pre-bone 
marrow harvest 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
x 
 
 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
 
x 
 
x 
x 
 
Urinalysis 
x 
 
 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
 
x 
 
x 
x 
 
Research blood samples* 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mantoux skin test 
 
x 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
Mantoux readout 
 
 
x 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
MRI 
 
 
 
 
x 
 
x 
 
x 
 
 
x 
 
x 
 
x 
 
 
x 
 
ECG 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Only part of the first phase of recruitment 


VERSION 6.0 18 DECEMBER 2014 
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Joint Research Compliance Office 
 
 
 
 
12. ASSESSMENT AND FOLLOW-UP 
 
12.1 STUDY ASSESSMENTS 
 
The trial will run for 48 weeks from the patient’s baseline visit. There will be a screening visit 10 
weeks before the scheduled baseline visit where informed consents will be taken and the patient’s 
eligibility assessed. Patients will be informed that they may withdraw consent at any point 
throughout the trial should they wish to do so and that their subsequent treatment will not be 
compromised by their withdrawal.  
 
 
12.2 SCHEDULE OF VISITS  
 
At scheduled visits, vital signs and adverse events will be recorded for every patient. Other 
procedures will be performed according to the study schedule as depicted in Figure 4. 
 
12.2.1 Study visits and treatment schedule 
 
Minus 10 weeks ± 7 days 
Subjects will be assessed for eligibility and will have the following performed: 
 
Sign informed consent to enter the study. 
 
Sign MRI consent form. 
 
Full medical and MS history will be taken. 
 
Concomitant medications will be recorded. 
 
The patient will undergo a full physical examination including vital signs.  
 
Blood will be taken for haematological and clinical chemistry parameter measurement. 
 
Pregnancy testing will be performed (if applicable). 
 
A pre-bone marrow sampling blood screen will be performed in accordance with JACIE 
(Joint Accreditation Committee International Society for Cellular Therapy – the European 
Group for Blood & Marrow Transplantation) requirements - participants will be tested for 
HIV 1,HIV 2, Hepatitis B, Hepatitis C, HTLV 1, HTLV 2, CMV, and Syphilis. Blood tests for 
HIV, Hepatitis B and C will be mentioned specifically on the consent form and we will 
ensure that subjects are adequately counselled so that they fully understand the 
implications of a positive test. 
 
Urinalysis will be performed. 
 
EDSS, MSFC, MSIS-29 and SF36 assessments will be carried out. 
 
A baseline 12 lead ECG (section 8.7.5). 
 
Randomisation to decide order in which the MSCs and dummy infusion will be given. 
 
 
Minus 8 weeks ± 7 days 
Subjects will be admitted as a day case to Hammersmith Hospital. The subjects will have the 
following performed: 
 
Informed consent will be confirmed. 
 
Inclusion/exclusion criteria will be reviewed. 
 
Concomitant medications will be recorded. 
 
Adverse events will be recorded. 
 
The patient will undergo a full physical examination including vital signs. 
 
An EDSS assessment will be carried out. 


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Joint Research Compliance Office 
 
 
 
 
 
80 ml blood research samples will be taken (section 12.7.5).* 
 
Subjects will then undergo four procedures: 
 
 
Bone marrow harvesting under sedation (section 12.7.1) 
 
Skin biopsy (section 12.7.2)* 
 
Lumbar puncture (section 12.7.3) 
 
Mantoux test (section 12.7.6) 
 
If successfully completed, MSC manufacturing will commence and the subjects will proceed further 
in the study. 
 
 
Minus 8 weeks ± 7 days +48/72 hours 
 
Concomitant medications will be recorded. 
 
Adverse events will be recorded. 
 
The patient will have their vital signs checked. 
 
Reading of the Mantoux test.  
 
80 ml blood research samples will be taken.* 
 
 
Minus 2 weeks ± 14 days 
This is a virtual visit not requiring patient attendance and defines a time point for MSC release. If 
the manufactured MSC product is released for clinical use, subjects will be eligible to continue in 
the study. 
 
 
Week 0  
Subjects will have the following performed: 
 
An MRI will be carried out prior to infusion of the study treatment (section 12.8). 
Subjects will then be admitted as a day case to Hammersmith Hospital. 
 
Inclusion/exclusion criteria will be reviewed especially to confirm that inclusion criteria 6 is 
fulfilled. 
 
Concomitant medications will be recorded. 
 
Adverse events will be recorded. 
 
The patient will undergo a full physical examination including vital signs.  
 
Blood will be taken for haematological and clinical chemistry parameter measurement.  
 
Pregnancy testing will be performed (if applicable).  
 
80 ml blood research samples will be taken.* 
 
A Mantoux test will be performed. 
 
Urinalysis will be performed. 
 
EDSS, MSFC, MSIS-29 and SF36 assessments will be carried out. 
 
The study treatment will be infused. 
 
 
Week 0 +48/72 hours 
Patients will have the following performed: 
 
Concomitant medications will be recorded. 
 
Adverse events will be recorded. 
 
The patient will have their vital signs checked. 
 


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Joint Research Compliance Office 
 
 
 
 
 
An EDSS assessment will be carried out. 
 
80mls of blood research samples will be taken.* 
 
Reading of the Mantoux test. 
 
 
Week 4 ± 7 days 
Patients will have the following performed: 
 
 
Concomitant medications will be recorded. 
 
Adverse events will be recorded. 
 
The patient will undergo a full physical examination including vital signs.  
 
Blood will be taken for haematological and clinical chemistry parameter measurement.  
 
Pregnancy testing will be performed (if applicable).  
 
80 ml blood research samples will be taken.* 
 
Urinalysis will be performed. 
 
EDSS, T25-FW, MSIS-29 and SF36 assessments will be carried out. 
 
An MRI will be carried out. 
 
 
Week 8 ± 7 days 
Patients will have the following performed: 
 
Concomitant medications will be recorded. 
 
Adverse events will be recorded. 
 
The patient will have their vital signs checked. 
 
80 ml blood research samples will be taken.* 
 
 
Week 12 ± 7 days 
Patients will have the following performed: 
 
Concomitant medications will be recorded. 
 
Adverse events will be recorded. 
 
The patient will undergo a full physical examination including vital signs. 
 
Blood will be taken for haematological and clinical chemistry parameter measurement.  
 
Pregnancy testing will be performed (if applicable).  
 
80 ml blood research samples will be taken.* 
 
Urinalysis will be performed. 
 
EDSS, T25-FW, MSIS-29 and SF36 assessments will be carried out. 
 
An MRI will be carried out. 
 
 
Week 16 ± 7 days 
Patients will have the following performed: 
 
Concomitant medications will be recorded. 
 
Adverse events will be recorded. 
 
The patient will have their vital signs checked.  
 
80 ml blood research samples will be taken.* 
 
 
Week 20 ± 7 days 
Patients will be admitted as a daycase and have the following performed: 
 


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Joint Research Compliance Office 
 
 
 
 
 
Concomitant medications will be recorded. 
 
Adverse events will be recorded. 
 
The patient will undergo a full physical examination including vital signs.  
 
Blood will be taken for haematological and clinical chemistry parameter measurement.  
 
Pregnancy testing will be performed (if applicable).  
 
Urinalysis will be performed. 
 
A lumbar puncture will be performed. 
 
80 ml blood research samples will be taken.* 
 
 
Week 24 ± 7 days 
Subjects will have the following performed: 
 
An MRI will be carried out prior to infusion of the second study treatment. 
 
Subjects will then be admitted as a day case to Hammersmith Hospital. 
 
Concomitant medications will be recorded. 
 
Adverse events will be recorded. 
 
The patient will undergo a full physical examination including vital signs. 
 
Blood will be taken for haematological and clinical chemistry parameter measurement.  
 
Pregnancy testing will be performed (if applicable).  
 
80 ml blood research samples will be taken.* 
 
A Mantoux test will be performed. 
 
Urinalysis will be performed. 
 
EDSS, MSFC, MSIS-29 and SF36 assessments will be carried out. 
 
The study treatment will be infused. 
 
 
Week 24 ± 7 days + 48/72 hours 
Patients will have the following performed: 
 
Concomitant medications will be recorded. 
 
Adverse events will be recorded. 
 
The patient will have their vital signs checked. 
 
An EDSS assessment will be carried out. 
 
80mls of blood research samples will be taken.* 
 
Reading of the Mantoux test. 
 
 
Week 28 ± 7 days 
Patients will have the following performed: 
 
Concomitant medications will be recorded. 
 
Adverse events will be recorded. 
 
The patient will undergo a full physical examination including vital signs.  
 
Blood will be taken for haematological and clinical chemistry parameter measurement. 
 
Pregnancy testing will be performed (if applicable).  
 
80 ml blood research samples will be taken.* 
 
Urinalysis will be performed. 
 
EDSS, T25-FW, MSIS-29 and SF36 assessments will be carried out. 
 
A MRI will be carried out. 
 
 
 


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Joint Research Compliance Office 
 
 
 
 
Week 32 ± 7 days 
Patients will have the following performed: 
 
Concomitant medications will be recorded. 
 
Adverse events will be recorded. 
 
The patient will have their vital signs checked. 
 
80 ml blood research samples will be taken.* 
 
 
Week 36 ± 7 days 
Patients will have the following performed: 
 
Concomitant medications will be recorded. 
 
Adverse events will be recorded. 
 
The patient will undergo a full physical examination including vital signs.  
 
Blood will be taken for haematological and clinical chemistry parameter measurement. 
 
Pregnancy testing will be performed (if applicable). 
 
80 ml blood research samples will be taken.* 
 
Urinalysis will be performed. 
 
EDSS, T25-FW, MSIS-29 and SF36 assessments will be carried out. 
 
A MRI will be carried out. 
 
 
Week 40 ± 7 days 
Patients will have the following performed: 
 
Concomitant medications will be recorded. 
 
Adverse events will be recorded. 
 
The patient will have their vital signs checked. 
 
