SERENDEM Study: MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
Phase: PHASE2
Conditions: Chronic Inflammatory Demyelinating Polyneuropathy, Peripheral Neuropathy, Charcot-Marie-Tooth Disease, Charcot-Marie-Tooth Disease Type 1A, Charcot-Marie-Tooth Disease, Type 1B, Anti-MAG Neuropathy
Sponsor: MedDay Pharmaceuticals SA

 
 
NOTICE: Part of all the information in this document may be unpublished and should be treated as the 
confidential property of MEDDAY, not divulged to unauthorised persons in any form, including 
publications and presentations, without the written consent of MEDDAY. 
 
SERENDEM study: MD1003 in patients suffering from demyelinating 
neuropathies, an open label pilot study 
CLINICAL TRIAL PROTOCOL 
Version No: 
4 
Dated: 10-Feb-2017 
Short title:  
SERENDEM 
Protocol No:  MD1003CT2015-01 SERENDEM 
EudraCT No:   2015-001150-15 
SPONSOR: MEDDAY SA 
Address: 
96 Boulevard Haussmann 
 
75008 Paris France 

 
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SIGNATURE PAGE 
INVESTIGATOR SIGNATURE 
My signature, in conjunction with the signature of the sponsor, confirms the agreement of both parties 
that the clinical study will be conducted in accordance with the protocol and all applicable laws and 
regulations including, but not limited to, the International Conference on Harmonisation (ICH) 
Guideline for Good Clinical Practice (GCP), the Code of Federal Regulations (CFR), the ethical 
principles that have their origins in the Declaration of Helsinki, and applicable privacy laws. 
Nothing in this document is intended to limit the authority of a physician to provide emergency medical 
care under applicable regulations. 
 
Principal Investigator: 
Professor Alain Créange 
Neurology Department 
HOPITAL HENRI MONDOR 
51, AVENUE DU MARECHAL DE LATTRE DE 
TASSIGNY  
94010 CRETEIL CEDEX  
 
 
 
Date :   
Signature : 
 
 
 
Sponsor: 
 
Dr Guillaume BRION 
Chief Operating Officer 
Medday SA 
Date : 10-Feb-2017 
Signature: 
 
 
 
 
 

 
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Table of content 
1 
Abreviations ................................................................................................................................... 6 
2 
Study summary ............................................................................................................................... 7 
3 
STUDY RATIONALE – HISTORICAL BACKGROUND ........................................................... 9 
3.1 
Disease aetiology, pathology, symptomatology and current treatments ......................... 9 
3.1.1 
Aetiology ......................................................................................................................................... 9 
3.1.2 
Clinical symptoms and evolution .................................................................................................... 9 
3.1.3 
Pathophysiology ............................................................................................................................ 10 
3.1.4 
Current treatments ......................................................................................................................... 11 
3.2 
Summary of findings from nonclinical and clinical studies with biotin ........................ 12 
3.2.1 
Roles of biotin in normal cell metabolism .................................................................................... 12 
3.2.2 
Biotin and biotin-responsive basal ganglia disease “BBGD”. ....................................................... 12 
3.2.3 
Biotin and primary or secondary progressive multiple sclerosis ................................................... 12 
4 
STUDY OBJECTIVES ................................................................................................................ 13 
4.1 
Primary objective ............................................................................................................... 13 
4.1.1 
Primary and secondary evaluation endpoints ................................................................................ 13 
4.2 
Secondary objective ........................................................................................................... 14 
5 
INVESTIGATIONAL PLAN ...................................................................................................... 14 
5.1 
Overall study design .......................................................................................................... 14 
5.1.1 
Methodology ................................................................................................................................. 14 
5.1.2 
Study flow chart ............................................................................................................................ 15 
5.2 
Approximate number of patients...................................................................................... 15 
5.3 
Selection and withdrawal of patients ............................................................................... 15 
5.3.1 
Inclusion criteria ............................................................................................................................ 15 
5.3.2 
Non-inclusion criteria .................................................................................................................... 16 
5.3.3 
Patient identification and assignment of patient’s number ............................................................ 16 
5.3.4 
Screen failures ............................................................................................................................... 17 
5.3.5 
Withdrawal of participation or arrest of treatment of an included patient ..................................... 17 
5.3.6 
Study suspension, termination and completion ............................................................................. 18 
5.4 
Investigational products administration .......................................................................... 18 
5.4.1 
Description of investigational medicinal products ........................................................................ 18 
5.4.2 
Packaging and labelling ................................................................................................................ 19 
5.4.3 
Treatment assignments .................................................................................................................. 19 
5.4.4 
Investigational product shipping, handling and storage ................................................................ 19 
5.4.5 
Treatment compliance, accountability and return of therapeutic units .......................................... 19 
5.4.6 
Destruction .................................................................................................................................... 20 
5.5 
Concomitant treatments .................................................................................................... 20 
5.6 
Visits schedule and evaluations ......................................................................................... 21 
5.6.1 
Patient follow-up schedule ............................................................................................................ 21 

 
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5.6.2 
Pre-inclusion visit - Visit 1 (W-4) ................................................................................................. 21 
5.6.3 
Inclusion visit and randomization – Visit 2 (W0) ......................................................................... 22 
5.6.4 
Visit 3 (W12 ± 10 days) ................................................................................................................ 23 
5.6.5 
Visit 4 (W24 ± 10 days) ................................................................................................................ 23 
5.6.6 
Visit 5 (W36 ± 10 days) ................................................................................................................ 24 
5.6.7 
Last visit – Visit 6 (W48 ± 15 days) ............................................................................................. 24 
5.6.8 
Duration of the study ..................................................................................................................... 25 
5.7 
Efficacy evaluations ........................................................................................................... 25 
5.7.1 
Main evaluation of efficacy: description and methods .................................................................. 25 
5.8 
Safety evaluations ............................................................................................................... 28 
5.8.1 
Rating table of adverse events ....................................................................................................... 28 
5.8.2 
Safety endpoints ............................................................................................................................ 28 
6 
ADVERSE EVENTS ................................................................................................................... 28 
6.1 
Definitions ........................................................................................................................... 28 
6.2 
Handling of Non-Serious Adverse Events ........................................................................ 29 
6.2.1 
Severity assessment ....................................................................................................................... 30 
6.2.2 
Causality assessment ..................................................................................................................... 30 
6.3 
Serious Adverse Events reporting .................................................................................... 31 
6.4 
Sponsor Reporting Requirements to Regulatory Authority .......................................... 31 
7 
STATISTICAL CONSIDERATIONS ......................................................................................... 32 
7.1.1 
Determination of sample size ........................................................................................................ 32 
7.1.2 
Definition of populations for analysis ........................................................................................... 32 
7.1.3 
General considerations .................................................................................................................. 32 
7.1.4 
Primary efficacy analyses .............................................................................................................. 32 
7.1.5 
Secondary efficacy analyses .......................................................................................................... 33 
7.1.6 
Safety analyses .............................................................................................................................. 34 
7.1.7 
Analysis by subgroups .................................................................................................................. 34 
7.1.8 
Handling of missing data ............................................................................................................... 34 
7.1.9 
Handling of changes in planned statistical analyses ...................................................................... 34 
8 
PRESTUDY DOCUMENTATION ............................................................................................. 34 
9 
INFORMED CONSENT ............................................................................................................. 35 
10 
DIRECT ACCESS, DATA HANDLING AND RECORD-KEEPING....................................... 36 
10.1 
Investigator ......................................................................................................................... 36 
10.2 
Sponsor ............................................................................................................................... 36 
10.3 
Source document requirements ........................................................................................ 36 
10.4 
The use and completion of electronic Case Report Forms (CRFs)................................ 36 
11 
ADMINISTRATIVE RULES ...................................................................................................... 37 
11.1 
Curriculum vitae ................................................................................................................ 37 
11.2 
Secrecy agreement ............................................................................................................. 37 
11.3 
Protocol amendments ........................................................................................................ 37 

 
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11.4 
Record retention in investigation centre(s) ...................................................................... 37 
11.5 
Insurance compensation .................................................................................................... 38 
11.6 
Quality control and assurance .......................................................................................... 38 
11.7 
Ownership of results - Publication ................................................................................... 38 
11.8 
Study-specific committees ................................................................................................. 38 
11.8.1 
Scientific and Steering committee to be updated ...................................................................... 38 
11.8.2 
Data Safety Monitoring Board (DSMB)................................................................................... 38 
12 
BIBLIOGRAPHY ........................................................................................................................ 40 
13 
APPENDICES ............................................................................................................................. 41 
 
 
 

 
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1 
ABREVIATIONS  
AE 
Adverse event 
ALT 
Alanine aminotransferase 
APTT Activated partial thromboplastin time 
AST 
Aspartate aminotransferase  
CRF 
Case report form 
CSF 
Cerebrospinal fluid 
DNA 
Deoxyribonucleic Acid 
DSMB Data safety monitoring board 
CRF 
electronic case report form 
EKG / ECG 
Electrocardiogram 
FAS  
Full analysis data set 
FDA 
Food and Drug Administration 
GCP 
Good clinical practice 
GGT 
Gamma glutamyl transferase 
IMP 
Investigational Medicinal Product 
INR 
International normalized ratio 
IRB / IEC 
Institutional Review Board / Independent Ethics Committee 
MS 
Multiple sclerosis 
NCV 
Nervous conduction velocity 
NIMP Non investigational medicinal product 
PC 
Personal computer 
PP 
Per protocol 
PT 
Prothrombin time 
QoL 
Quality of life 
RBC 
Red blood cell  
SAE 
Serious adverse event 
SAP 
Statistical analyses plan 
SD 
Standard deviation 
SUSAR Suspected unexpected serious adverse reaction 
WBC White blood cell 
 
 

 
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2 
STUDY SUMMARY 
Study Protocol Title 
SERENDEM study: MD1003 in patients suffering from 
demyelinating neuropathies, an open label pilot study  
Short title 
SERENDEM 
Study Protocol Number 
MD1003CT2015-01-SERENDEM 
EudraCT Number 
2015-001150-15 
Methodology and study 
design 
open label, uncontrolled, pilot study in 3 distinct groups of 5 patients 
suffering from a specific aetiology pattern of peripheral neuropathy 
Study Center 
Henri Mondor Hospital, Créteil France 
Objectives 
To assess efficacy of MD1003 given orally thrice a day on motor and 
sensory conduction, in patients suffering from demyelinating 
polyneuropathies. 
Number of patients 
15 patients: 3 groups of 5 patients (CIDP, anti-MAG, CMT1a, 
CMT1b) 
Diagnosis and main 
inclusion criteria  
 
Male and female aged between 20 and 85 years. 
 
Patients fulfilling one of the following diagnosis on both 
clinical and neurophysiological grounds, either with:  
 
CIDP 
 
proven genetic diagnosis of CMT1a 
 
proven genetic diagnosis of CMT1b 
 
anti-MAG polyneuropathy 
 
Electrophysiological parameters worsening for the past 3 
years 
 
Available EMG record, performed during the past 6 months 
to assess variability of NCV parameters 
 
Having given informed consent 
 
Non-inclusion criteria 
 
For CIDP patients, relapse in the past 3 months before 
inclusion 
 
Pregnancy 
 
Women of childbearing potential without effective 
contraception 
 
Investigational Product 
MD1003, 100 mg capsule 
Control therapy 
No control arm 
Concomitant therapies 
Best standard of care 
Duration of administration 
48 weeks 
Evaluation criteria 
Primary objective: 

 
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The primary endpoint will be evaluated as follows: significant change 
from baseline to week 48 in at least two out of the four criteria of 
demyelination: 
• 
motor nerve conduction velocity,  
• 
distal latency,  
• 
F wave latency,  
• 
length of motor nerve potential,  
 
8 nerves will be assessed for those 4 parameters. Change will be 
considered significant when the last value is 10% improved 
compared to the baseline value for 2 out of the 4 parameters in at 
least 3 nerves out of 8 investigated nerves. 
The secondary endpoints are changes from baseline to week 48 in 
ONLS, MRC, INCAT, Posturometry, Timed 10-meter walk test, 6-
min walk test, Min-max absolute refractory period, Refractoriness, 
Supernormality, Strength-duration time constant, Rheobase 
Secondary objective: 
To evaluate the safety of high doses of biotin. 
Statistical methodology 
Exploratory descriptive analyses 
Duration of patient 
participation 
48 weeks 
Study duration 
52 weeks 
 
 
 

 
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3 
STUDY RATIONALE – HISTORICAL BACKGROUND  
3.1 
Disease aetiology, pathology, symptomatology and current treatments 
3.1.1 
Aetiology 
3.1.1.1 
Chronic inflammatory demyelinating polyradiculoneuropathy  
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired paralytic illness 
affecting peripheral nerves and caused by a demyelinating process.  
CIDP is a rare disease. The various epidemiological studies show that prevalence may vary from 
1.24/100 000 (Laughlin 2009) to 8.9/100 000 (Mahdi-Rogers 2013). Due to the ambiguities of 
diagnosing CIDP, the true prevalence of the disease may be underestimated or overestimated. The 
etiology of CIDP is unknown even if rare cases can be associated with different conditions, such as 
diabetes mellitus, sarcoidosis, disseminated lupus erythematosus, or idiopathic monoclonal 
gammopathy. 
3.1.1.2 
Demyelinating neuropathy associated with immunoglobulin M (IgM) monoclonal 
gammopathy and antibodies against myelin-associated glycoprotein (MAG) 
Polyneuropathy associated with IgM monoclonal gammopathy and antibodies against myelin-associated 
glycoprotein (MAG) belongs to the group of chronic demyelinating polyneuropathies. It is a chronic 
progressive disorder that leads to a variable degree of functional impairment and disability. 
3.1.1.3 
Charcot Marie Tooth Ia and Ib (CMT Ia and Ib) neuropathy   
Charcot-Marie-Tooth disease Type 1A (CMT1a) belongs to the group of inherited, progressive, chronic 
sensory and motor peripheral neuropathies referred to as Charcot-Marie-Tooth (CMT) disease or as 
“Hereditary Motor and Sensory Neuropathy” (HMSN). CMT1a accounts for 70% of patients with CMT, 
with an estimated prevalence of 10 in 100,000. CMT1a is an autosomal dominant disorder caused in the 
vast majority of cases by a 1.4 megabase-long duplication of chromosome 17p11.2, encompassing the 
PMP22 gene.  
Charcot-Marie-Tooth disease Type 1B (CMT1b) belongs to the group of inherited, progressive, chronic 
sensory and motor peripheral neuropathies referred to as Charcot-Marie-Tooth (CMT) disease or as 
“Hereditary Motor and Sensory Neuropathy” (HMSN). CMT1b accounts for 6%-10% of patients with 
CMT, with an estimated prevalence of 1.5:100.000. CMT1b is an autosomal dominant disorder caused 
in the vast majority of cases by mutations change in the single protein building blocks (amino acids) in 
myelin protein zero (MPZ), located in the chromosome 1. 
 
3.1.2 
Clinical symptoms and evolution  
3.1.2.1 
Chronic inflammatory demyelinating polyneuropathy  
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune neuropathy; its diagnosis 
has challenged physicians since its first description by Dyck and others (Dyck, 1975). As a result, this 
condition has undergone more than 10 revisions of its diagnostic criteria (Dyck, 1975; Hughes et al., 
2001; 2005; Barohn et al., 1989; Nevo and Topaloglu, 2002; Saperstein et al., 2001; Thaisetthawatkul 
et al., 2002; Magda et al., 2003; AAN task Force, 1991; Joint Task Force of the EFNS and the PNS, 
2010). These criteria are based mainly on clinical and neurophysiological parameters that may help 
distinguish CIDP from other neuropathies, including chronic idiopathic axonal polyneuropathy, diabetic 
polyneuropathies and amyotrophic lateral sclerosis. Furthermore, several variants of inflammatory 
neuropathy have been defined, including multifocal motor neuropathy with conduction blocks, 
multifocal motor and sensory neuropathy with conduction blocks and distal acquired demyelinating 
polyneuropathy (Larue et al., 2011; Viala et al., 2010). 

 
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The most recent recommendation by the European Federation of Neurological Societies allows for the 
distinction among definite, probable and possible CIDP diagnoses based on the clinical diagnostic 
criteria of typical CIDP and atypical CIDP (Joint Task Force of the European Federation of the 
Neurological Societies [EFNS] and the Peripheral Nerve Society [PNS], 2010. The clinical diagnosis of 
typical CIDP is easier to identify than the diagnosis of atypical CIDP due to the possibility of variants 
with pure motor or pure sensory presentations and asymmetric or focal presentations with atypical CIDP. 
Moreover, the existence of several neurophysiological classifications of demyelination and the 
possibility of presentations with axonal features exacerbates the process of accurate classification. 
Typical CIDP is characterized by a chronically progressive, stepwise, or recurrent symmetric proximal 
and distal weakness and sensory dysfunction of all extremities, developing over at least 2 months; cranial 
nerves may be affected; and absent or reduced tendon reflexes in all extremities.  
Atypical CIDP (still considered CIDP but with different features) may have  normal tendon reflexes in 
unaffected limbs: predominantly distal (distal acquired demyelinating symmetric, DADS) or 
asymmetric [multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), Lewis-
Sumner syndrome] or focal (e.g., involvement of the brachial or lumbosacral plexus or of one or more 
peripheral nerves in one upper or lower limb) ; or pure motor ; or pure sensory (including chronic 
immune sensory polyradiculopathy affecting the central process of the primary sensory neuron) 
neurological deficits.  
The temporal course may be characterized by a subacute onset or acute onset, a relapsing-remitting 
course or a progressive course (Joint Task Force of the EFNS and the PNS, 2010). The long term 
prognosis of CIDP patients is not so good after five years with 39% of patients still requiring immune 
treatments and 13% with severe disabilities (Kuwabara 2006). The prognosis of CIDP is related to 
axonal loss secondary to inflammatory demyelination (Hughes et al., 2006; van Schaik et al., 2006). 
3.1.2.2 
Demyelinating neuropathy associated with immunoglobulin M (IgM) monoclonal 
gammopathy and antibodies against myelin-associated glycoprotein (MAG)   
Polyneuropathy associated with IgM monoclonal gammopathy and antibodies against myelin-associated 
glycoprotein (MAG) is a chronic progressive disorder that leads to a variable degree of functional 
impairment and disability. Most patients have a symmetric sensorimotor polyneuropathy, sensory 
ataxia, painful paresthesia and upper limb tremor. The disease may progress slowly over many years in 
some patients, whereas others develop significant disability mostly due to dysesthesia and ataxia; thus, 
there is a need to develop effective treatments (EFNS and PNS guideline, 2010). 
3.1.2.3 
Charcot Marie Tooth Ia and Ib (CMT Ia and Ib) neuropathy   
Typical clinical features of CMT1A and CMT1B are similar including weakness of the foot and lower 
leg and foot deformities (most frequently pes cavus), which appear to be due to weakness of the small 
intrinsic muscles of the feet. Later in the disease, weakness and muscle atrophy may occur in the hands, 
resulting in difficulty with fine motor skills. The severity of symptoms is quite variable from one patient 
to another and even among affected members of the same family. 
3.1.3 
Pathophysiology 
3.1.3.1 
Chronic inflammatory demyelinating polyneuropathy  
The underlying pathologic mechanisms are still unclear but an autoimmune aetiology is probable. 
Various mechanisms may be instrumental in CIDP including presence of auto-antibodies, inflammatory 
mediators (tumor necrosis factor alpha, interleukin 1, matrix metalloproteinases 2 and 9, complement 
fractions, chemokines), lymphocyte proliferation, modulation of the Fcγ RII / Fcγ RIII ratio on 
macrophages. Whatever the involved mechanisms, the consequences include alteration of nerve 
excitability due to demyelination, decrease of Na+/K+ ATPase pump function, intra-axonal Na+ 
accumulation associated with energetic failure, leading process to axonal degeneration in inflammatory 
demyelinating processes (Stys and Waxman, 1994; Bechtold and Smith, 2005). 

 
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3.1.3.2 
Demyelinating neuropathy associated with immunoglobulin M (IgM) monoclonal 
gammopathy and antibodies against myelin-associated glycoprotein (MAG)   
A causative role of the IgM M protein in the polyneuropathy is illustrated by the presence of circulating 
anti MAG antibodies or other antibodies directed at the myelin sheath of peripheral nerves that lead to 
enlargement of the myelin sheath.  Patients present with a striking immunochemical profile, suggesting 
the possibility of an autoimmune mechanism: monoclonal IgM recognizes a carbohydrate MAG epitope, 
which is shared with a number of other glycoconjugates involved in cell adhesion, including the Po 
glycoprotein of myelin, peripheral myelin protein–22, sulfated sphingolipid, and other related 
glycolipids (Latov et al. , 1995; Eurelings et al., 2001). The nerve examination shows widening of 
myelin lamellae. 
3.1.3.3 
Charcot Marie Tooth Ia and Ib (CMT Ia and Ib) neuropathy   
PMP22 encodes a transmembrane peripheral myelin protein.  The duplication of the PMP22 gene results 
in its overexpression and in abnormal Schwann cell differentiation. The consequences are a 
homogeneous and diffuse nerve conduction slowing and dysmyelination, eventually leading to axonal 
loss and muscle wasting. 
The altered myelin protein zero probably cannot interact properly with other myelin components, which 
may disrupt the formation and maintenance of myelin. As a result, peripheral nerve cells cannot activate 
muscles used for movement or relay information from sensory cells back to the brain, leading to the 
weakness and sensory problems characteristic of Charcot-Marie-Tooth disease. 
 