80 ml blood research samples will be taken.* 
 
 
Week 44 ± 7 days 
Patient will have the following performed: 
 
Concomitant medications will be recorded. 
 
Adverse events will be recorded. 
 
The patient will undergo a full physical examination including vital signs. 
 
Blood will be taken for haematological and clinical chemistry parameter measurement.  
 
Pregnancy testing will be performed (if applicable). 
 
Urinalysis will be performed. 
 
A lumbar puncture will be performed. 
 
80 ml blood research samples will be taken.* 
 
 
Week 48 ± 7 days 
Patients will have the following performed: 
 
A MRI will be carried out. 
Subjects will then be admitted as a day case to Hammersmith Hospital. 
 
Concomitant medications will be recorded. 
 
Adverse events will be recorded. 
 
The patient will undergo a full physical examination including vital signs.  
 
Blood will be taken for haematological and clinical chemistry parameter measurement. 
 
Pregnancy testing will be performed (if applicable). 
 
80 ml blood research samples will be taken.* 


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Joint Research Compliance Office 
 
 
 
 
 
A Mantoux test will be performed. 
 
Urinalysis will be performed. 
 
EDSS, MSFC, MSIS-29 and SF36 assessments will be carried out. 
 
 
Week 48 ± 7 days + 48/72 hours 
Patients will have the following performed: 
 
Concomitant medications will be recorded. 
 
Adverse events will be recorded. 
 
The patient will have their vital signs checked. 
 
80mls of blood research samples will be taken.* 
 
Reading of the Mantoux test.  
 
 
* Only for the patients in the first phase of recruitment 
 
 
Conclusion of the active stage of the trial 
Once a patient has finished the active stage of the study, they will continue to be followed-up on 
the NHS for at least 2 years after the last study drug administration. They will be offered 
appropriate treatment according to best medical practice.   
 
 
12.2.2. Unscheduled visits 
 
If subjects have a significant relapse (defined as one which affects the EDSS), an unscheduled 
visit will need to take place as soon as possible. Minor relapses should be reported at the next 
scheduled visit. In addition, if adverse effects develop which require clinical evaluation, 
unscheduled visits will be arranged and patients will be assessed by a treating clinician and 
managed as medically appropriate. 
 
 
12.3 EVALUATION OF MS  
Relapses will be assessed according to the protocol definition. Disability will be assessed using the 
Expanded Disability Status Scale (EDSS) rating scale (Appendix 1).  
 
12.3.1. MS relapses 
Only relapses meeting the protocol definition will initially be determined, but a separate analysis 
will also include relapses not meeting the protocol definition. 
Definition of a relapse: any perceived change in symptoms or signs that persist for  48 hours in 
the absence of flu or fever and is accompanied by objective changes on EDSS functional 
subscores (FSS) that leads to either a 1.0 point change in EDSS (for baseline EDSS 2.0 - 5.0) or a 
0.5 point change (for baseline EDSS  5.5) together with FSS changes of 2 points in any one FSS 
or 1 point in any 2 FS. 
 
12.3.2. Progression of disability 
Definition of EDSS progression is any 6-month sustained increase in EDSS: 
 
For baseline EDSS <5.5, any 1 point increase in EDSS. 
 
For baseline EDSS ≥ 5.5, any 0.5 point increase in EDSS. 
 
 


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Joint Research Compliance Office 
 
 
 
 
12.4 LOSS TO FOLLOW-UP 
 
Subjects will be under the governance of the clinicians running the trial. The GP will be contacted 
and permission sought to contact subjects by phone. 
 
 
12.5 TRIAL CLOSURE 
 
12.5.1. Premature closure of the study 
This study may be prematurely terminated, if in the opinion of the investigator, there is sufficient 
reasonable cause. The terminating party will provide written notification documenting the reason 
for study termination to the investigator. Circumstances that may warrant termination include, but 
are not limited to: 
 
Treatment related mortality exceeding 30% at 24 hours from the beginning of the 
treatment. 
 
Determination of unexpected, significant, or unacceptable risk to patients. 
 
Failure to enter patients at an acceptable rate. 
 
Insufficient adherence to protocol requirements. 
 
Insufficient complete and/or valuable data. 
 
Protocol violation. 
 
Administrative decision. 
 
New data able to influence the willingness of the investigators to pursue the study 
 
12.5.2. Closure of the study after completion 
Once a subject has completed 48 weeks of the study they will be considered to have completed 
the trial. The study will be closed when all participants have completed all study assessments and 
all regulatory requirements have been fulfilled. 
 
 
12.6 CLINIC-BASED ASSESSMENTS  
 
12.6.1. EDSS 
The EDSS will be assessed regularly throughout the study. It will be performed by a neurostatus 
trained doctor (Appendix 1).  
 
12.6.2. MSIS-29 
 
The MSIS-29 is a self-assessment questionnaire that is used to assess disability in patients with 
MS. Patients may use a computer-based version of the MSIS-29 which they will complete online 
at the scheduled visits. In the event that the computer version is not available at the time of the 
clinic visit, the patient will be asked to complete a paper version at the clinic (Appendix 2). 
 
12.6.3. MSFC 
The MSFC is a combination of a timed walk, a nine-hole peg test and the Paced Auditory Serial 
Addition Test (PASAT) and will be undertaken by the EDSS assessor or a trained nurse. Two 
practice sessions will be completed at the screening visit to account for learning effects (Appendix 
3). 
 
 
 


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Joint Research Compliance Office 
 
 
 
 
12.6.4. SF-36 
The Short Form 36 (SF-36) has been designed to measure the quality of life of a patient.  Some of 
the questions deal with physical parameters such as walking and climbing stairs etc whilst others 
deal with aspects such as extent of pain, mental aspects such as mood and an assessment of 
how a patient’s condition affects their social life (Appendix 4). 
 
 
12.7 OTHER STUDY EVALUATIONS  
 
12.7.1. Bone marrow harvest 
Bone marrow aspiration will be performed by the trained Registrar in charge of aspirates 
according to the SOP for mesenchymal stem cell preparation. Bone marrow will be collected 
under local anaesthesia and sedation will be administered if required. 
 
12.7.2. Dermal tissue sampling* 
A punch skin biopsy will be taken concurrently to the bone marrow procedure during a 
single Daycare attendance at the Hammersmith Hospital. The biopsy sample will be placed in cell 
culture medium and a same-day courier will ship it to the research laboratory in an approved 
container. 
 
The skin biopsy will provide the opportunity to generate induced pluripotent stem cells (iPSCs) 
through manipulation of adult somatic cells for in-vitro research studies aiming to model the in-vivo 
treatment effect of MSCs. Generation of patient specific lines with neuronal derivatives using such 
factors has been recently reported for a range of neurological disorders, including derivation of 
motor neurons from patients with inherited MND and spinal muscular atrophy. Here we will 
generate neurons from a sample of recruited patients in order to establish an in-vitro assay of 
neuronal injury and putative protection. 
 
IPSCs will be generated from patient dermal fibroblasts obtained from skin biopsy. We will 
generate highly enriched central neurons in order to use an in vitro disease model assay to test (i) 
the effects on IPSC-derived cultured neurons of autologous PBMCs (obtained pre-MSC infusion) 
alone and with co-culture of potentially protective autologous MSCs; and (ii) the effects on IPSC-
derived cultured neurons of  autologous PBMCs (obtained post-MSC infusion). As a further 
mechanistic refinement we will also test (iii) the effects on IPSC-derived cultured autologous 
neurons of pre-MSC infusion-derived antigen-specific, activated Th1, Th17 and cytotoxic cell lines 
alone and with co-culture of autologous MSCs. The prediction is that pre-MSC stimulated PBMCs 
and pro-inflammatory T helper cells will be injurious on IPSC-derived neurons and that this will be 
ameliorated by co-culture with MSCs, owing to their anti-inflammatory, neuroprotective actions. 
 
* Only for the patients in the first phase of recruitment 
 
 
12.7.3. Lumbar puncture (LP)  
A diagnostic lumbar puncture for CSF analysis will be performed, by a trained clinician, during the 
Daycase visit in accordance with the NHS Trust Guidelines for LP. 
 
Standard investigations will be performed including cell count, protein, glucose and oligoclonal 
bands to assess the clinical effects of MSCs on the CSF inflammatory activity. We will also aim to 
collect samples for further analysis including T- and B-cell receptor repertoire studies and for 
biomarkers including markers of neuronal damage. 
 


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Joint Research Compliance Office 
 
 
 
 
12.7.4. Electrocardiogram (ECG) 
A standard 12-lead ECG will be obtained at the screening visit. 
 
12.7.5. Research blood samples* 
Blood samples will be taken at the indicated time points to carry out immunological mechanistic 
studies aimed at assessing the effects of MSC infusion on peripheral blood immune cell subsets as 
well as the effects on immune responses potentially associated with disease pathogenesis or 
progression.  
To characterise changes following MSC infusion in phenotypically defined T, B, NK, monocyte and 
dendritic cell populations ex-vivo, we will utilise a flow cytometric panel that also allows the 
phenotypic identification and enumeration of putative pro-inflammatory cell subsets. Immunological 
studies will include comparison of the pre- versus post-MSC infusion in-vitro T cell responses 
(proliferation, cyto- and chemokines) against a group of relevant antigens including viral and myelin 
proteins. All immunological assays have been employed successfully in other studies. 
 
* Only for the patients in the first phase of recruitment 
 
 
12.7.6. Mantoux tuberculin skin test (TST) 
This will be performed to provide an in-vivo method of assessing the effect of the mesenchymal 
stem cells. It will be carried out at 4 time-points: pre-infusion (-8 weeks) and then with each 
subsequent infusion (Weeks 0 and 24) and at the end of the trial (Week 48). The Mantoux test, 
whilst typically a standard test of determining whether a person is infected by Mycobacterium 
tuberculosis, is being used to  allow measurement of the delayed type hypersensitivity or cell-
mediated immunity which causes tissue injury.  
It involves introducing an antigen intradermally over the forearm – typically 2 TU (tuberculin units) 
of Statens Serum Institute (SSI) tuberculin RT23 in 0.1mls of solution - which generates a wheal 6-
10mm in diameter. The induration, measured in millimetres, is read 48-72 hours later. 
 