3.1.4 
Current treatments 
3.1.4.1 
Chronic inflammatory demyelinating polyneuropathy  
Corticosteroids, plasma exchange, and intravenous (IV) immunoglobulin (IVIg) have shown efficacy in 
controlled trials. The choice of therapy depends on several factors, including disease severity, 
concomitant illnesses, adverse-effect profile, potential drug interactions, venous access, age-related 
risks, and cost of treatment.  Corticosteroids is considered as a first line or second line treatment option 
and have been used to treat CIDP for a long time. It is usually initiated with a dose of 1mg/kg with a 
tapering after several months according to clinical response. IVIg is widely used in the treatment of 
CIDP. Treatment by intravenous immunoglobulins, (IVIgs) can provide significant clinical benefits in 
more than 60% of CIDP patients (Vermeulen et al., 1993; Hahn et al., 1996; Mendell et al., 2001). 
Clinical improvement often occurs within a few days following IVIg infusions (Kaji et al., 1992; 
Chaudhry et al., 1993; Nobile-Orazio et al., 1993; Van den Berg et al., 1995; 1998; Léger et al., 2001). 
However, such improvement usually lasts for a few weeks and periodic IVIg infusions are required to 
maintain therapeutic benefit. Finally, the long term effect of IVIG has not been investigated for more 
than 6 months (Hughes 2009). Moreover, there is no data on the prevention of axonal degeneration with 
these treatment options.  
3.1.4.2 
Demyelinating neuropathy associated with immunoglobulin M (IgM) monoclonal 
gammopathy and antibodies against myelin-associated glycoprotein (MAG)   
There is no consensus about the best treatment strategy, besides the timing of initiation of treatment has 
not been determined for anti-MAG neuropathy. Immunotherapy and chemotherapy may act through 
direct suppression or elimination of the B cell clone, or by suppression of the inflammatory cascade 
(Lunn et Al. 2012).  There is insufficient evidence from most pilot studies or randomized controlled 
trials (RCT) on IgM anti-MAG demyelinating neuropathy to recommend any particular immunotherapy. 
The last controlled trial for rituximab did not show any benefit (Léger et Al. 2013). 
3.1.4.3 
Charcot Marie Tooth Ia and Ib (CMT Ia and Ib) neuropathy   
There is currently no approved treatment for CMT1A and for CMT1B. Supportive therapies mainly 
address disease symptoms such as neuropathic pain, weakness and limb deformities. They include 

 
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treatment of pain (anti-inflammatory/analgesics, anti-depressants or anti-convulsants for neuropathic 
pain), physiotherapy (muscle strength training), occupational therapy, orthopaedic devices (including 
braces and high top shoes) and orthopaedic surgery.  However, these treatments are not sufficient to 
limit impairment of motor function and worsening of disability. Ascorbic acid (AA) has shown to 
promote myelination in vitro and to possibly decrease PMP22 expression. Following this, six clinical 
trials assessing efficacy and tolerability of 1- or 2-year AA treatment were published, but no clinical 
benefit was observed in any of these trials. In addition, the results from a double-blind, randomized, 
placebo-controlled dose ranging phase 2 study of PXT3003 (a low dose combination of three already 
approved compounds: (RS)-baclofen, naltrexone hydrochloride and D-sorbitol) were recently published. 
This trial confirmed the potential good safety and tolerability of PXT3003. The highest dose showed 
preliminary but consistent evidence of efficacy, with a modest clinical benefit in these adult patients.   
3.2 
Summary of findings from nonclinical and clinical studies with biotin 
3.2.1 
Roles of biotin in normal cell metabolism 
Biotin (or vitamin H) is a ubiquitous water-soluble vitamin which is naturally found in many foods, such 
as offal, eggs and some vegetables. In mammals, biotin acts as a coenzyme for four important 
carboxylases involved in key steps of energy metabolism and fatty acids synthesis. Biotin-dependent 
mitochondrial carboxylases include PC (pyruvate carboxylase), PCC (propionyl CoA carboxylase), and 
MCC (methylcrotonyl CoA carboxylase). All these three enzymes ultimately provide intermediates for 
the Krebs cycle including acetyl CoA, succinyl-CoA and oxaloacetate. These anaplerotic reactions 
trigger increased ATP production in neurons (Rinholm et al., 2011). 
3.2.2 
Biotin and biotin-responsive basal ganglia disease “BBGD”. 
High doses of biotin have been demonstrated to be a therapeutic option in “biotin responsive basal 
ganglia disease”, an orphan neurometabolic disease (Ozand et al., 1998; Debs et al., 2010) which is 
caused by mutations in the SLC19A3 gene coding for a thiamine transporter (Zeng et al., 2005; 
Subramanian et al., 2006). A hypothesis explaining the effect of high doses of biotin in BBGD is that 
biotin activates the Krebs cycle downstream of the pyruvate and α-ketoglutarate dehydrogenases that 
are impaired in situations of defect in thiamine transport. 
3.2.3 
Biotin and primary or secondary progressive multiple sclerosis 
Previous human experience in a pilot study and results of two phase IIb/III studies (EudraCT No. 2013-
002113-35 and 2013-002112-27, namely MS-SPI study and MS-ON study, respectively) have provided 
evidences of a favourable benefit/risk balance of MD1003 (biotin 300 mg/day) in adult patients with 
progressive MS, but not in MS patients with relapsing-remitting MS.  
The randomized, double-blinded MS-SPI study included adult patients with PP and SP MS with no 
evidence of inflammatory activity (n=103 in the MD1003 group and n=54 in the placebo group). 
Improvement was defined as either a decrease in disability score (EDSS) or an improvement in TW25 
(a timed 25-foot walk) as compared to the best EDSS and TW25 scores obtained either at the screening 
or randomisation visits. Results demonstrated a strong and clinically meaningful benefit of MD1003 
compared to placebo with (1) improvement of a significant proportion of patients after 9 months 
confirmed at 12 months (primary endpoint, p=0.005), (2) stabilized mean EDSS score (p=0.014) and (3) 
better clinical global impression of change (p<0.0001). 
The randomized, double-blinded MS-ON study included adult patients with either visual loss following 
an optic neuritis relapse (ON relapses, n=62) or chronic progressive optic neuritis (progressive ON, 
n=31). The primary endpoint was the mean change in 100% contrast visual acuity (VA) at 6 months 
from baseline of the worst eye. In patients with ON relapses, VA improved in both placebo and MD1003 
groups by a mean of 0.06 LogMAR, i.e. 3 letters in both groups, without any superiority of MD1003. In 
the progressive ON subgroup, VA worsened by a mean of 0.03 LogMAR in the placebo group, while it 
improved by a mean of 0.06 LogMAR in the MD1003 group. Although the number of patients was too 

 
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small to reach statistical significance, these results are in line with the positive results of the MS-SPI 
trial and indicate that MD1003 should be indicated in progressive MS only. 
It is hypothesized that the positive effects of high doses of biotin in progressive MS are linked to: 
(1) Increased energy production in demyelinated neurons. This would avoid neurodegeneration and 
would improve neuronal functioning. 
(2) Stimulation of myelin repair through activation of the acetyl CoA carboxylase in oligodendrocytes. 
This induction of myelin repair could explain the very long-term effects of the treatment with continuous 
improvement overtime even after 14 months of treatment. 
We hypothesized that chronic inflammatory demyelinating polyradiculoneuropathy, demyelinating 
neuropathy associated with immunoglobulin M (IgM) monoclonal gammopathy and antibodies against 
myelin-associated glycoprotein (MAG), Charcot Marie Tooth Ia and Ib (CMT Ia and Ib) neuropathy 
and progressive multiple sclerosis share some similarities including demyelinating processes, and 
chronic progressive disorders leading to a variable degree of functional impairment and disability. 
Considering previous positive results in progressive MS it is justified to investigate the MD1003 in a 
population of demyelinating neuropathies of different aetiologies, as a proof of concept / pilot study 
using various measurement methods. 
4 
STUDY OBJECTIVES 
The primary objective of the study is to assess the effect of MD1003 on motor and sensory conduction, 
in patients suffering from demyelinating polyneuropathies. 
The secondary objective is to evaluate safety of MD1003 in this patient population. 
This pilot study will not be controlled by a placebo. It is aiming to evaluate the acceptability of the 
treatment in this population, to assess the intra and inter-individual variability of the neurophysiological 
procedures proposed in this study protocol, and to assess the robustness of the evaluation criteria. The 
results will serve as hypothesis for the sample size calculation of a larger placebo controlled trial. 
4.1 
Primary objective 
4.1.1 
Primary and secondary evaluation endpoints 
4.1.1.1 
Primary evaluation endpoint 
The primary endpoint is the change between baseline and end of the study of each following 
electrophysiological criteria of demyelination measured on 8 nerves: 
 
motor nerve conduction velocity, 
 
distal latency, 
 
F wave latency, 
 
length of motor nerve potential, 
A 10% improvement for 2 out of these 4 criteria, in at least 3 out of 8 nerves will be considered as 
clinically meaningful. 
4.1.1.2 
Secondary evaluation endpoints 
Secondary endpoints will be part of exploratory analyses. They will consist in studying mean change or 
proportions for the following clinical and electrophysiological parameters. 
Clinical endpoints: 
 
ONLS 
 
Timed 10-meter walk test 
 
MRC 

 
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 
INCAT sensory score 
 
6-minute walk test 
 
Posturometry 
Electrophysiological testing endpoints: 
 
Supernormality (%) 
 
Strength-duration time constant (ms) 
 
Rheobase (mA) 
 
Refractoriness (%) 
 
Min-max absolute refractory period (ms) 
4.2 
Secondary objective 
The secondary objective will evaluate the safety of MD1003. 
Safety of MD1003 will be assessed by recording of adverse events in the three groups of patients. 
Laboratory testing (haematology and biochemistry safety panel) will also be used to detect any drug 
intolerance. The following parameters will be measured at prior first administration and after 12 months 
of treatment: 
 
RBC, WBC, platelets 
 
Ionogram, creatinin, glycemia 
 
AST, ALT, bilirubin, GGT, alkaline phosphatase 
 
Triglyceride, cholesterol 
 
aPTT, INR 
5 
INVESTIGATIONAL PLAN 
5.1 
Overall study design 
5.1.1 
Methodology 
5.1.1.1 
Experimental plan 
This pilot, open label, uncontrolled monocentric study is stratified a priori to recruit 5 patients per 
etiologic diagnosis group.  
5.1.1.2 
Number of centers 
This study is a monocentric study.  
The investigational centre’s address is: 
 HOSPITAL HENRI MONDOR 
51, AVENUE DU MARECHAL DE LATTRE DE TASSIGNY  
94010 CRETEIL CEDEX  
 
 
 

 
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5.1.2 
Study flow chart 
 
5.2 
Approximate number of patients 
The study will include 15 patients in total divided into 3 subgroups of 5 patients suffering from either 
CIDP, anti-MAG or CMT1a or CMT1b. 
5.3 
Selection and withdrawal of patients 
5.3.1 
Inclusion criteria 
Patients must fulfill all the following criteria:  
 
Male and female aged between 20 and 85 years. 
 
Patients fulfilling one of the following diagnosis:  
 
Five patients with chronic inflammatory demyelinating polyneuropathy on both clinical and 
neurophysiological grounds. 
 
Five patients with proven genetic diagnosis of CMT1a or CMT1b 
 
Five patients with anti-MAG polyneuropathy. 
 
Electrophysiological parameters worsening for the past 3 years 
 
Available EMG record, performed during the past 6 months to assess variability of NCV 
parameters 
 
Signed and dated written informed consent to participate in the study in accordance with local 
regulations 
 
Likely to be able to participate in all scheduled evaluation and complete all required study 
procedures, 
 
In the opinion of the investigator, the patient will be compliant and have a high probability of 
completing the study. 
 
Both male and female subjects who are not either surgically sterile (tubal ligation/obstruction or 
removal of ovaries or uterus) or post-menopausal (no spontaneous menstrual periods for at least 
one year confirmed by a negative hormone panel) must commit to using TWO highly effective 
method of birth control for the duration of the study and for two months after the treatment 
termination. A highly effective method of birth control is defined as those which result in a low 
failure rate (i.e., less than 1% per year) when used consistently and correctly such as implants, 
injectable or combined oral contraceptives, IUDs, sexual abstinence or vasectomized partner. 
Acceptable forms of effective contraception include: 
W0
W48
W36
W24
W12
W-4
- Informed consent
- Inclusion criteria
- Non incusion criteria
- Medical history
- Clinical examination
- Concomitant therapies
- Biological test 
- Serum sample
- Inclusion criteria
- Non incusion criteria
- Clinical  examination
- Neurophysiological 
examination
- MRC sum score
- INCAT sensory Score
- Posturography score
- ONLS score
- Timed 10-meter walk test
- 6-min walk test
- Excitability testing 
- AEs reporting
- Concomitant therapies
- Study drug dispensation
- Clinical  examination
- MRC sum score
- INCAT sensory Score
- ONLS score
- Timed 10-meter walk test
- 6-min walk test
- AEs reporting
- Concomitant therapies
- Study drug dispensation
- Compliance check
- Clinical  examination
- Neurophysiological 
examination
- MRC sum score
- INCAT sensory Score
- Posturography score
- ONLS score
- Timed 10-meter walk test
- 6-min walk test
- Excitability testing 
- AEs reporting
- Concomitant therapies
- Serum sample
- Study drug dispensation
- Compliance check
- Clinical  examination
- MRC sum score
- INCAT sensory Score
- ONLS score
- Timed 10-meter walk test
- 6-min walk test
- AEs reporting
- Concomitant therapies
- Study drug dispensation
- Compliance check
- Clinical  examination
- Neurophysiological 
examination
- MRC sum score
- INCAT sensory Score
- Posturography score
- ONLS score
- Timed 10-meter walk test
- 6-min walk test
- Excitability testing 
- AEs reporting
- Concomitant therapies
- Biological test
- Serum sample
- Compliance check
Weeks
Chronic Inflammatory Demyelinating Polyneuropathy (n=5)
Anti-Myelin Associated Glycoprotein demyelinating neuropathy (n=5)
Charcot-Marie-Tooth type 1a (n=5)

 
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o Established use oral, injected or implanted hormonal methods of contraception. 
o Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
o Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository. Notice that, when used alone, the 
diaphragm and condom are not highly effective forms of contraception. 
o The use of additional spermicides does confer additional theoretical contraceptive 
protection. Spermicides alone are inefficient at preventing pregnancy when the whole 
ejaculate is spilled. Therefore, spermicides are not a barrier method of contraception 
and should not be used alone. 
o True abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception.  
o Male sterilisation: subjects must present with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate. For female subjects on the study, 
the vasectomised male partner should be the sole partner for that subject. 
5.3.2 
Non-inclusion criteria 
 
Any general chronic handicapping disease other than peripheral neuropathy 
 
Impossibility to perform the 10 meters walking test 
 
Impossibility to assess electrophysiological parameters 
 
Patients with uncontrolled hepatic disorder, renal or cardiovascular disease, or cancer, 
 
Patients with hypersensitivity to MD1003 excipients (lactose) 
 
Laboratory tests out of normal range according to the reference laboratory values. Deviations 
may be accepted if considered by the investigator as not clinically significant with regards to 
the study continuation, 
 
Patients with history or presence of alcohol abuse or drug addiction, 
 
Patients likely to be non-compliant to the study procedures or for whom a long-term follow-up 
seems to be difficult to achieve. 
 
Any new medication for neuropathy initiated less than 3 months prior to inclusion.  
For CIDP patients, relapse in the past 3 months before inclusion 
 
Not easily contactable by the investigator in case of emergency or not capable to call the 
investigator 
 
Subjects without effective contraception 
5.3.3 
Patient identification and assignment of patient’s number 
Patients will be numbered sequentially. Each patient in the study must be assigned a unique subject 
number and must keep that number throughout the study even if he comes to be transferred to another 
site. A patient who is screened but not randomized may be re-screened at a later time. A screening 
number must never be reassigned for any reason. The investigator must maintain a patient master log 
linking the patient’s number to the patient’s name. The investigator must follow all applicable privacy 
laws in order to protect a patient’s privacy and confidentiality. Information that could identify a patient 
will be masked on material received by the sponsor. 
The allocation of patient’s number will be done at the first visit (V1/selection) in chronological order of 
signature of the informed consent form. Once patient numbers are assigned, they cannot be reassigned. 
Information on the randomization number and treatment number for the whole study will be given by 
the investigator. The patient’s initials (the first letters of the patient’s name and first name) may be 
collected in the CRF. 

 
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5.3.4 
Screen failures 
Patients who sign an informed consent form but fail to meet the eligibility criteria are defined as screen 
failures. For all screen failures, the investigator is asked to maintain a screening log that documents the 
screening number (patient’s number), patient’s initials and reason(s) for screen failure. A copy of this 
log should be retained in the investigator’s study file. The demography, the eligibility and end of trial 
forms will be completed and returned to the sponsor for screen failures. 
5.3.5 
Withdrawal of participation or arrest of treatment of an included patient 
5.3.5.1 
Withdrawal by the patients 
Participation in the study is voluntary. The patients have the right to withdraw from the study at any 
time for any reason. If a patient chooses to withdraw, he must inform the Investigator immediately.  
5.3.5.2 
Reasons for treatment arrest 
The Investigator has the right to terminate the treatment of any patient at any time if it is deemed to be 
in the patient’s best interest. 
Main reason for premature treatment discontinuation is the occurrence of a Serious Adverse Event 
(SAE) attributed to the treatment; the investigator must inform the sponsor of these SAE and follow 
them until resolution.  
The reasons and circumstances for premature treatment discontinuation will be documented in the 
patient’s CRF at time of withdrawal. 
It is important to distinguish the following situations: 
 
Temporary cessation of treatment, the investigator must document the reason(s), the stop date 
and the restart date 
 
Early termination of treatment. In this case, the investigator must: 
o Document the reason(s) of early termination (effectiveness or failure of treatment),  
SAE (s), non-compliance of the patient to visits, other medical problems, patient 
personal reasons)  
o Make every effort to convince the patient to have a last visit to evaluate at least safety 
data and if possible efficacy data.  
o Make every effort to convince the patient to have a safety follow-up in the case of AE. 
 
Subject lost to follow-up: it is not known what became of the subject. The investigator must: 
o Make every effort to reconnect with the subject in order to know at least if the subject 
is alive or dead  
If the subject is contacted: 
o Document the reason(s) 
o Offer to realize at least an evaluation of safety and if possible of efficacy, if the subject 
agrees 
In case of the withdrawal or lost to follow-up of a subject, the data may be used in the absence of 
opposition of the subject. Explicit withdrawal of consent is a particular situation, where the subject 
clearly expresses that he withdraws the consent he signed. In case of consent withdrawal, data on the 
subject cannot be used unless the subject expresses no objection to their use in writing. In practice, the 
subject leaves the trial. 
The subject may be withdrawn from the trial for several reasons, such as: the subject's condition worsens, 
the subject has a serious adverse effect, other medical problems, personal reason of the subject (family, 
work ...), without the patient withdrawing his consent. 
The CRF must document the different possible reasons of withdrawal of a subject: 
 
Serious adverse event, 
 
Decision of the patient 

 
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 
Poor compliance to the treatment  
 
Other medical problem 
 
Personal reasons from the subject 
5.3.5.3 
Follow up of patients withdrawn from the study 
The withdrawal of a patient from the study will in no way impact his/her usual treatment and follow-up 
for the disease by his/her referring physician.  
Patients withdrawn from the study will be asked to undergo a physical examination on the same dates 
as those scheduled in the study.   
Should a serious adverse event occur resulting in withdrawn of the patient from the study by the principal 
investigator, the patient will be asked to be followed for a duration that will be determined by the 
principal investigator depending on the nature and severity of the SAE.  
5.3.6 
Study suspension, termination and completion 
The sponsor may suspend or terminate the study or part of the study at any time for any reason.  
If the investigator suspends or terminates the study, the investigator will promptly inform the sponsor 
or designee and the IRB/IEC and provide them with a detailed written explanation. The investigator will 
also return all investigational product bottles, and other study materials to the sponsor. 
Upon study completion, the investigator will provide the sponsor, IRB/IEC, and regulatory agency with 
final reports and summaries as required by regulations. 
In case of premature discontinuation of the study, the sponsor will inform in writing, all investigators, 
Ethics Committees and Regulatory Authorities about the reasons for cancelling the study. 
When a patient discontinues or is withdrawn from the treatment and/or from the study, the investigator 
will notify the sponsor and when possible the safety and efficacy determinations designated under the 
final visit will be obtained on the last day on which the patient receives the investigational products or 
as soon as possible thereafter. 
An effort must be made to determine why a patient is lost to follow-up for the subject’s CRF. A 
registered letter should be sent to document this effort if other attempts to contact the patient fail. 
5.4 
Investigational products administration 
Investigational products will be administered only to patients who have provided informed consent. 
5.4.1 
 Description of investigational medicinal products 
Capsules (MD1003, dose 100 mg) are taken orally three times a day (one in the morning, one at noon, 
and one in the evening) with or without food. Capsules should be swallowed with a glass of water.  
The biotin capsules will be supplied by MEDDAY SA.  
5.4.1.1 
Investigational Medicinal Product 
Investigational drugs units will be supplied by MEDDAY SA or designee. 
The investigational drug will consist in capsules of biotin 100 mg and excipients (lactose, magnesium 
stearate, croscarmellose sodium, Silica). 
Precaution for use: 
Some laboratory tests may potentially be distorted by this medicine. These are tests that require the use 
of a biotin-based reagent (hormonal dosages, tumor, cardiac, anaemia, bone metabolism and 
inflammation markers, testing for antigen and antibodies to viral infectious diseases, tissue pathology 
examination). A non-exhaustive list of these parameters is displayed in Appendix 1. 

 
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An information patient card will be given to all patients regarding this precaution for use. 
For additional information, investigators may connect at www.medday-lab.com  
5.4.1.2 
Dose regimen 
The dose regimen will be 1 capsule three times a day (one in the morning, one at noon and one in the 
evening). 
5.4.2 
Packaging and labelling 
MEDDAY SA or designee will prepare and ship investigational product to the study pharmacist. Each 
investigational product packaged in plastic bottles will be labelled according to regulation. For all 
patients, the treatment will be dispensed by the hospital pharmacy in boxes containing the quantity of 
bottles needed to cover the period until the next visit.  
Capsules will be conditioned in plastic bottles containing 90 capsules each corresponding to one month 
of treatment. 
A label with legal requirements will be stuck on the bottles with a space allowing pharmacist to indicate 
the patient’s number and the treatment period. 
5.4.3 
Treatment assignments 
All patients will be assigned to receive active drug 300 mg/day, open label, one capsule in the morning, 
one capsule at noon and one capsule in the evening. 
5.4.4 
Investigational product shipping, handling and storage 
The investigational product will be shipped directly to the pharmacist/dispenser designated by the 
Investigator after required regulatory and legal documents have been received by the sponsor or 
designee. 
Upon receipt of the investigation products, the pharmacist will verify the condition of the study supplies, 
including inspection of document per instructions in the Pharmacy Binder. There is no specific 
requirement regarding temperature during shipment for this study. 
The sealed investigational product bottles must not be opened until they are used for administration. 
Once unpacked and inspected, investigational products must be stored at room temperature. 
The pharmacist must store the sealed investigation products in a secured area with access restricted to 
authorized personnel only. 
The investigational product must be stored as indicated. Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor or designee. 
Once a deviation is identified, the investigational product must be quarantined and not used until the 
sponsor provides documentation of permission to use the investigational product. 
Once the investigational products have been allocated and dispensed to the patient, the investigational 
products must be maintained at room temperature. 
Once opened the bottles containing 90 capsules each may be used for 1 month. 
5.4.5 
Treatment compliance, accountability and return of therapeutic units 
Regulatory agencies require accounting for the disposition of all investigational drugs (IMP and NIMP) 
received by each clinical site. Information on drug disposition required by law consists of the date 
received; date administered, quantity administered, and the patient to whom the drug was allocated and 
dispensed. The investigator is responsible for the accounting for all unused investigational products and 
all used investigational product containers through the pharmacist. The pharmacist uses this information 
to maintain an accurate and complete dispensing and inventory record supplied by the sponsor or 