 
 
12.8 MRI PROCEDURES 
 
12.8.1. Outline 
All  patients will be scanned at one site: the MS Society-funded 3T MRI scanner at the UCL 
Institute of Neurology. Scans will be acquired at weeks 0, 4, 12, 24, 28, 36 and 48. If drop-out 
occurs before the study ends, all remaining MRI scans will be obtained, if possible, at the 
scheduled time-points or if this will not be possible, at an unscheduled visit (exit visit). The MRIs 
will be analysed by Professor Miller’s group at the Institute of Neurology but as the data will also 
contribute to the international collaborative effort, these MRIs will be anonymised and sent to the 
Medical Image Analysis Centre (MIAC), located in Basel, Switzerland which is being used for 
analysis of the primary outcomes.  
 
12.8.2. Data management  
Site qualification: dummy run procedure 
As required by the Central MRI Analysis Facility in Basel. 
Scan labelling 
As required by the Central MRI Analysis Facility in Basel. 
Data transfer  
Images required for local analysis will use a DICOM to DICOM server transfer (peer to peer) 
 


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Quality control of images  
Images required for local analysis will undergo a rigorous quality control (QC) process. This will 
ensure that scans have been performed using the study imaging protocol and to ensure that scans 
are suitable for analysis. For MTR this will include a segmentation and registration to check that 
the MTR scans have been acquired consistently and are biologically plausible. 
 
12.8.3. MRI acquisition protocol  
1. Conventional T2//T1/Gd sequences 
As required by the Central MRI Analysis Facility in Basel 
2. 3D T1 sequences 
A volumetric T1-weighted scan of the brain at 1x1x1 mm3 resolution will be acquired, covering 
the whole brain. The total acquisition time will be of the order of 5 minutes.   
3. Magnetisation Transfer Imaging 
Images with MT-weighting on and off will be acquired, with full brain coverage and matching 
the voxel size of the 3D T1 protocol, at a resolution of 1x1x1 mm3. This data will allow MTR 
maps to be calculated. Total scan time will be of the order of 20 minutes. 
4. Diffusion-Weighted Imaging 
Diffusion-weighted data of the whole brain will be acquired for advanced diffusion analysis 
methods. Voxel size will be of the order of 2x2x2 mm3 and cardiac gating will be employed to 
reduce physiological noise contamination. The total acquisition time will depend on the heart 
rate of the subject and will be of the order of 25 minutes. 
 
12.8.4. Outcome measures  
1. Cumulative number of new Gad-enhancing lesions weeks 4-24 inclusive (primary outcome 
measure to be analysed centrally by Dr Radu’s group in Basel) 
2. Cumulative number of new Gad-enhancing lesions weeks 28 to 48 inclusive 
3. Cumulative number of persistent Gad-enhancing lesions weeks 4-24 and 28-48 
4. Cumulative number of total Gad-enhancing lesions weeks 4-24 and 28-48 
5. Volume of total Gad-enhancing lesions weeks 4-24 and 28-48 
6. Cumulative number of new active lesions (new Gad-enhancing and new non-enhancing T2 
lesions) weeks 4-24 and 28-48 
7. Cumulative number of new and enlarging T2 lesions weeks 12 and 24 compared to 
baseline (week 0) and weeks 36 and 48 compared to week 24 
8. Cumulative number of new T1 hypointense lesions on Gad-enhanced T1-weighted spin 
echo scans weeks 12 and 24 compared to baseline (week 0) and weeks 36 and 48 
compared to week 24 
9. Percentage brain volume change (PBVC) on 3D T1-weighted scans at weeks 12 and 24 
compared to baseline (week 0) and weeks 36 and 48 compared to week 24  
10. Regional atrophy changes in grey matter (using 3D T1-weighted scans and voxel based 
morphometry) and core white matter structural changes (using advanced diffusion analysis) 
at weeks 12 and 24 compared to baseline (week 0) and weeks 36 and 48 compared to 
week 24. 
11. Serial analysis including all time points of magnetisation transfer ratio (MTR) measures of 
non-enhancing T2 lesions present at baseline (week 0) 
12. Serial analysis including all time points of MTR measures of non-enhancing T1 hypointense 
lesions present at baseline (week 0) 
13. Serial analysis including all time points of MTR measures of Gad-enhancing lesions present 
at baseline (week 0) 
14. Serial analysis including all time points of MTR measures of new Gad-enhancing lesions 
that occur during the trial 
15. Serial MTR measures at weeks 0, 12, 24, 36 and 48 of normal appearing grey matter 
16. Serial MTR measures at weeks 0, 12, 24, 36 and 48 of normal appearing white matter 
 


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17. Serial analysis of diffusion-weighted imaging (DWI) data at all time points to assess axonal 
integrity and structural changes.  
 
12.8.5. Analysis methods 
1. Lesion counts 
(i) 
The number of new or enlarging T2 lesions will be assessed from PD/T2 fast spin 
echo images. 
(ii) 
New T1 hypo-intense lesion measures will be recorded as seen on the post-contrast 
T1 weighted spin echo scans. 
2. Lesion volumes 
A T2 and T1 lesion load calculation will be undertaken by an observer, blinded to the 
patient details using a semi-automated lesion contouring application programme. 
3. Brain atrophy 
(i) 
Percentage Brain Volume Change (PBVC) will be measured from volumetric T1 
weighted scans using the SINA analysis application. 
(ii) 
Regional atrophy measure using voxel-based morphometry (VBM), which is an 
unbiased automated technique designed to detect areas of grey matter atrophy 
independent of the anatomical constraints necessarily associated with a priori 
operator-defined region of interest analysis. 
4. MTR 
(i) 
Lesion MTR maps will be determined from the MT scan. White matter lesion masks 
will be outlined on the MT-off scan and the masks applied to the MTR map to 
calculate the lesional MTR at each time point. This measure is expected to reflect 
de- and re-myelination. 
(ii) 
GM and NAWM MTR: As well as calculating the lesional MTR, grey and white 
matter masks will be segmented and applied to the MTR map to evaluate the mean 
normal appearing grey and white matter MTR value. Lesion masks will be removed 
in order to assess the non-lesional tissue. 
5. Diffusion 
Diffusion-based measures: Diffusion weighted images allow calculation of indices of 
structural integrity based on the diffusion coefficient of water molecules and their 
surrounding environment. These indices can reflect the underlying structural integrity as the 
hindrance and restriction of water molecules changes with disease.  
 
 
 
13. STATISTICS AND DATA ANALYSIS 
 
13.1 RATIONALE 
 
The main aim of each national trial participating in this international collaborative effort, including the 
present one, is to assess the feasibility, safety and the toxicity of MSC infusion, as administered 
within this specific treatment protocol, in active MS. To fulfill this aim, all randomised patients 
receiving at least one MSCs infusion (or infusion media) will be followed for at least two years after 
the last study drug administration. All adverse events will be recorded and compared in the two 
treatment groups. Comparative analyses of the incidence of new GEL at MRI acquired on 
conventional 1.5 T MRI scans over 24 weeks will be conducted as well, to provide preliminary data 
on the activity of the experimental treatment. However, the main analyses of safety, toxicity and 
activity will be those on the entire data set obtained by pooling the results of all national trials, for an 
expected total of 160 randomised patients. 
 


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13.2 SAMPLE SIZE 
 
Up to 23 patients are expected to be enrolled in the clinical trial for evaluation of the primary 
outcome (safety). Data from this clinical trial and from all other national trials will be pooled together 
for efficacy evaluation which will be evaluated as a decrease in the number of GEL (co-primary 
outcome). 
A sample size of 160 patients was estimated to give an 80% power at a significance level of 5% to 
detect a decrease of 50% in the number of GEL counted during the 6 months duration of treatment. 
This number was estimated assuming that the average number of total GEL on 3 MRI scans (scan 
at weeks 4, 12 and 24) will be 7.4 (SD=11.4), that is half of the number of total number of GEL 
counted over 6 monthly scans in the phase 2 study of oral fingolimod for MS [43] .  
 
 
13.3 EVALUATION OF PRIMARY OUTCOME VARIABLES  
 
 
Primary outcome: To assess the safety of intravenous therapy with autologous MSCs in MS 
patients. The safety of MSCs infusion will be evaluated including frequency, timing and 
severity of any adverse events in both MSCs and placebo treatment groups. A statistical 
comparison of the number of adverse events between treatment groups will be carried out 
using a chi-square test.  
 
Co-Primary outcome: To assess the activity of autologous MSCs in MS patients. The total 
number of gadolinium-enhancing lesions (GEL) at MRI at week 4, 12 and 24 will be 
compared between treatment groups using a Negative Binomial (NB) regression analysis, 
adjusting for the number of GEL at baseline.  
 
 
13.4 EVALUATION OF SECONDARY OUTCOME VARIABLES  
 
Secondary outcomes: To gather preliminary information about the efficacy of the experimental 
treatment in terms of combined MRI activity, incidence of relapses and disability progression. 
 
The total number of GEL lesions at MRI at weeks 4,12 and 24 in the group originally 
randomised to placebo will be compared with the number of GEL lesions at MRI at weeks 
28, 36 and 48 following the infusion using a mixed effect generalised model with NB errors. 
 
The dependence on time of the total number of GEL at MRI will be analysed in the group 
originally randomised to active treatment using a mixed effect generalised model with NB 
errors. 
 
Combined unique MRI activity (new or enlarging T2, or enhancing or re-enhancing lesions). 
The total number of new or enlarging T2, or enhancing or re-enhancing lesions at MRI at 
week 4, 12 and 24 post-treatment will be recorded in the two groups using a Negative 
Binomial (NB) regression analysis with the treatment group as covariate. 
 
Number of relapses in MSCs treatment group vs. placebo group will be acquired and using a 
Negative Binomial (NB) regression analysis with treatment group as covariate 
 
Time to sustained progression of disability (RRMS group) will be analyzed with a Cox 
proportional-hazards model 
 
Proportion of progression-free patients in two groups will be compared with the use of a chi-
square test (RRMS patients). 
 
Mean changes in Multiple Sclerosis Functional Composite (MSFC) score in MSC treatment 
group vs. placebo group compared to baseline will be analysed with a one-way ANOVA test. 
 


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13.5 EVALUATION OF EXPLORATORY OUTCOMES*  
Patients will undergo biological ‘proof of principle studies’ addressing the effect of MSC treatment 
on immune responses. Immune parameters will be compared within the patients longitudinally and 
cross-sectionally between post-MSC vs. post-infusion media treatment time points.  
 
* Only for the patients in the first phase of recruitment 
 
 
13.6 DATA ANALYSIS  
 
The number of GEL counted over 3 MRI scans will be considered a NB variable and analysed using 
a NB regression model. The model will be adjusted for the number of GEL on the baseline scan and 
will include treatment group as covariate. The number of relapses during the study period will be 
analysed with a NB regression model. Time to event variables will be studied with the Cox 
proportional-hazards model and visualised using the Kaplan-Meier survival curves. Proportion of 
events in the two treatment groups will be analysed by the chi-square test.  
A paired-data analysis will be run to compare the number of GEL during the placebo and during the 
treatment arm in the group originally randomised to placebo, using both a parametric mixed model 
with NB errors and a non-parametric Wilcoxon test.  
 
 
13.7 RECORD RETENTION  
 
The investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s). Data and all appropriate documentation will be stored for a minimum of 10 years 
after the completion of the study, including the follow-up period. If the investigator withdraws from 
the responsibility of keeping the study records, custody must be transferred to a person willing to 
accept the responsibility. 
 
 
 
14. MONITORING 
 
14.1 RISK ASSESSMENT  
 
14.1.1. MRI 
Magnetic Resonance Imaging (MRI) is a safe and non-invasive method to visualise structure and 
function in vivo of the human brain and body.  Earplugs and ear defenders will be provided to 
attenuate scanner noise, and subjects will be made comfortable with pillows and blankets to 
prevent lower back pain associated with lying still on the scanner table for up to 90 minutes. All 
subjects will have a call button should they wish to speak with the radiographer or to stop the scan 
at any time. At times, atypical findings can present on MRI scanning. Reviewing radiologists will 
report directly to the treating team if such a finding occurs as per the standard procedures at the 
MRI centre. 
 
14.1.2. Gadolinium 
Gadolinium is a widely used and safe contrast agent in MRI.  However, a link has been established 
between Gadolinium administration and a serious systemic fibrosing disease in patients with  
 


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moderate to end-stage kidney disease.  Furthermore, Gadolinium is contraindicated in patients 
with severe renal impairment or those underdoing liver transplantation. Patients will therefore be  
carefully screened for any unidentified renal impairment – and any patients with serum creatinine 
clearance < 30 ml/min will be excluded from the study.  
 
14.1.3. Bone marrow sampling 
The two most common complications that may occur from this procedure are bleeding and 
infection at the puncture site. The bleeding at the puncture site is usually controlled with external 
compression and gauze. Local infection at the puncture site is rare, but may require oral 
antibiotics. The procedure is performed under sterile conditions to prevent infections and with local 
anaesthetic to minimise any pain from the procedure.  
 
14.1.4. Lumbar puncture  
Common side effects from the lumbar puncture include: (i) Local pain in the lower back: this can 
occur soon after the procedure and generally settles over 24-48 hours. Local anaesthetic is 
administered during the procedure to minimise such pain and discomfort. (ii) Headache: 24hrs after 
the procedure, some people experience a headache that is worse on sitting or standing up. 
Prolonged headaches, lasting longer than 7 days, develop in only 0.5 - 2 percent of people (about 
one in 50 - 200 patients). These prolonged headaches usually resolve within 2 weeks of the lumbar 
puncture. 
 
14.1.5. Skin biopsy* 
A punch skin biopsy will be performed. Common risks are bleeding and scarring. Pigmented and 
oily skins tend to have more scar formation than pale, dry skins. Other complications during and 
after the procedure are uncommon. Those risks and complications can include, but are not limited 
to: protracted bleeding, discolouration, cheloid formation, adverse reactions to anaesthesia, 
infection, pain, and numbness at the biopsy site.  
 
* Only for the patients in the first phase of recruitment 
 
 
14.1.6. Mesenchymal stem cell infusion 
During the infusion, allergic reactions can occur - these include transient fever and headaches. 
Potentially more significant allergic reactions can occur but are very rare. 
 
14.1.7. Mantoux tuberculin skin test (TST) 
Minor reactions such as mild itching, swelling or irritation can occur but do not require treatment. If 
the patient does not attend for the readout at 48-72 hours, then the test will need to be repeated. 
 
 
14.2 MONITORING AT THE STUDY COORDINATION CENTRE  
 
Patients registration, randomisation and data entry of all clinical, laboratory and MRI data will be 
performed via a e-CRF accessible to authorized researchers through the following address: 
http://ctrials.hsanmartino.it/ist/rnd and http://ctrials.hsanmartino.it/ist/rde. The Centro Clinical Trials 
will provide the required login and password to each researcher to allow remote registration and 
randomisation of patients and data entry. Data management will be carried out in compliance with 
all applicable regulation. 
 
 
 


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14.3 MONITORING AT LOCAL SITE  
 
This will be performed by the Imperial College Joint Research Compliance Office (JRCO). 
 
 
 
15. DOCUMENTATION 
 
15.1 CASE REPORT FORMS  
 
Case Report Forms (CRFs) for individual subjects will be used to record all clinical trial data. They 
will be completed for every visit and will record patient demographics, informed consent, clinical  
evaluation at each visit and adverse events. All CRFs will be stored in the subject study binder that 
will be maintained locally and stored securely. Appropriate coded identification will be used so that 
subjects will not be identifiable from the CRF.  
 
Data correction within the CRF should be dated, initialled, and explained (if necessary) and should 
not obscure the original entry i.e. an audit trail should be maintained. Any protocol deviation will be 
recorded on the form as shown in Appendix 5. 
 
 
15.2 SOURCE DOCUMENTATION  
 
Source documents including, but not limited to, original signed Informed Consent Forms, 
prescription forms and laboratory test results will be maintained at the study site in the subject 
study binder 
 
 
15.3 SAFETY MONITORING COMMITTEE  
 
A Data Safety and Monitoring Committee (DSMC) will be established to meet at 12 months to 
review the side-effect profile of both arms of the trial. It is unlikely that a large positive or negative 
effect from the study medication will be seen, and as such, efficacy data will remain blinded until 
the end of the study. Data will be presented by the study statistician.   
 
 
15.4 DATA RETENTION AND ARCHIVING  
 
In compliance with ICH/GCP guidelines and applicable regulatory requirements, the Chief 
Investigator will be responsible for maintaining all study records and documents pertaining to the 
conduct of the study. This will include Informed Consent Forms, CRFs and laboratory test results 
and will be retained as appropriate under current GCP guidelines.  
 
Imperial College London policy is to retain all study documentation for 10 years. 
 
 


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16. REGULATORY ISSUES 
 
16.1 CLINICAL TRIALS AUTHORISATION  
 
This study has Clinical Trials Authorisation from the UK Competent Authority; MHRA.  Reference: 
19174/0326/001-0001. 
 
 
16.2 ETHICS APPROVAL 
 
The Study Coordination Centre has obtained approval from the Gene Therapy Advisory Committee 
(GTAC). The  Study Coordination  Centre  will  require  a  copy of  the  Trust  R&D  approval  letter  
before accepting participants into the study. The study will be conducted in accordance with the 
recommendations for physicians involved in research on human subjects adopted by the 18th 
World Medical Assembly, Helsinki 1964 and later revisions. Any subsequent amendments to the 
protocol will require sponsor approval before being submitted to the ethics committee. Once this is 
obtained, further Trust R&D approval is required before the amendments can be implemented at 
the site. 
 
 
16.3 CONSENT 
 
Consent to enter the study must be sought from each participant only after a full explanation has 
been given, an information leaflet offered and time allowed for consideration.  Signed participant 
consent should be obtained. The right of the participant to refuse to participate without giving 
reasons must be respected. After the participant has entered the trial the clinician remains free to 
give alternative treatment to that specified in the protocol at any stage if he/she feels it is in the 
participant’s best interest, but the reasons for doing so should be recorded. In these cases the 
participants remain within the study for the purposes of follow-up and data analysis. All participants 
are free to withdraw at any time from the protocol treatment without giving reasons and without 
prejudicing further treatment. 
 
 
16.4 CONFIDENTIALITY 
 
Participants’ identification data will be required for the registration process. The Study 
Coordination Centre will preserve the confidentiality of participants taking part in the study and is 
registered under the Data Protection Act. All data arising as part of this study will be treated 
confidentially, and kept in an anonymised format wherever possible.  Personal contact details will 
be held for communication with the patients participating in the study.  Subjects will be assigned a 
personal study code number which will be used throughout the study and in the analysis of data. 
The study code will be kept secure in a locked cabinet with only the CI having access.  Coded 
samples or images will also be treated with confidentiality when undergoing analysis. Study data 
will be kept in a secure database (at the Imperial College Healthcare Trust) entered with the 
patient’s consent.   Data will be backed up on secure servers at Imperial College as per standard  
university procedures.  For further analysis, linked anonymised data will be downloaded to local 
computers.  Only linked anonymised data will be available outside of the patient’s treating team.  
 