 
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designee. At the completion or termination of the study, a final drug accountability review and 
reconciliation must be completed; any discrepancies must be investigated and their resolution 
documented. 
All unused investigational products must be returned to the sponsor/contract distribution center with the 
appropriate form. 
Investigational products will be administered by the pharmacy and the date of the administration will be 
documented in the patient’s record in addition to the CRF.  
The remaining study medication will be checked at each visit by the investigator and the pharmacist 
before completing the drug administration records. 
The remaining study medication, labels and dispensing records will be checked by the monitor to verify 
accurate dose dispensing. 
5.4.6 
Destruction 
Remaining test medication and packaging of used and non-used investigational medicinal products will 
be returned to MEDDAY or its designee for destruction. 
Recording of destruction operations should be carried out in such a manner that all operations may be 
accounted for. The records will be kept by the sponsor. This destruction will be done only after the 
finalisation of the clinical trial and the compilation of the final study report. 
5.5 
Concomitant treatments 
Any drug(s) that are NOT suspected of causing the event or reaction and that are administered to the 
patient AT THE TIME the case is reported should be listed as concomitant medication. 
For the purpose of this study, concomitant medication is defined as any medication that is taken at the 
same time as the first administration of investigational product and will be recorded on the concomitant 
medication page of CRF. 
All usual treatments are authorized all along the study for patients already treated by these drugs. All 
drugs have to be introduced at least three months prior to inclusion. Introduction of any of these drugs 
during the trial should be avoided, and if absolutely necessary, should be documented in the CRF. 
All medications will be recorded into the CRF and the patient’s source documents. 
If the patient used to follow a continuous physical therapy program at least the month prior to inclusion, 
this program should be maintained throughout the period of the study and should not be discontinued. 
Intensive physical therapy program should be avoided as much as possible within the 3 months prior to 
inclusion and during the trial since it may modify EVALUATION CRITERIA values. 

 
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5.6 
Visits schedule and evaluations 
5.6.1 
Patient follow-up schedule 
 
Week -4 
Week 0 
Week 12 
Week 24 
Week 36 
Week 48 
 
Selection Inclusion 
Follow-up 
End 
STUDY WINDOWS 
 
+/-5 days 
+/-10 days 
+/- 15 days 
Informed consent 
X 
 
 
 
 
 
Inclusion criteria 
X 
X 
 
 
 
 
Non-inclusion criteria 
X 
X 
 
 
 
 
Medical history  
X 
 
 
 
 
 
Clinical examination 
X 
X 
X 
X 
X 
X 
Neurophysiological 
examination  
 
X 
 
X 
 
X 
MRC sum score 
 
X 
X 
X 
X 
X 
INCAT sensory Score 
 
X 
X 
X 
X 
X 
Posturography score 
 
X 
 
X 
 
X 
ONLS score 
 
X 
X 
X 
X 
X 
Timed 10-meter walk test 
 
X 
X 
X 
X 
X 
6-min walk test 
 
X 
X 
X 
X 
X 
Excitability testing  
 
X 
 
X 
 
X 
AEs reporting 
 
X 
X 
X 
X 
X 
Concomitant therapies 
X 
X 
X 
X 
X 
X 
Biological test 1 
  X 2 
 
 
 
 
X 
Serum sample 
X 
 
 
X 
 
X 
Study drug dispensation 
 
X 
X 
X 
X 
 
Compliance check 
 
 
X 
X 
X 
X 
1 Biological safety panel includes: RBC, hemoglobin, mean corpuscular volume, WBC, platelets, electrolytes 
(Na, K, HCO3, Ca), protein, creatinine, glomerular filtration rate, fasting blood glucose, AST, ALT, total and 
free bilirubin, gamma glutamyl transferase, alkaline phosphatase, triglyceride, cholesterol, PT, aPTT, INR 
2 Biological aetiology additional panel: Serum protein electrophoresis, IgA measurement, HbA1c, HBsAg, HIV, 
HCV tests, fibrinogen 
5.6.2 
Pre-inclusion visit - Visit 1 (W-4)  
During the pre-inclusion visit, the investigators will check inclusion, non-inclusion criteria and obtain 
informed consent for study participation. 
The following study procedures will be carried out during the screening and the following information 
will be recorded into the CRF: 
- 
Demographic data 
- 
History of the patient's disease 
- 
Relevant other medical history and ongoing concomitant diseases 
- 
Vital signs: Systolic and diastolic blood pressure, temperature, heart rate 
- 
Clinical examination 
- 
Neurophysiological examination  
- 
MRC sum score 
- 
INCAT sensory Score 

 
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- 
Posturography score 
- 
ONLS score 
- 
Timed 10-meter walk test 
- 
6-min walk test 
- 
Excitability testing 
- 
Biological testing including: 
o 
Safety panel: RBC, hemoglobin, mean corpuscular volume, WBC, platelets, electrolytes (Na, K, 
Cl, HCO3), protein, creatinine, glomerular filtration rate, fasting blood glucose, AST, ALT, total 
and free bilirubin, gamma glutamyl transferase, alkaline phosphatase, triglyceride, cholesterol, 
PT, aPTT, INR 
o 
Aetiology additional panel: Serum protein electrophoresis, IgA measurement, HbA1c, HBsAg, 
HIV, HCV tests, fibrinogen 
o 
For women of childbearing potential: highly sensitive pregnancy test (HCG) 
- 
Concomitant therapies 
The investigator will assign a patient number starting from 01, in chronologic order of patient’s 
inclusion. 
5.6.3 
Inclusion visit and randomization – Visit 2 (W0) 
The investigators will check again for inclusion and non-inclusion criteria and will record following 
information into the CRF: 
- 
Clinical examination 
- 
Neurophysiological examination  
- 
MRC sum score 
- 
INCAT sensory Score 
- 
Posturography score 
- 
ONLS score 
- 
Timed 10-meter walk test 
- 
6-min walk test 
- 
Excitability testing  
- 
AEs reporting 
- 
Concomitant therapies 
- 
Study drug dispensation 
The investigator will fill a "drug delivery form" for the hospital pharmacy to dispense study medication. 
The number of treatment delivered and written on the bottles' label by the pharmacist will be the patient’s 
inclusion number. 
The patient will be supplied with the study drugs dispensed by the hospital pharmacy and advised to 
open one bottle per month of treatment. Each kit will contain three bottles for a total of three months of 
treatment. The patient will be asked to use only one bottle of 90 capsules per month and to take from 
this bottle one capsule in the morning, one capsule at noon and one capsule in the evening. Capsules 
have to be swallowed with a glass of water. 
Women of childbearing potential will be provided with 3 urinary pregnancy tests to be used at home 
every month until next visit to eliminate any risk of pregnancy during the study. 

 
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5.6.4 
Visit 3 (W12 ± 10 days) 
The investigators will record the following information into the CRF: 
- 
Clinical examination 
- 
MRC sum score 
- 
INCAT sensory Score 
- 
ONLS score 
- 
Timed 10-meter walk test 
- 
6-min walk test 
- 
AEs reporting 
- 
Concomitant therapies 
- 
Study drug dispensation 
The investigator will provide patient with a drug delivery form for the hospital pharmacy. 
The patient will be supplied with the study drugs dispensed by the hospital. 
Women of childbearing potential will be provided with 3 urinary pregnancy tests to be used at home 
every month until next visit to eliminate any risk of pregnancy during the study. 
5.6.5 
Visit 4 (W24 ± 10 days) 
The investigators will record the following information into the CRF: 
- 
Clinical examination 
- 
Neurophysiological examination  
- 
MRC sum score 
- 
INCAT sensory Score 
- 
Posturography score 
- 
ONLS score 
- 
Timed 10-meter walk test 
- 
6-min walk test 
- 
Excitability testing  
- 
AEs reporting 
- 
Concomitant therapies 
- 
Serum sample 
- 
Study drug dispensation 
- 
Compliance check 
The investigator will provide patient with a drug delivery form for the hospital pharmacy. 
The patient will be supplied with the study drugs dispensed by the hospital. 
Women of childbearing potential will be provided with 3 urinary pregnancy tests to be used at home 
every month until next visit to eliminate any risk of pregnancy during the study. 

 
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5.6.6 
Visit 5 (W36 ± 10 days) 
The investigators will record the following information into the CRF: 
- 
Clinical examination 
- 
MRC sum score 
- 
INCAT sensory Score 
- 
ONLS score 
- 
Timed 10-meter walk test 
- 
6-min walk test 
- 
AEs reporting 
- 
Concomitant therapies 
- 
Study drug dispensation 
The investigator will provide patient with a drug delivery form for the hospital pharmacy. 
The patient will be supplied with the study drugs dispensed by the hospital pharmacy. 
Women of childbearing potential will be provided with 3 urinary pregnancy tests to be used at home 
every month until next visit to eliminate any risk of pregnancy during the study. 
5.6.7 
Last visit – Visit 6 (W48 ± 15 days) 
The investigator will record the following information into the CRF: 
- 
Clinical examination 
- 
Neurophysiological examination  
- 
MRC sum score 
- 
INCAT sensory Score 
- 
Posturography score 
- 
ONLS score 
- 
Timed 10-meter walk test 
- 
6-min walk test 
- 
Excitability testing  
- 
AEs reporting 
- 
Concomitant therapies 
- 
Biological safety panel testing: 
o 
RBC, hemoglobin, mean corpuscular volume, WBC, platelets, electrolytes (Na, K, Cl, HCO3), 
protein, creatinine, glomerular filtration rate, fasting blood glucose, AST, ALT, total and free 
bilirubin, gamma glutamyl transferase, alkaline phosphatase, triglyceride, cholesterol, PT, aPTT, 
INR 
o 
For women of childbearing potential: highly sensitive pregnancy test (HCG) 
- 
Serum sample 
- 
Compliance check 

 
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5.6.8 
Duration of the study 
Duration of the inclusion phase: 12 Weeks 
Duration of baseline period: 
4 Weeks 
Duration of treatment: 
48 Weeks 
Total duration of the trial: 
64 Weeks 
The end of the study corresponds to the end of the treatment’s duration of the last patient included. 
5.7 
Efficacy evaluations 
5.7.1 
Main evaluation of efficacy: description and methods 
5.7.1.1 
Neurophysiological examination 
This examination will be performed according to specific centre protocol as described below according 
to initial diagnosis and patient status. 
Overall the four limbs will be investigated, including one motor and one sensitive nerve for a total of 
maximum 8 nerves. The same protocol will be applied at each visit for one patient, aiming to record on 
the same nerves the studied demyelination criteria. 
The investigator will be free to define the most relevant protocol according to patient disease status at 
baseline. However, the same protocol will be applied in a patient all along the study and the investigator 
will apply his best efforts to comply with this rule. 
5.7.1.1.1 
Polyneuropathy protocol: 
1. Test most involved limb first if mild; if severe do least involved limb first. 
2. Test at least 2 limbs, upper and lower, do 3rd limb for symmetry. 
3. Lower extremity do sural sensory, peroneal motor with conduction, tibial motor with an F-
wave. 
4. Upper extremity do a sensory either median or ulnar, also a motor either median or ulnar with 
conduction and an F-wave.  
5.7.1.1.2 
Polyradiculopathy protocol 
1. Sural sensory ankle; stimulate 14 cm proximal to recording electrode. 
2. If sural equivocal or technically difficult: 
a. Opposite sural 
b. Median sensory (index); stimulate at wrist and elbow. 
3. Peroneal motor (EDB); stimulate at knee and ankle with F-response latency. 
4. Tibial motor (abductor hallucis brevis); stimulate knee and ankle with F-response 
latency. 
5. Ulnar motor (hypothenar); stimulate at wrist and elbow with F-response latency. 
6. If clinically indicated, consider: 
a. Median (thenar); stimulate at wrist and elbows with F-response latency. 
b. Musculocutaneous (biceps brachii); stimulate at axilla. 
c. Facial (orbicularis oculi); stimulate at ankle of jaw. 