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16.5 INDEMNITY  
 
Imperial College London holds negligent harm and non-negligent harm insurance policies that 
apply to this study if harm arises either out of design or management of the research. Imperial 
College Healthcare NHS Trust holds standard NHS Hospital Indemnity and insurance cover with 
NHS Litigation Authority for NHS Trusts in England, which apply to this study where harm arises to 
participants in the conduct of the research. 
 
 
16.6 SPONSOR 
 
Imperial College London will act as the main Sponsor for this study. Delegated responsibilities 
will be assigned to the NHS trusts taking part in this study. 
 
 
16.7 FUNDING  
 
The UK MS Society and UK Stem Cell Foundation are jointly funding this study. The grant is 
administered by the MS Society.   
 
 
16.8 AUDITS AND INSPECTIONS 
 
The study may be subject to inspection and audit by Imperial College London under their remit 
as Sponsor, the Study Coordination Centre and other regulatory bodies to ensure adherence to 
GCP. 
 
 
 
17. TRIAL MANAGEMENT 
A Trial Management Group will be appointed and will be responsible for overseeing the 
progress of the trial. The day-to-day management of the trial will be co-ordinated through the Study 
Coordination Centre. 
 
Patients registration, randomisation and data entry of all clinical, laboratory and MRI data will be 
performed via an e-CRF accessible to authorised researchers through the following address: 
http://ctrials.hsanmartino.it/ist/rnd/ and http://ctrials.hsanmartino.it/ist/rde/. The Centro Clinical 
Trials, will provide the required login and password to each researcher to allow remote registration 
and randomisation of patients and data entry. Data management will be carried out in compliance 
with all applicable regulation. 
 
There will also be a centralised safety committee that will liaise with the local safety monitoring 
committee on a regular and as-needed basis. 
 
 


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18. PUBLICATION POLICY 
The study primary outcomes will be pooled from all studies participating in the International Trial 
Consortium. All other outcomes and ancillary studies will be analysed and published independently 
or as seen appropriate by the Investigators. A writing group will be formed by all contributors who 
played a substantial role in the acquisition, analysis or interpretation of the data and will be chaired 
by the Principal Investigator. Authorship will be determined on the basis of the specific contribution 
to the study and to the article write-up. Minor contributions or paid technical work will be 
acknowledged as appropriate. 
 
All publications and presentations relating to the study will be authorised by the Trial Management 
Group.  The first publication of the trial results will be in the name of the Trial Management Group, 
if this does not conflict with the journal’s policy.  If there are named authors, these will include at 
least the trial’s Chief Investigator, Statistician and Trial Coordinator.  Members of the trial 
management group and the Data Monitoring Committee will be listed and contributors will be cited 
by name if published in a journal where this does not conflict with the journal’s policy.  Authorship 
of parallel studies initiated outside of the Trial Management Group will be according to the 
individuals involved in the project but  must  acknowledge  the  contribution  of  the  Trial  
Management  Group  and  the  Study Coordination Centre. Authorship of publications resulting 
from this study will be based on generally accepted criteria for major medical journals. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Kappos, L., et al., Oral Fingolimod (FTY720) for Relapsing Multiple Sclerosis. New England 
Journal of Medicine, 2006. 355(11): p. 1124-1140. 


VERSION 6.0 18 DECEMBER 2014 
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20. APPENDICES 
 
Appendix 1: Kurtzke Expanded Disability Status Scale (EDSS) 
 
The EDSS provides a total score on a scale from 0 to 10. Scores of 1.0 to 4.5 refer to people with a high 
degree of ambulatory ability and subsequent levels 5.0 to 9.5 refer to loss of ambulatory ability. In addition, it 
quantifies disability in eight functional systems (FS) and allows neurologists to assign a Functional System 
Score (FSS) in each of these.   
 
The functional systems are: (1) Pyramidal  (2) Cerebellar  (3) Brainstem  (4) Sensory   (5) Bowel and Bladder  
(6) Visual  and (7) Cerebral or Mental. 
 
The Functional systems are scored on a scale of 0-5 to best reflect the level of disability observed clinically. 
The ‘other’ category is not rated numerically. 
 
EDSS scores below 4.0 are determined by the FSS alone. Scores between 4.0 and 9.5 are determined by 
both gait abilities and the FSS.  
 
0 
Normal neurological exam (all grade 0 in Functional Systems (FS); cerebral grade 1 acceptable). 
1 
No disability, minimal signs in one FS (i.e. one grade 1 excluding cerebral grade 1). 
1.5 
No disability, minimal signs in more than one FS (more than one grade 1 excluding cerebral grade 1). 
2.0 
Minimal disability in one FS (one FS grade 2, others 0 or 1). 
2.5 
Minimal disability in two FS (two FS grade 2, others 0 or 1). 
3.0 
Moderate disability in one FS (one FS grade 3, others 0 or 1), or mild disability in three or four FS (three-
four FS grade 2, others 0 or 1). 
3.5 
Fully ambulatory but with moderate disability in one FS (one grade 3 and one or two FS grade 2) or two FS 
grade 3, others 0 or 1, or five FS grade 2, others 0 or 1. 
4.0 
Fully ambulatory without aid, self-sufficient, up and about some 12 hours a day despite relatively severe 
disability consisting of one FS grade 4 (others 0 or 1), or combinations of lesser grades exceeding limits of 
previous steps. Able to walk without aid or rest some 500 meters or 0.3 miles. 
4.5 
Fully ambulatory without aid, up and about much of the day, able to work a full day, may otherwise have 
some limitation of full activity or require minimal assistance; characterized by relatively severe disability. 
(Usually consisting of one FS grade 4 (others 0 or 1) or combinations of lesser grades exceeding limits of 
previous steps. Able to walk without aid or rest for some 300 meters or 975 ft). 
5.0 
Ambulatory without aid or rest for about 200 meters or 650 ft; disability severe enough to impair full daily 
activities (e.g., to work full day without special provisions). (Usual FS equivalents are one grade 5 alone 
(others 0 or 1); or combinations of lesser grades usually exceeding specifications for step 4.0.) 
5.5 
Ambulatory without aid or rest for about 100 meters or 325 ft; disability severe enough to impair full daily 
activities. (Usual FS equivalents are one grade 5 alone (others 0 or 1); or combinations of lesser grades 
usually exceeding specifications for step 4.0.) 
6.0 
Intermittent or constant unilateral assistance (cane, crutch, or brace) required to walk about 100 meters or 
325 ft. with or without resting. (Usual FS equivalents are combinations with more than two FS grade 3+.) 
6.5 
Constant bilateral assistance (canes, crutches, or braces) required to walk about 20 meters or 65 ft.  (Usual 
FS equivalents are combinations with more than two FS grade 3+.) 
7.0 
Unable to walk beyond about 5 meters or 16 ft. even with aid, essentially restricted to wheelchair, wheels 
self in standard wheelchair a full day and transfers alone; up and about in wheelchair some 12 hours a day. 
(Usual FS equivalents are combinations with more than one FS grade 4+; very rarely pyramidal grade 5 
alone.) 
7.5 
Unable to take more than a few steps; restricted to wheelchair; may need aid in transfers, wheels self but 
cannot carry on in standard wheelchair a full day; may require motorised wheelchair. (Usual FS equivalents 
are combinations with more than one FS grade 4+.) 
8.0 
Essentially restricted to bed or chair or perambulated in wheelchair; but may be out of bed much of the day; 
retains may self-care functions; generally has effective use of arms. (Usual FS equivalents are 
combinations, generally grade 4+ in several systems.) 
8.5 
Essentially restricted to bed for much of the day; has some effective use of arm(s); retains some self-care 
functions. (Usual FS equivalents are combinations, generally grade 4+ in several systems.) 
9.0 
Helpless bed patient; can communicate and eat. (Usual FS equivalents are combinations, mostly grade 4.) 
9.5 
Totally helpless bed patient; unable to communicate or effectively eat/swallow. (Usual FS equivalents are 
combinations, almost all grade 4+.) 
10 
Death due to MS. 


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Appendix 2: Multiple Sclerosis Impact Scale (MSIS-29) 
 
 
 
 
       The MSIS-29 is a questionnaire whereby the patient indicates the impact of MS on their 
       daily life over the past two weeks by placing a circle around the answer that best  
       represents their situation. 
 
 
 
 
In the past 2 weeks how much has your 
MS limited your ability to 
Not at 
all 
A 
little 
Moderately 
Quite a 
bit 
Extremely 
1 
2 
3 
Do physically demanding tasks? 
Grip things tightly (e.g. turning on taps)? 
Carry things? 
1 
1 
1 
2 
2 
2 
3 
3 
3 
4 
4 
4 
5 
5 
5 
 
In the past 2 weeks how much have 
you been bothered by 
Not at 
all 
A 
little 
Moderately 
Quite a 
bit 
Extremely 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Problems with your balance? 
Difficulties moving about indoors? 
Being clumsy? 
Stiffness? 
 Heavy arms and/or legs? 
Tremor of your arms or legs? 
Spasms in your limbs? 
Your body not doing what you want it to? 
Having to depend on others to do things 
for you? 
 
1 
1 
1 
1 
1 
1 
1 
1 
1 
 
2 
2 
2 
2 
2 
2 
2 
2 
2 
3 
3 
3 
3 
3 
3 
3 
3 
3 
4 
4 
4 
4 
4 
4 
4 
4 
4 
5 
5 
5 
5 
5 
5 
5 
5 
5 
 
Please check that you have answered 
all the questions above before going 
onto the next section. 
 