 
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d. Trigeminal (orbicularis oculi); stimulate supraorbital nerve. 
Electrophysiological measures will be performed at W0, W24 and W48 and following parameters will 
be recorded in the CRF: 
 
motor nerve conduction velocity, 
 
distal latency, 
 
F wave latency, 
 
length of motor nerve potential 
5.7.1.2 
Excitability testing 
Nerve excitability testing is a non-invasive approach in investigating the pathophysiology of peripheral 
nerve disorders, which determines the electrical properties of the nerve membrane at the site of 
stimulation 
5.7.1.3 
Medical Research Council (MRC) sum score 
This score is a summation of the strength of 6 muscle groups tested on both sides according to the 
Medical Research Council (MRC) scale; it yields the so-called “MRC-sum score,” ranging from 0 (total 
paralysis) to 60 (normal strength). 
Good validity and interobserver reliability for this scale have been demonstrated in patients with 
Guillain–Barré syndrome and other neuropathies (Kleyweg 1991). 
The score is the sum of the MRC score of 6 muscles (3 at the upper and 3 at the lower limbs) on both 
sides, each muscle graded from 0 to 5. The following muscles are examined: 
- 
Deltoid 
- 
Biceps 
- 
Wrist extensor 
- 
Ileopsoas 
- 
Quadriceps femoris 
- 
Tibialis anterior 
The MRC sum score will be assessed at each visit and recorded in the CRF. 
5.7.1.4 
INCAT sensory Sum Score (ISS) 
The Inflammatory Neuropathy Cause and Treatment (INCAT) Group introduced the ISS and 
extensively evaluated it in patients with immune mediated polyneuropathies (Merkies 2000) 
This sensory scale comprises pin prick and vibration sense plus a two point discrimination value in the 
arms and legs, and ranges from 0 (“normal sensation”) to 20 (“most severe sensory deficit”). 
The scale is displayed in appendix, will be completed at each visit and the result recorded in the CRF. 
5.7.1.5 
Posturography score 
Computerized dynamic posturography (CDP) is a non-invasive specialized clinical assessment 
technique used to quantify the central nervous system adaptive mechanisms (sensory, motor and central) 
involved in the control of posture and balance, both in normal and abnormal conditions. Due to the 
complex interactions among sensory, motor, and central processes involved in posture and balance, CDP 
requires different protocols in order to differentiate among the many defects and impairments which 
may affect the patient's posture control system. Thus, CDP challenges it by using several combinations 
of visual and support surface stimuli and parameters. 
Center of gravity (COG) is an important component of balance and should be assessed when evaluating 
someone’s posture. COG excursion and velocity are recorded through computerized recording. COP 
excursion is defined by Collins & De Luca (1993) as the displacement in the anterior/posterior and 
medial/lateral directions within the base of support (perimeter around the feet). 

 
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Body sway during quiet upright stance will be recorded at 40 Hz using a force platform (Posturolab 
40/16, Columbus, Ohio); each trial will last for 51.2 sec and, during this period, subjects will be asked 
to stand upright and barefoot on the platform as still as possible with arms at their sides. Recordings will 
be made under 4 conditions, while adding or not a layer of foam rubber (5 cm thick, density of 2.5 pcf) 
to the base of support, with the eyes either open or closed: condition 1 = hard surface and eyes open; 
condition 2 = hard surface and eyes closed; condition 3 = soft surface and eyes open; condition 4 = soft 
surface and eyes closed. Before each trial, the feet will be positioned according to the manufacturer 
reference, and small adjustments will authorize to make online; recordings with the eyes closed will be 
obtained just after acquiring the data with the eyes open, without moving the feet (Herrera-Rangel 2014). 
The test will be performed at each visit; length (mm) and area (mm2) of sway will be recorded in the 
CRF for each of the four conditions. 
5.7.1.6 
Overall Neuropathy Limitation Scale (ONLS) 
The Overall Neuropathy Limitations Scale (ONLS), was derived by modifying the Overall Disability 
Sum Score (ODSS) slightly.  
The ODSS focuses on upper and lower limb functions, and consists of a checklist for interviewing 
patients. It is scored from 0 to 5 on the upper limb section and from 0 to 7 on the lower limb section. A 
score of 0 indicates no limitations (the ceiling of the scale) and a score of 5 or 7 indicates no purposeful 
movement. 
To reduce a possible ceiling effect, Graham et al. have modified the ODSS to include climbing stairs 
and running. Specifically, the ODSS item ‘‘Does the patient have difficulty walking?’’ has been 
supplemented with ‘‘Does the patient have difficulty running or climbing stairs?’’ on the new measure, 
the Overall Neuropathy Limitations Scale. Therefore, to score 0 (indicating no limitations) on the lower 
limb section of the ONLS, the patient must now have no difficulty running or climbing stairs, in addition 
to walking. The remaining scoring criteria are not different from those in the ODSS. 
The simplicity of the ODSS is shared by the ONLS, but the ONLS has better content validity and less 
ceiling effect, which may make it more useful for clinical practice and research (Graham 2006). 
The reliability of this scale is substantial in CMT patients (Solari 2007). 
The ONLS is displayed in appendix, and will be recorded in the CRF at each visit. 
5.7.1.7 
Timed 10-meter walk test 
In this test the patient is instructed to walk at a comfortable, normal pace for 10 meters. Only the middle 
6 m, however, is timed to eliminate the effects of acceleration and deceleration. Start and stop of 
performance time coincides with the toes of the leading foot crossing the 2-m mark and the 8-m mark, 
respectively. From these data, the speed may be calculated by dividing the middle 6 m by the time (in 
seconds) required to walk the 6 m (Wolf 1999). 
The reliability of this test is excellent for CMT patients (Solari 2007). 
A full instruction for the realisation of the test is displayed in appendix. The test will be performed and 
result recorded in the CRF at each visit. 
5.7.1.8 
6-min walk test 
The 6MWT is a practical simple test that requires a 30 m (100-ft) hallway but no exercise equipment or 
advanced training for technicians. This test measures the distance that a patient can quickly walk on a 
flat, hard surface in a period of 6 minutes. The patient is allowed to self-pace and is encouraged every 
two minutes by the examiner as he traverses back and forth along a marked walkway. 
The reliability and validity of this test has been investigated extensively as it has been used as a 
functional outcome measure for adults with cardiopulmonary dysfunction. (American Thoracic Society 
statement: guidelines for the 6MWT, 2002). It has also been used as a functional outcome measure for 
individuals with multiple sclerosis (Goldman et Al 2008). 

 
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The test is more extensively described in appendix and will be performed and recorded in the CRF at 
each visit. 
5.8 
Safety evaluations 
At each visit, the presence of all serious Adverse Drug Reactions (ADR) will be notified into the CRF 
and immediately reported to sponsor in the SAE form. SAE/ADR will immediately be reported to the 
Pharmacovigilance Unit of the sponsor. 
5.8.1 
Rating table of adverse events 
Safety will be evaluated by vital signs, physical examination (including neurological examination), and 
biological signs. The following safety endpoints will be checked and recorded in the CRF:  
 
Adverse events presence, 
 
Vital signs including heart rate, blood pressure and weight. 
 
Clinical examination abnormalities, 
 
Standard laboratory testing abnormalities. 
5.8.2 
Safety endpoints 
Standard clinical and adverse event monitoring will be done at each visit. 
Standard laboratory testing (plasma biochemistry and haematology) will be done at W0 and W48 and 
consists in measurement of: 
o 
Safety panel: RBC, hemoglobin, mean corpuscular volume, WBC, platelets, electrolytes (Na, K, 
Cl,  HCO3), protein, creatinine, glomerular filtration rate, fasting blood glucose, AST, ALT, 
total and free bilirubin, gamma glutamyl transferase, alkaline phosphatase, triglyceride, 
cholesterol, PT, aPTT, INR 
6 
ADVERSE EVENTS 
6.1 
Definitions 
Adverse Event (AE): 
Any untoward medical occurrence in a patient administered a pharmaceutical product and which does 
not necessarily have a causal relationship with this treatment. 
An adverse event can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding, for example), symptom or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not considered related to the medicinal (investigational) product. 
Examples of AEs include, but are not limited to, the following: 
 
Abnormal test findings (see definition below) 
 
Clinically significant symptoms and signs 
 
Hypersensitivity 
 
Progression/worsening of underlying disease, 
 
Drug abuse 
 
Drug dependency 
 
Protocol-related adverse event (see definition below) 
 
Additionally, they may include the signs or symptoms resulting from 
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o Drug withdrawal 
o Drug misuse 
o Drug interactions 
o Exposure during pregnancy 
o Exposure via breastfeeding 
o Medication error 
A protocol-related adverse event is an AE occurring during a clinical study that is not related to the 
investigational product, but is considered to be related to the research conditions, i.e., related to the fact 
that a patient is participating in the study.  
Serious Adverse Event (SAE): 
A serious adverse event (SAE) is any untoward medical occurrence that, at any dose: 
 
Results in death 
 
Is life-threatening, (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the patient 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 more severe.) 
 
Requires hospitalization or prolongation of existing hospitalization 
 
Results in disability/incapacity  
 
Is a congenital anomaly/birth defect. 
Medical or scientific judgment should be exercised in deciding whether reporting is appropriate 
in other situations, such as important medical events that may not be immediately life 
threatening or result in death or hospitalization but may jeopardize the patient or may require 
medical or surgical intervention to prevent one of other outcomes listed in the above definition. 
These should also be considered serious. 
Important:  
All AE/SAE occurring in the study associated or not to the study drug shall be notified to the Sponsor 
Pharmacovigilance Unit. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) suspected to be related to an interaction 
between an IMP and a NIMP should be reported. 
Medication Errors: 
In this protocol, a reportable medication error includes the following: 
 
The administration of an unassigned treatment. 
 
An investigational medicinal product temperature excursion not approved by the Sponsor’s 
clinical pharmacy or designee. 
 
Inadvertent or accidental exposure to an investigational product with or without an AE. 
Whether or not the medication error is accompanied by an AE, as determined by the investigator, the 
medication error and, if applicable, any associated adverse event(s) is captured on an adverse event (AE) 
on the CRF (refer to Adverse Event Reporting section for further details).  
6.2 
Handling of Non-Serious Adverse Events 
All AEs encountered during the clinical study will be reported on the CRF.  
 
All AEs and SAEs must be recorded on patient’s source documents.  
 
All AEs and SAEs for patients who receive a treatment assignment code will be recorded in the 
CRFs. During the active reporting period specified above, all AEs will be reported on the AE 
page(s) of the CRF. It should be noted that the form for collection of SAE information is not the 
same as the AE CRF. Where the same data are collected, the forms must be completed in a 

 
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consistent manner. For example, the same AE term should be used on both forms. AEs should 
be reported using concise medical terminology on the CRFs as well as on the form for collection 
of SAE information. 
 
Each AE is to be assessed to determine if it meets the criteria for SAEs. If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate. 
 
Withdrawal due to AE should be distinguished from withdrawal due to insufficient response, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF page. 
The information to be entered in the CRF will include: 
 
The time of onset of any AE or the worsening of a previously observed AE 
 
The specific type of reaction in standard medical terminology 
 
The duration of the AE (start and stop dates) 
6.2.1 
Severity assessment 
The severity of the adverse event (AE). The severity should be rated as: 
 
Mild: discomfort noted, but no disruption of normal daily activity. 
 
Moderate: discomfort noted of sufficient severity to reduce or adversely affect normal activity. 
 
Severe: incapacitating, with inability to work or perform normal daily activity. 
6.2.2 
Causality assessment 
An assessment of the relationship of the adverse event (AE) to the study medication, i.e., according to 
the definitions below: 
Definite: a clinical event, including laboratory test abnormality, occurring in a plausible time 
relationship to drug administration, and which cannot be explained by concurrent disease or other drugs 
or chemicals. The event must be pharmacologically or phenomenologically plausible, and its clinical 
response to withdrawal of the drug (dechallenge) should be clinically plausible. It must also be 
confirmed by a satisfactory rechallenge procedure. 
Probable/likely: a clinical event in which a relationship to the IMP seems probable because of such 
factors as a clear temporal association with the use of the IMP, lack of alternative explanations for the 
event or other factors. 
Possible: the essential distinctions between ‘Probable’ and ‘Possible’ are that in the latter case there 
may be another equally likely explanation for the event (could also be explained by disease or other 
drugs) and/or there is no information or uncertainty with regard to what has happened after stopping. 
Unlikely: a clinical event with a temporal relationship to IMP administration that makes a causal 
relationship improbable and / or in which other factors suggesting an alternative aetiology exist. Such 
factors include a known relationship of the adverse event to concomitant drug, the patient’s disease state 
or environmental factors including common infectious diseases. 
Conditional/Unclassified: A clinical event, including laboratory test abnormality, reported as an 
adverse reaction, about which more data are essential for a proper assessment or the additional data are 
under examination. 
Unassessable: A report suggesting an adverse reaction which cannot be judged because information is 
insufficient or contradictory, and which cannot be supplemented or verified. 
Not related: Not suspected to be reasonably related to the IMP.  A reasonable alternative explanation 
must be available. 
In addition, if the investigator determines an SAE is associated with study procedures, the investigator 
must record this causal relationship in the source documents and CRF, as appropriate, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable. 

 
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As far as possible, all investigators should follow-up participants with AEs until the event is resolved or 
until, in the opinion of the investigator, the event is stabilized or determined to be chronic. Details of 
AE resolution must be documented in the CRF. Participants should be followed-up for 30 days after 
receiving the last dose of study medication and any AEs, which occur during this time, should be 
reported according to the procedures outlined above. Any significant changes in AEs should be reported 
even though the patient has completed the study, including the protocol-required post-treatment follow-
up. 
6.3 
Serious Adverse Events reporting 
All SAEs and follow-up information must be reported to the sponsor on a SAE form within 24 hours of 
investigator awareness of the event.  
All non-serious AE notified at the same time of serious AE shall be recorded and notified to the 
Pharmacovigilance unit of the sponsor.  
The description of SAE will include a description of the AE with sufficient details to allow for a 
complete medical assessment of the case and independent determination of possible causality. 
Information on other possible causes of the event, such as concomitant medications and illnesses must 
be provided. In the case of a patient death, a summary of available autopsy findings must be submitted 
as soon as possible to Sponsor or its designated representative. 
All adverse events encountered during the clinical study must be reported on the CRF as soon as 
the data are available. Therefore, data will be accessible immediately by the sponsor or designee.   
Serious adverse events (SAEs), whether or not associated with study medication administration, 
will be recorded both on the Adverse Event form of the CRF and the SAE form (available from the 
CRF web site or from the Investigator’s study files). 
ALL SAEs occurring during this study and up to 30 days after a patient discontinued or completed the 
study, whether or not related to the administration of study medications, must be reported by faxing the 
completed SAE form, after reviewing the report for consistency and accuracy within 24 hours of 
awareness by the investigator, to: 
Pharmacovigilance Department 
Fax: 33 (0)1 85 08 02 23 
Medical Assistance 
If there is a need to discuss any medical issues concerning a serious adverse event or to report a serious 
adverse event during the business hours, MEDDAY can be contacted at: 
frederic.sedel@medday-pharma.com 
guillaume.brion@medday-pharma.com 
6.4 
Sponsor Reporting Requirements to Regulatory Authority 
Adverse event reporting, including suspected serious unexpected adverse reactions, will be carried out 
in accordance with applicable local regulations. 
In case of occurrence of SAEs attributable to experimental treatment, the DMSB will be seized by the 
investigator and / or sponsor to decide on the continuation of the trial. 

 
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7 
STATISTICAL CONSIDERATIONS 
7.1.1 
Determination of sample size 
This pilot study is exploratory. The various clinical and electrophysiological endpoints will allow 
defining which of them will be the most relevant in confirmatory randomized controlled trials. 
It is assumed that 15 patients is a sufficient sample size for 1) detect an effect of MD1003 in 
demyelinating peripheral neuropathies, and 2) rank the best endpoints for confirmatory studies in the 
three most common demyelinating peripheral neuropathies. 
7.1.2 
Definition of populations for analysis 
Safety population 
All patients who receive at least one dose of study medication will be included. 
Intent-to-treat population (ITT) 
All patients who receive at least one dose of study medication and with at least one assessment at 
baseline and during the study will be included. 
All analyses will be according to the intent-to-treat principle (all patients will be analysed). 
Per Protocol population (PP) 
All patients of the ITT and without major protocol deviations. 
7.1.3 
General considerations 
Descriptive analyses will be performed. 
Data will be summarized as follows: Continuous variables by descriptive statistics (number of 
patients [N], mean, standard deviation, minimum, median and maximum); categorical data by absolute 
and relative frequencies (n and %). No imputation will be performed on missing data. 
The analyses described below are those intended to be performed based on an estimate of the available 
data. If the applicable data is not available; the analyses will be adapted accordingly.  
The analyses described below are those intended to be performed based on an estimate of the available 
data. If applicable data are not available; the analyses will be adapted using the Last Observation Carried 
Forward (LOCF) imputation method.  
Quality assurance of the data and statistical analysis and the development of the statistical part of the 
study report will be made by Medday or designee.  
All clinical data recorded as verbatim into the CRF will be encoded in MedDRA last version. 
All analyses will be conducted on the ITT with a global significance level of 5%. 
Primary and secondary endpoints will be considered as exploratory analyses with no defined order of 
analysis. 
7.1.4 
Primary efficacy analyses 
Principal analysis of the primary efficacy endpoint 
The primary endpoint will be evaluated as the change from baseline to week 48 of the following criteria 
of demyelination: 
• 
Motor nerve conduction velocity, 
• 
Distal latency, 
• 
F wave latency, 
• 
Length of motor nerve potential. 

 
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Eight nerves will be assessed for those four criteria. Change will be considered significant when the last 
value is 10% improved compared to the baseline value for two out of these four parameters in at least 
three nerves out of eight investigated nerves. 
7.1.5 
Secondary efficacy analyses 
The analysis of the secondary endpoints will be descriptive: 
1. Change in the ONLS score; 
2. Change in the MRC sum score 
3. Change in INCAT sensory Score 
4. Change in the posturography score; 
5. Changes in the time to 25 feet walk and the 6 minutes walk test; 
6. Changes in minimal and maximal duration of the absolute refractory period (in ms), in 
refractoriness and supernormality (in %), in strength-duration time constant (in ms) and in 
rheobase (in mA) for the ulnar motor nerve. 
The secondary clinical endpoints will be ranked differently according to initial diagnosis: 
 
CIDP: 
1. ONLS 
2. Timed 10-meter walk test 
3. MRC 
4. INCAT sensory score 
5. 6-minute walk test 
6. Posturometry 
 
Anti-MAG group: 
1. ONLS 
2. INCAT sensory score 
3. Timed 10-meter walk test 
4. MRC 
5. Posturometry 
6. 6-minute walk test 
 
CMT-1a and CMT-1b: 
1. ONLS 
2. MRC 
3. Timed 10-meter walk test 
4. 6-minute walk test 
5. INCAT sensory score 
6. Posturometry 
Regarding the electrophysiological testing, the secondary endpoints will be ranked as follows: 
1. Supernormality (%) 
2. Strength-duration time constant (ms) 
3. Rheobase (mA) 
4. Refractoriness (%) 
5. Min-max absolute refractory period (ms) 
The secondary endpoints are changes from baseline to week 48 in ONLS, MRC, INCAT, Posturometry, 
Timed 10-meter walk test, 6-min walk test, Min-max absolute refractory period, Refractoriness, 
Supernormality, Strength-duration time constant, Rheobase 
Secondary objective: 
The evaluation endpoint is the proportion of patients with WHO grade III adverse events. 

 
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7.1.6 
Safety analyses 
All treated patients will be included in the safety analysis. All safety data will be displayed and analyzed 
using descriptive statistical methods. No formal statistical analysis is planned. 
Time of the analyses 
Safety data will be reviewed on a regular basis by the DSMB. 
A complete safety analysis as described below will be performed at the time the primary efficacy 
endpoint is analysed. After withdrawal or completion of the study by all included patients, whole or part 
of the safety analyses will be performed again. The details of these final analyses will be given in the 
SAP. 
Adverse events 
In general, analysis of adverse events is descriptive.  
Statistical analysis and reporting of adverse events will concentrate on treatment emergent adverse 
events. All adverse events with an onset after the first dose of biotin up to a certain number of days (D) 
(inclusive) after the last dose of biotin will be considered ‘treatment emergent’ and will be assigned to 
the treatment phase for evaluation. The number of days D will be given in the SAP. Adverse events that 
start before first drug intake and deteriorate under treatment will also be considered as ‘treatment-
emergent’. Other adverse events will be assigned either to the screening or safety follow-up, or post 
study phase, as appropriate. 
Vital signs, physical exam, standard laboratory tests 
The set of summary statistics will be n (number of patients with non-missing values), mean, standard 
deviation (SD), minimum, maximum, median and interquartile range, and will be n (number patient with 
non-missing values) and percentage (%) for continuous and categorical endpoints, respectively. 
7.1.7 
Analysis by subgroups 
Analyses in subgroups will be performed in order to assess the homogeneity of treatment’s effect as 
exploratory analyses. 
7.1.8 
Handling of missing data 
Missing data due to dropouts may occur for two major classes of reasons: non-informative reasons 
(essentially random, e.g., a study subject moves to another city) and informative reasons (essentially 
non-random, and possibly related to treatment assignment or outcomes, e.g., the study subject develops 
intolerable side effects).  
The last observation carried forward (LOCF) approach will be used to handle missingness on the 
primary evaluation criterion. 
7.1.9 
Handling of changes in planned statistical analyses 
The Statistical Analyses Plan will be validated with the principal investigator prior the data base lock at 
which the primary efficacy endpoint will be analysed. Any later modification will be described in a 
complementary SAP. 
8 
PRESTUDY DOCUMENTATION 
The investigator must provide the sponsor with the following documents BEFORE enrolling any 
patients: 
- 
Completed and signed statement of investigator form (i.e., FDA form 1572 or Alternate 1572 
form, if required by local regulations, an equivalent). 