 
 
 
 
 
 
In the past 2 weeks how much have 
you been bothered by 
 
Not at 
all 
A 
little 
Moderately 
Quite a 
bit 
Extremely 
13 
 
14 
 
15 
 
16 
 
 
17 
 
18 
19 
 
20 
21 
22 
23 
24 
25 
26 
 
27 
28 
29 
 
Limitations in your social and leisure 
activities at home? 
Being stuck at home more than you 
would like to be? 
Difficulties using your hands in everyday 
tasks? 
Having to cut down the amount of time 
you spent on work or other daily 
activities? 
Problems using transport (e.g. car, bus, 
train, taxi etc)? 
Taking longer to do things? 
Difficulty doing things spontaneously (e.g. 
going out on the spur of the moment)? 
Needing to go to the toilet urgently? 
Feeling unwell? 
Problems sleeping? 
Feeling mentally fatigued? 
Worries related to your MS? 
Feeling anxious or tense? 
Feeling irritable, impatient or short 
tempered? 
Problems concentrating? 
Lack of confidence 
Feeling depressed? 
1 
 
1 
 
1 
 
1 
 
 
1 
 
1 
1 
 
1 
1 
1 
1 
1 
1 
1 
 
1 
1 
1 
 
2 
 
2 
 
2 
 
2 
 
 
2 
 
2 
2 
 
2 
2 
2 
2 
2 
2 
2 
 
2 
2 
2 
3 
 
3 
 
3 
 
3 
 
 
3 
 
3 
3 
 
3 
3 
3 
3 
3 
3 
3 
 
3 
3 
3 
4 
 
4 
 
4 
 
4 
 
 
4 
 
4 
4 
 
4 
4 
4 
4 
4 
4 
4 
 
4 
4 
4 
5 
 
5 
 
5 
 
5 
 
 
5 
 
5 
5 
 
5 
5 
5 
5 
5 
5 
5 
 
5 
5 
5 
 
Please check that you have circled ONE number for each question only. 


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Appendix 3: Multiple Sclerosis Function Composite Score (MSFC) 
 
 
This is a series of tests including: 
 
 The Timed 25 – Foot Walk 
 The 9 - Hole Peg Test 
 The Paced Auditory Serial Addition Test (PASAT) 
 
 
The Timed 25 – Foot Walk (T25-FW) 
 
The T25-FW is a quantitative mobility and leg function performance test based on a timed 25-foot 
walk. It is the first component of the MSFC to be administered at each visit. The patient is directed 
to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as 
possible, but safely. The time is calculated from the initiation of the instruction to start and ends 
when the patient has reached the 25 feet mark. The task is immediately administered again by 
having the patient walk back the same distance. Patients may use an assistive device when 
performing this task. 
The score for the T25-FW is the average of the two completed trials.  This score can either be 
used individually or as part of the MSFC composite score. 
 
 
The 9-Hole Peg Test (9-HPT) 
 
The 9-Hole Peg Test (9-HPT) is a brief, standardised quantitative test of upper extremity function. 
Reliability and validity have been assessed and normative data is available. Both the dominant and 
non-dominant hands must be tested twice.  
The patient should be seated at a table with a small shallow container holding nine pegs and a 
wood or plastic block containing nine empty holes. The patient is instructed to pick up the nine 
pegs, place them in the holes and then remove them as quickly as possible (one at a time), to 
replace them in the original shallow container. The total time to complete the task is recorded using 
a stopwatch.   
The final score for the 9-HPT is the average of the four trials.  The two trials with each hand are 
averaged, converted to the reciprocals of the mean times for each hand and then the two 
reciprocals are averaged. This score can be used individually or as part of the MSFC composite 
score. 
 
 
Paced Auditory Serial Addition Test (PASAT) 
 
This is a measure of cognitive function that assesses auditory information processing speed and 
flexibility as well as calculation ability. The PASAT is presented using an audio cassette tape or 
compact disc to ensure standardisation in the rate of stimulus presentation. Single digits are 
presented every 3 seconds and the patient must add each new digit to the immediately prior to it.  
(Shorter inter-stimulus intervals e.g. every 2 seconds or less have been used with PASAT but tend 
to increase the difficulty of the test).  
The score for the PASAT is the total number correct out of 60 possible answers. This score can be 
used individually or as part of the MSFC composite score. 


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Appendix 4: SF-36 Assessment (Version 2)  
 
 
THE FOLOWING QUESTIONS ASK FOR YOUR VIEWS ABOUT YOUR HEALTH AND HOW YOU FEEL ABOUT LIFE 
IN GENERAL. IF YOU ARE UNSURE ABOUT HOW TO ANSWER ANY QUESTION, TRY AND THINK ABOUT YOUR 
OVERALL HEALTH AND GIVE THE BEST ANSWER YOU CAN. DO NOT SPEND TOO MUCH TIME ANSWERING, AS 
YOUR IMMEDIATE RESPONSE IS LIKELY TO BE THE MOST ACCURATE ANSWER. 
 
PLEASE TICK () THE ANSWER THAT BEST REPRESENTS YOUR RESPONSE. 
 
1. 
In general, how would you say your health is? 
 
 
Excellent 
 
Very Good 
 
Good 
 
Fair 
 
Poor 
 
2. 
Compared to 3 months ago, how would you rate your health in general now? 
 
 
Much better than 3 months ago 
 
Somewhat better now than 3 months ago 
 
About the same as 3 months ago 
 
Somewhat worse now than 3 months ago 
 
Much worse now than 3 months ago 
 
3. 
The following items are about activities you might do during a typical day. Does your health limit you in these 
activities? If so, how much? 
 
a. Vigorous activities, such as running, lifting heavy objects, participating in strenuous sports. 
 
Yes, limited a lot 
 
Yes, limited a little 
 
No, not limited at all 
 
b. 
Moderate activities, such as moving table, pushing a vacuum cleaner, bowling or playing golf. 
 
Yes, limited a lot 
 
Yes, limited a little 
 
No, not limited at all 
 
c. Lifting or carrying groceries. 
 
Yes, limited a lot 
 
Yes, limited a little 
 
No, not limited at all 
 
d. Climbing several flights of stairs. 
 
Yes, limited a lot 
 
Yes, limited a little 
 
No, not limited at all 
 
e. Climbing one flight of stairs. 
 
Yes, limited a lot 
 
Yes, limited a little 
 
No, not limited at all 
 
f. Bending, kneeling and stooping. 
 
Yes, limited a lot 
 
Yes, limited a little 
 
No, not limited at all 
 
g. Walking more than one mile. 
 
Yes, limited a lot 
 
Yes, limited a little 
 
No, not limited at all 
 
h. Walking several blocks. 
 
Yes, limited a lot 
 
Yes, limited a little 
 
No, not limited at all 


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SF-36 Assessment (Version 2) continued  
 
 
 
 
Page 2 of 5 
 
 
 
i. Walking one block. 
 
Yes, limited a lot 
 
Yes, limited a little 
 
No, not limited at all 
 
j. Bathing or dressing yourself. 
 
Yes, limited a lot 
 
Yes, limited a little 
 
No, not limited at all 
 
4. 
During the past 2 weeks, what proportion of the time have you had any of the following problems with your work or 
other regular daily activities as a result of your physical health? 
 
a. Cut down the amount of time you spent on work or other activities. 
 
All of the time 
 
Most of the time 
 
Some of the time 
 
A little of the time 
 
None of the time 
 
b. Accomplished less than you would like. 
 
All of the time 
 
Most of the time 
 
Some of the time 
 
A little of the time 
 
None of the time 
 
c. Were limited in the kind of work or other activities. 
 
All of the time 
 
Most of the time 
 
Some of the time 
 
A little of the time 
 
None of the time 
 
d. Had difficulty performing the work or any other activity (for example, it took more effort) 
 
All of the time 
 
Most of the time 
 
Some of the time 
 
A little of the time 
 
None of the time 
 
5. 
During the past 2 weeks, what proportion of the time have you had any of the following problems with your work or 
other regular daily activities as a result of emotional problems (such as feeling depressed or anxious)? 
 
a. Cut down the amount of time you spent on work or other activities. 
 
All of the time 
 
Most of the time 
 
Some of the time 
 
A little of the time 
 
None of the time 
 
b. Accomplished less than you would like. 
 
All of the time 
 
Most of the time 
 
Some of the time 
 
A little of the time 
 
None of the time 
 
c. Didn’t do work or other activities as carefully as usual. 
 
All of the time 
 
Most of the time 
 
Some of the time 
 
A little of the time 
 
None of the time 
 


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SF-36 Assessment (Version 2) continued  
 
 
 
 
Page 3 of 5 
 
 
 
6. 
During the past 2 weeks, to what extent has your physical health or emotional problems interfered with your normal 
social activities with family, friends, neighbours or groups? 
 
Not at all 
 
Slightly 
 
Moderately 
 
Quite a bit 
 
Extremely 
 
7. 
How much bodily pain have you had during the past 2 weeks? 
 
None 
 
Very Mild 
 
Mild 
 
Moderate 
 
Severe 
 
Very Severe 
 
8.  
During the past 2 weeks, how much did pain interfere with your normal work (including both work outside the home 
and housework)? 
 
Not at all 
 
Slightly 
 
Moderately 
 
Quite a bit 
 
Extremely 
 
9.  
These questions are about how you feel and how things have been with you during the past 2 weeks. For each 
question, give the answer that comes closest to the way you have been feeling. How much of the time during the past 2 
weeks? 
 
a. Did you feel “full of life”? 
 
All of the time 
 
Most of the time 
 
A good bit of the time 
 
Some of the time 
 
A little of the time 
 
None of the time 
 
b. Have you been a very nervous person? 
 
All of the time 
 
Most of the time 
 
A good bit of the time 
 
Some of the time 
 
A little of the time 
 
None of the time 
             
             c. Have you felt so “down in the dumps” nothing could cheer you up? 
 
All of the time 
 
Most of the time 
 
A good bit of the time 
 
Some of the time 
 
A little of the time 
 
None of the time 
 
d. Have you felt calm and peaceful? 
 
All of the time 
 
Most of the time 
 
A good bit of the time 
 
Some of the time 
 
A little of the time 
 
None of the time 
 
e. Did you have a lot of energy? 
 
All of the time 
 
Most of the time 
 
A good bit of the time 
 
Some of the time 


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SF-36 Assessment (Version 2) continued  
 
 
 
 
Page 4 of 5 
 
 
 
A little of the time 
 
None of the time 
 
 
f. Have you felt downhearted and blue? 
 
All of the time 
 
Most of the time 
 
A good bit of the time 
 
Some of the time 
 
A little of the time 
 
None of the time 
 
g. Did you feel worn out? 
 
All of the time 
 
Most of the time 
 
A good bit of the time 
 
Some of the time 
 
A little of the time 
 
None of the time 
 
            h. Have you been a happy person? 
 
All of the time 
 
Most of the time 
 
A good bit of the time 
 
Some of the time 
 
A little of the time 
 
None of the time 
 
i. Did you feel tired? 
 
All of the time 
 
Most of the time 
 
A good bit of the time 
 
Some of the time 
 
A little of the time 
 
None of the time 
 
10.  During the past 2 weeks, how much of the time your physical health or emotional problems interfered with your social 
activities (like visiting friends, relatives, etc.)? 
 
 
All of the time 
 
Most of the time 
 
A good bit of the time 
 
Some of the time 
 
A little of the time 
 
None of the time 
 
11.  How TRUE or FALSE is each of the following statements for you? 
 
a. I seem to get sick a little easier than other people 
 
Definitely true 
 
Mostly true 
 
Not Sure 
 
Mostly false 
 
Definitely false 
 
b. I am as healthy as anybody I know 
 
Definitely true 
 
Mostly true 
 
Not Sure 
 
Mostly false 
 
Definitely false 
 
c. I expect my health to get worse 
 
Definitely true 
 
Mostly true 
 
Not Sure 


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SF-36 Assessment (Version 2) continued  
 
 
 
 
Page 5 of 5 
 
 
 
 
Mostly false 
 
Definitely false 
 
 
d. My health is excellent 
 
Definitely true 
 
Mostly true 
 
Not Sure 
 
Mostly false 
 
Definitely false 
 
 
 
 
 
--------------------------------THANK YOU FOR COMPLETING THE QUESTIONNAIRE---------------


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Appendix 5: Protocol deviation form 
 
 
 
PROTOCOL DEVIATION FORM 
TRIAL TITLE: 
 Stem cells in Rapidly Evolving 
Active Multiple Sclerosis 
PHASE: II 
PATIENT INITIALS: 
SCREENING NUMBER: 
CLINICAL TRIAL NUMBER: 
REASON FOR DEVIATION 
ASSESSMENT OF DEVIATION 
1. Major deviation 
         
2. Minor deviation                     
APPROVED BY 
Name                     Signature                   
Date 
Principal Investigator/Sub-investigator              


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Appendix 6: Declaration of Helsinki 
 
Recommendations guiding medical doctors in biomedical research involving human subjects.   
Adopted by the 18th World Medical Assembly, Helsinki, Finland 1964 amended by the 29th World 
Medical Assembly, Tokyo, Japan 1975 and the 35th World Medical Assembly, Venice, Italy, 
October 1983 and the 41st World Medical Assembly, Hong Kong, September 1989. 
 
INTRODUCTION 
It is the mission of the medical doctor to safeguard the health of people.  His or her knowledge and 
conscience are dedicated to the fulfilment of this mission. 
 
The Declaration of Geneva of the World Medical Association binds the physician with the words, 
‘The health of my patient will be my first consideration’, and the international code of medical 
Ethics declares that, ‘A physician shall act only in the patient’s interest when providing medical 
care which might have the effect of weakening the physical and mental condition of the patient’ 
 
The purpose of biomedical research involving human subjects must be to improve diagnostic, 
therapeutic, and prophylactic procedures and the understanding of the aetiology and pathogenesis 
of disease. 
 
In current medical practice, most diagnostic, therapeutic, or prophylactic procedures involve 
hazards.  This applies especially to biomedical research.  Medical progress is based on research, 
which ultimately must rest in part on experimentation involving human subjects. 
 
In the field of biomedical research a fundamental distinction must be recognized between medical 
research in which the aim is essentially diagnostic or therapeutic for a patient and medical 
research, the essential object of which is purely scientific and without implying direct diagnostic or 
therapeutic value to the person subjected to the research. 
 
Special caution must be exercised in the conduct of research that may affect the environment. In 
addition, the welfare of animals used for research must be respected. 
 
Because it is essential that the results of laboratory experiments be applied to human beings to 
further scientific knowledge and to help suffering humanity, the World Medical Association has 
prepared the following recommendations as a guide to every physician in biomedical research 
involving human subjects.  They should be kept under review in the future.  It must be stressed that 
the standards as drafted are only a guide to physicians all over the world.  Physicians are not 
relieved from criminal, civil and ethical responsibilities under the laws of their own countries. 
 
 
I     Basic Principles 
 
1. Biomedical research involving human subjects must conform to generally accepted 
scientific principles and should be based on adequately performed laboratory and animal 
experimentation and on a thorough knowledge of the scientific literature. 
2. The design and performance of such experimental procedure involving   
human subjects should be clearly formulated in an experimental protocol which should be 
transmitted for consideration, comment and guidance to a specially appointed committee 
independent of the Investigator and the sponsor provided that this independent committee 
is in conformity with the laws and regulations of the country in which the research 
experiment is performed. 


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3. Biomedical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person.  The 
responsibility for the human subject must always rest with a medically qualified person and 
never rest on the subject of the research, even though the subject has given his or her 
consent. 
4. Biomedical research involving human subjects cannot legitimately be carried out unless the 
importance of this objective is in a proportion to the inherent risk to the subject. 
5. Every biomedical research project involving human subjects should be preceded by careful 
assessment of predictable risks in comparison with foreseeable benefits to the subject or to 
others.  Concern for the interests of the subject must always prevail over the interests of 
science and society. 
6. The right of the research subject to safeguard his or her integrity must always be respected.  
Every precaution should be taken to respect the privacy of the subject and to minimize the 
impact of the study on the subject’s physical and mental integrity and on the personality of 
the subject. 
7. Physicians should abstain from engaging in research projects involving human subjects 
unless they are satisfied that the hazards involved are believed to be predictable.  
Physicians should cease any investigation if the hazards are found to out weigh the 
potential benefits. 
8. In publication of the results of his or her research, the physician is obliged to preserve the 
accuracy of the results.  Reports of experimentation not in accordance with the principles 
laid down in this Declaration should not be accepted for publication. 
9. In any research on human beings, each potential subject must be adequately informed of 
the aims, methods, anticipated benefits and potential hazards of the study and the 
discomfort it may entail.  He or she should be informed that he or she is at liberty to abstain 
from participation in the study and that he or she is free to withdraw his or her consent to 
participation at any time.  The physician should then obtain the subject’s freely given 
informed consent, preferably in writing. 
10. When obtaining informed consent for the research project, the physician should be 
particularly cautious if the subject is in a dependent relationship to him or her or may 
consent under duress.  In that case informed consent should be obtained by a physician 
who is not engaged in the investigation and who is completely independent of his official 
relationship. 
11 In case of legal incompetence, informed consent should be obtained from the legal 
guardian in accordance with the national legislation.  Where physical form or mental 
incapacity makes it impossible to obtain informed consent or when the subject is a minor, 
permission from the responsible relative replaces that of the subject in accordance with the 
national legislation. 
Whenever the minor child is in fact able to give consent, the minor’s consent must be 
obtained in addition to the consent of the minor’s legal guardian. 
12. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that the principles enunciated in the present declaration are 
complied with.  
 
 
II    Medical research combined with professional care (clinical research) 
 
1. In the treatment of the sick person, the physician must be free to use a new diagnostic and 
 therapeutic measure, if in his or her judgment it offers hope of saving life, re-establishing 
health or alleviating suffering. 
2. The potential benefits, hazards and discomforts of a new measure should be weighed 
against the advantages of the best diagnostic and therapeutic methods. 
3. In any medical study, every patient including those of a control group, if any, should be 


VERSION 6.0 18 DECEMBER 2014 
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Joint Research Compliance Office 
 
 
 assured of the best proven diagnostic and therapeutic method. 
4. The refusal of the patient to participate in a study must never interfere with the physician-
patient relationship. 
5. If the physician considers it essential not to obtain informed consent the specific reasons for 
this proposal should be stated in the experimental protocol for transmission to the 
independent committee (1.2.) 
6. The physician can combine medical research with professional care, the objective being the 
acquisition of new medical knowledge, only to the extent that medical research is justified 
by its potential diagnostic or therapeutic value for the patient. 
 
 
III Non-therapeutic biomedical research involving human subjects (non-clinical biomedical 
research) 
 
1. In the purely scientific application of medical research carried out on a human being, it is 
 the duty of the physician to remain the protector of the life and health of that person on whom 
biomedical research is being carried out. 
2. The subjects should be volunteers – either healthy persons or patients for whom the 
experimental design is not related to the patient’s illness. 
3. The Investigator or the Investigating team should discontinue the research if in his/her or 
their judgment it may, if continued, be harmful to the individual. 
4. In research on man, the interest of science and society should never take precedence over 
considerations related to the well-being of the subjects. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 7: Stem cell referrals standard operating procedure 
 
 
MULTIPLE SCLEROSIS TRIALS COLLABORATION 
 
STANDARD OPERATING PROCEDURE FOR 
MANAGING STEM CELL REFERRALS 
 
AUTHOR: DAVID WILKIE 
17 October 11 
VERSION: 1.0 
 
 
BACKGROUND 
The following system has been devised to help manage the influx of referrals from different channels enquiring 
about stem cell research, as follows: 
Methods of Referral: 
 
Healthcare Professionals  
 
Professional Bodies e.g. MS Society/Trust  
 
Self-referrals (Patient) 
 
Friends or Relatives 
 
Overseas enquiries 
 
Other  
Via the following Channels:  
- 
Written (post)  
- 
E-mail  
- 
Phone 
- 
Voicemail 
Following a number of meetings with the study team, it was agreed that one point of reference for all incoming 
referrals was the most appropriate way to proceed.  Thus, the following e-mail address was created: 
stemcellms@imperial.ac.uk 
Dr Paolo Muraro, as Principal Investigator, had previously responded to a selection of patients up to a known time 
point, but not those enquiring beyond this.  For this reason, the first task was to organise correspondence and split 
these into two time periods and by methods of referral. 
All referrals were input into an electronic database for future reference including the following information if known: 
1. Name of person making contact (if other than the patient) 
2. Patient’s name (Surname, First name) 


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3. Mailing address 
4. Date of first enquiry 
5. Tel no 1 
6. Tel no 2 
7. Email address 
8. GP/Consultant information 
9. How did they hear of trial? 
10. MS details 
11. Method 
12. Response Date 
The team decided on two separate auto-responses to send to patients outlining the basic entry criteria for the trial 
as follows: 
The first aimed at those who had received a previous response via MS Society: 
 
Thank you for your interest in the stem cell study that was recently covered in the media.  Following the press 
release in the media on 28th July 2011, we received a very high number of phone calls, letters and e-mails from 
interested subjects.  It has been difficult to manage such a massive flow of enquiries and soon after the initial 
response we felt we could not consider additional subjects for potential participation.  After consulting the MS 
Society, on 1st August we issued a statement that the study had identified enough participants.  
We have now put in place a study management team and we would like to give everyone who contacted us more 
information about the study and the opportunity for them to know if they would meet the study basic entry criteria 
and, if so, to reconfirm their interest in participating. 
 
Summary of the basic entry criteria: 
1)     Confirmed diagnosis of MS - Relapsing-Remitting, Secondary Progressive or Primary Progressive MS 
2)     Age 18-50 (inclusive) 
3)     Disease duration between 2 and 10 years (inclusive) 
4)     Ability to walk at least 20 metres with bilateral assistance - without resting 
 
There will be additional entry criteria and the participation in the study is restricted to those eligible for treatment 
under the NHS and who reside in the UK for the duration of the study. 
The study has yet to receive ethical approval.  Until this occurs, we will only register your interest at this stage. 
If you feel you are interested and meet the basic criteria, please e-mail stemcellms@imperial.ac.uk and write 
“CONFIRMATION OF INTEREST” into the subject field.  
 
This is an experimental treatment and a safety study and thus there is no guarantee that it will have any benefit to 
participants.  For this reason we do not recommend any delay in treatment that has been offered to you. 
We are unable to reply to individual questions but we will release more information to those that have confirmed 
interest as soon as it becomes available. 
 
Sincerely, 
On behalf of the study team 
Dr Paolo Muraro  
Clinical Reader in Neuroimmunology 
Honorary Consultant Neurologist 
Centre for Neurosciences 
Division of Experimental Medicine 
Department of Medicine, Imperial College 
-------------------------------------------- 
The second to all new enquiries: 
Thank you for your interest in the stem cell study that was recently covered in the media.  
We have received a high number of enquiries and for this reason, we would like to apologise for the delay in 
responding.   
We are unable to reply to individual questions but we will aim to release information on the study in the hope that 
this will answer your queries. 
The study has yet to receive ethical approval.  Until this occurs, we will only register interest at this stage and 
enclose a summary of the basic entry criteria: 


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1)     Confirmed diagnosis of MS - Relapsing-Remitting, Secondary Progressive or Primary Progressive MS 
2)     Age 18-50 (inclusive) 
3)     Disease duration between 2 and 10 years (inclusive) 
4)     Ability to walk at least 20 metres with bilateral assistance - without resting 
 
There will be additional entry criteria and the participation in the study is restricted to those eligible for treatment 
under the NHS and who reside in the UK for the duration of the study. 
 
If you feel you are interested and meet the basic criteria, please e-mail stemcellms@imperial.ac.uk and write 
“CONFIRMATION OF INTEREST” into the subject field.  
 
This is an experimental treatment and a safety study and thus there is no guarantee that it will have any benefit to 
participants.  For this reason we do not recommend any delay in treatment that has been offered to you. 
We will release more information to those that have confirmed interest as soon as it becomes available. 
 
Sincerely, 
On behalf of the study team 
Dr Paolo Muraro  
Clinical Reader in Neuroimmunology 
Honorary Consultant Neurologist 
Centre for Neurosciences 
Division of Experimental Medicine 
Department of Medicine, Imperial College 
--------------------------------------------------------- 
 
Managing On-going and new referrals  
 
NB: All patient information should be recorded in the electronic database and a written record stored in 
the ‘Stem Cell Referrals’ folder.  The response date and method should also be recorded. 
 
All e-mail enquiries should be responded to with the appropriate e-mail auto-response (as above). 
 
All patients who send written correspondence should be responded to with the appropriate auto-response 
(as above) on Imperial headed paper. 
 
All phone enquiries should be responded to and the person enquiring advised to e-mail 
stemcellms@imperial.ac.uk to register interest. 
 
If an e-mail is ambiguous in content and clarification is needed then the best approach is to alert Paolo 
Muraro who will respond accordingly.  Please keep a record of any correspondence that is forwarded on 
for follow-up. 
 
It may also be necessary for Paolo Muraro to respond to e-mails from healthcare professionals or 
professional bodies.  Again, he should be alerted to this.  In such instances, the autoresponse may not be 
the most appropriate response. 
 
Confirmation of Interest 
If a patient confirms their interest in the trial (irrespective of their eligibility), their interest should still be recorded in 
the ‘confirmation of interest’ section of the electronic database.   
A paper copy of the confirmation e-mail should also be filed – especially if new information has been added.   
Electronic Database 
This encompasses all referrals to date.  It is especially important to keep a log of phone referrals as a written 
record does not exist and to manage any updates to existing data. 
When any updates are made to the database, the file name should be updated to reflect the date of change for eg. 
‘Stem Cell Patient Referrals 17Oct11’ and saved to an encrypted hard drive – ideally the X Drive setup especially 
for the MS Service and accessible only by David Wilkie, Richard Nicholas and Paolo’s Muraro’s team. 
‘Stem Cell Referrals’ folder.   
 
Correspondence is ordered A-Z.   


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 
It is ordered with priority given to patient’s surnames but when this is not known, the referrer’s surname 
should be used. 
 
When a patient’s details have been entered into the electronic database, a corresponding print off of the 
e-mail should be filed. 
 
When correspondence has been entered on to the electronic database, a tick should be placed in the top 
right hand corner of the correspondence to acknowledge that this has occurred – so as to avoid double-
entry. 
Stem Cell MS E-mail Management 
 
When an e-mail has been printed and/or recorded in the electronic database, the e-mail should be tagged 
green and can be archived if necessary. 
 
The tag can be achieved by right clicking on the appropriate message with Outlook and selecting 
‘categorize’ then ‘Green category’. 
 
Ideally the e-mails should be checked on a daily basis to determine if any messages require urgent follow-
up. 


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Appendix 8: MRI Patient Information Sheet 
 
Version 1.0 14 May 2012 
 
 
MRI Patient Information Sheet  
 
 
What is a MRI? 
MRI stands for Magnetic Resonance Imaging, a screening technique used to visualise the 
soft tissue inside your body. 
 
How does MRI work? 
MRI combines a powerful magnet with radio-frequency pulses.  These collect signals that 
are then processed by a sophisticated computer to form pictures of your brain. 
 
What is MRI used for? 
MRI gives highly detailed pictures of the brain.  Doctors can use MRI scans to see if there 
are any changes to a patient’s brain over time. 
 
What do I need to do before my MRI scan? 
No special preparation is needed for your scan and you may continue to eat and drink as 
normal and take any prescribed medicines. 
 
It is helpful if you can come for your scan in clothing without metal parts, such as hooks or 
zips.  If this is not possible, then you will need to change into a hospital gown.  We would 
also request that you leave any valuable possessions at home. 
 
Before your scan, you will need to complete a safety questionnaire.  Due to the powerful 
magnet that is used in MRI, not all patients can be scanned – such as those with surgical 
clips, metal hip replacements, a pacemaker or metal fragments in the eyes.   
If you are concerned in any way, please contact our team before your scan appointment 
on telephone number 020 8383 0675 
 
What will happen during your scan? 
For your scan, you will lie down on a scanning bed that will slowly move into a small 
tunnel.  You will experience no discomfort or pain, but may hear quite loud mechanical 
sounds from the scanner.  Ear plugs will be provided to minimise any discomfort from 
these sounds.  If you suffer from claustrophobia (fear of small places) you may not be able 
to have an MRI scan. 
 
In order to obtain good quality pictures of your brain, it is important that you do not move 
during the scanning procedure.  Special supports will be used to help keep your head still.  
The radiographer operating the scanner can both see and hear you throughout the 
procedure so if you have any concerns, you only have to say.  You can expect to be in the 
scanner for up to 90 minutes. The scans will then be sent electronically to the scan centre 
to be analysed over the course of the clinical study.  Only those staff involved in the clinical 
study will be allowed to see the scans. 


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Appendix 9: Informed consent for MRI Scan 
 
Version 1.0 14 May 2012 
 
 
 
 
Informed Consent for MRI Scans 
 
 
 
  
 
 
 
 
 
 
Patient’s initials 
 
1.      I have read and understood the patient information sheet  
         relating to the MRI scans. 
 
 
2. 
I have had the opportunity to ask questions regarding the 
 
procedures and have obtained answers to my satisfaction. 
 
 
3. 
I have completed and understood the safety questionnaire. 
 
 
4. 
I confirm that I give my consent to undergo MRI scans. 
 
 
 
 
 
 
Please print and sign your name below and add today’s date. 
 
 
 
 
……………………………..      …………………………                     …………….. 
       Name of patient                 Signature of patient                              Date 
 
 
 
 
……………………………..      …………………………                     …………….. 
       Name of person                 Signature of person                              Date 
       Taking consent                     taking consent