 
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- 
All applicable country-specific regulatory forms. 
- 
Current signed and dated curriculum vitae for the principal investigator, sub-investigators, 
determination of eligibility, efficacy, or safety) who are listed on the statement of 
investigator form (i.e., FDA form 1572 or Alternate 1572 form and, if required by local 
regulations, an equivalent). 
- 
Copy of the IRB/IEC approval letter for the protocol and informed consent. All advertising, 
recruitment, and other written information provided to the patient must be approved by the 
IRB/IEC.  Written assurance of continuing approval (at least annually) and, where required, 
a copy of the annual progress report submitted to the IRB/IEC must also be provided to the 
sponsor. 
- 
Copy of the IRB/IEC-approved informed consent document to be used. 
- 
If applicable, a list of the IRB/IEC members and their qualifications and a description of the 
committee’s working procedure. 
- 
Copy of the protocol sign-off page signed by the investigator. 
- 
Fully executed CSA. 
- 
If applicable, a financial disclosure form. 
- 
A written document containing the name, location, certification number, and date of 
certification of the laboratory to be used for laboratory assays and those of other facilities 
conducting tests. This document should be returned along with the statement of investigator 
form. The sponsor must be notified if the laboratory is changed or if any additional laboratory 
is to be used. 
- 
List of normal laboratory values and units of measure for all laboratory tests required by the 
protocol. This is required for each laboratory to be used during the study. The 
sponsor/designee must be notified if normal values or units of measurement change. 
9 
INFORMED CONSENT 
The investigator will provide for the protection of the patients by following all applicable regulations. 
These regulations are available upon request from the sponsor or designee. The informed consent 
document(s) used during the informed consent process must be reviewed by the sponsor, approved by 
the IRB/IEC, and available for inspection.  
Before any protocol-required procedures are performed, a patient must: 
- 
Be informed of all pertinent aspects of the study and elements of informed consent. 
- 
Be given time to ask questions and time to consider the decision to participate. 
- 
Voluntarily agree to participate in the study. 
- 
Sign and date an IRB/IEC-approved informed consent document. 
The investigator must explain to each patient (or legally authorised representative) the nature of the 
study, its purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved and any discomfort it may entail. Each subject must be informed that participation in the study 
is voluntary and that he/she may withdraw from the study at any time and that withdrawal of consent 
will not affect his/her subsequent medical treatment or relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, in non-technical 
language. The subject should read and consider the statement before signing and dating it, and should 
be given a copy of the signed document. 

 
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10 DIRECT ACCESS, DATA HANDLING AND RECORD-KEEPING 
10.1 Investigator 
The investigator will permit study-related monitoring, audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and documents. 
All information will be recorded on source documents. The CRFs must be fully completed and include 
all required data. All CRF data must be submitted to the sponsor throughout and at the end of the study. 
Remote data capture will be used to record and transmit data electronically to the sponsor or designee. 
If an investigator retires, relocates, or otherwise withdraws from conducting the study, the investigator 
must notify the sponsor to agree upon an acceptable storage solution. Regulatory agencies will be 
notified with the appropriate documentation. An updated statement of investigator form (i.e., US Food 
and Drug Administration [FDA] form 1572 or Alternate 1572 form if required by local regulations, an 
equivalent) will be filed with the sponsor or designee for any changes in the study personnel reported in 
the current statement of investigator form. 
Investigators must notify their IRB/IEC of protocol violations in accordance with local regulatory and 
IRB/IEC requirements. 
The investigator will allow the monitor to visit the site facilities where the study will take place in order 
to ensure that the site complies with the requirements of the protocol and the GCP. 
10.2 Sponsor 
The CRF data are stored in a database and processed electronically. The sponsor or designee reviews 
the data for safety information. The data are reviewed for legibility, completeness, and logical 
consistency. Automated validation programs identify missing data, out-of-range data, and other data 
inconsistencies. Requests for data clarification are forwarded to the investigative site for resolution. 
At regular intervals during the study, the monitor will visit the site, to check the completeness of 
patients’ records, the accuracy of entries on the CRF, the adherence to protocol and to Good Clinical 
Practice, the progress of enrolment, and to ensure that study medication is being stored and accounted 
for according specifications. 
The investigator and key trial personnel must be available to assists the monitor during these visits. 
10.3 Source document requirements 
The investigator must give the monitor direct access to relevant hospital or clinical records, to confirm 
their consistency with the CRF data entries. 
The consent form will include a statement by which the patients allows the sponsor's duly authorized 
personnel (trial monitoring team) to have direct access to source data which supports data on the 
electronic case report forms. These personnel, bound by professional secrecy, will not disclose any 
personal identity or personal medical information. 
10.4 The use and completion of electronic Case Report Forms (CRFs) 
It is responsibility of the Investigator to maintain adequate and accurate CRFs in recording all 
observations and other data pertinent to the clinical investigation on ongoing basis into the CRFs 
designed by an CRF provider. 
CRFs are implemented electronically (CRF), using third party software application that is fully validated 
and conforms to regulatory requirements for electronic data capture, where applicable.  
The CRF enables data capture via an on-line system on a personal computer (PC). 

 
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 
Designated staff at participating site shall enter data required by the protocol into the CRF.  
 
All access to the system is administered by the CRF administrator, and will only be granted after 
appropriate and documented training. A dedicated account (with login and password) will be 
provided at each user by the CRF administrator. 
 
Specific guidelines for data completion will be available. 
 
The data will be recorded via the application into a central database over encrypted lines using the 
SSL (Secure Sockets Layer) protocol.  
 
Personal health identifiers are stored in the central database in encrypted form. 
 
All entries and modifications of data are logged in an audit trail. 
 
Electronic signatures will be used where required. 
 
Automated validation program check for data discrepancies in the CRFs will be implemented where 
appropriate. 
11 ADMINISTRATIVE RULES 
11.1 Curriculum vitae 
An updated copy of the curriculum vitae of the investigator will be provided to the sponsor prior to the 
beginning of the study. 
11.2 Secrecy agreement 
By signing the protocol, the investigator agrees to keep all information provided by the sponsor in strict 
confidence and to request similar confidentiality from his/her staff and the IRB/EC. Study documents 
provided by the sponsor will be stored appropriately to ensure their confidentiality. 
The information provided by the sponsor to the investigator may not be disclosed to others without direct 
written authorization from the sponsor, except to the extent necessary to obtain informed consent from 
patients who wish to participate in the trial. 
11.3 Protocol amendments 
Any change in the study plan requires a protocol amendment. An investigator must not make any 
changes to the study without IRB/IEC and sponsor approval except when necessary to eliminate 
apparent immediate hazards to the subjects. A protocol change intended to eliminate an apparent 
immediate hazard to subjects may be implemented immediately, but the change must then be 
documented in an amendment, reported to the IRB/IEC within 5 working days, and submitted to the 
appropriate regulatory agency in the required time frame. 
All protocol amendments must be reviewed and approved by the sponsor and investigator. 
11.4 Record retention in investigation centre(s) 
The investigator shall retain and preserve 1 copy of all data collected or databases generated in the 
course of the study, specifically including but not limited to those defined by GCP as essential, for the 
longer of (a) 2 years after the last marketing authorization for the study drug has been approved or the 
sponsor has discontinued its research with respect to such drug or (b) such longer period as required by 
applicable global regulatory requirements. At the end of such period, the investigator shall notify the 
sponsor in writing of his or her intent to destroy all such material. The sponsor shall have 30 days to 

 
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respond to the investigator’s notice, and the sponsor shall have a further opportunity to retain such 
materials at the sponsor’s expense. 
11.5 Insurance compensation 
The sponsor certifies having taken out a liability insurance policy which covers the investigators and his 
co-workers and which is in accordance with the local laws and requirements. 
A certificate of insurance will be provided to the investigator. 
11.6 Quality control and assurance  
The sponsor or designee performs quality control and assurance checks on all clinical studies that it 
sponsors. Before enrolling any subjects in this study, sponsor personnel or designee and the investigator 
review the protocol, the investigator’s brochure, the CRFs and instructions for their completion, the 
procedure for obtaining informed consent, and the procedure for reporting AEs and SAEs. A qualified 
representative of the sponsor will monitor the conduct of the study. During these site visits, information 
recorded in the CRFs is verified against source documents. 
11.7 Ownership of results - Publication 
The results from this study are the exclusive property of the sponsor. 
No information concerning the study or its results may be published or communicated without the prior 
written and signed agreement of the sponsor. 
The sponsor’s decision to publish or otherwise publicly communicate the results of this study will be 
made in accordance with all applicable laws, regulations, and sponsor policies regarding publication and 
communication of clinical study results. 
11.8 Study-specific committees  
11.8.1 Scientific and Steering committee to be updated 
Members: Dr Frederic SEDEL, Dr Guillaume BRION 
Mission: defining the objective, compiling the protocol, and proposing protocol amendments during the 
study. 
Defining the general organization of the study, coordinating the information, initially determining the 
methodology, and monitoring implementation of the study. 
Proposing management during the study taking into account the recommendations of the data safety 
monitoring board (DSMB), if appropriate. 
11.8.2 Data Safety Monitoring Board (DSMB) 
Members: Pr Philippe LECHAT, Pr Jean François DHAINAUT, Pr Richard LEVY 
DSMB's mission is 1) to ensure throughout the study the safety of patients involved in the study, and 2) 
to preserve the scientific and ethical integrity of the study. DSMB is an advisory committee to provide 
the sponsor for its biomedical research advice and recommendations on the conduct of the study. 
DSMB can help sponsor and investigators of the study to be taken during the study for which decisions 
independent judgment is desirable. DSMB may for this purpose: 
 
Recommend further analysis to the interpretation of the results of an interim review of data ; 

 
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 
Recommend minor or major modifications of the protocol became necessary because of 
recruitment, or follow-up testing or, to take account of new scientific data ; 
 
Recommend early termination of the trial. 
In case of occurrence of SAEs attributable to experimental treatment, the DMSB will be seized by the 
investigator and / or sponsor to decide on the continuation of the trial. 
 
 

 
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12 BIBLIOGRAPHY 
Merkies ISJ, Schmitz PIM, van der Meché FGA, et al. Psychometric evaluation of a new sensory scale in immune-
mediated polyneuropathies. Neurology 2000;54:943–7. 
Bohannon, R. W. Comfortable and maximum walking speed of adults aged 20-79 years: reference values and 
determinants." Age Ageing. 1997;26(1): 15-9. 
Bohannon RW, Andrews AW, Thomas MW. Walking speed: reference values and correlates for older adults. J 
Orthop Sports Phys Ther. 1996;24(2):86-90. 
Wolf SL, Catlin PA, Gage K, Gurucharri K, Robertson R, Stephen K. Establishing the reliability and validity of 
measurements of walking time using the Emory Functional Ambulation Profile. Phys Ther. 1999;79(12):1122-33. 
American Thoracic Society statement: guidelines for the 6-Minute walking test. Am J Respir Crit Care Med. 2002 
Jul 1;166(1):111-7. 
Goldman MD, Marrie RA, Cohen JA. Mult Scler. 2008 Apr;14(3):383-90 
Graham, RC.; Hughes, RAC.; A modified peripheral neuropathy scale: the Overall Neuropathy Limitations Scale, 
Journal of Neurology, Neurosurgery and Psychiatry, 2006 Vol 77, pp 973-976 
Hughes RA ; Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy: the 
ICE trial; Expert Rev Neurother. 2009 Jun; 9(6):789-95 
Léger JM1, Viala K, Nicolas G, Créange A, Vallat JM, Pouget J, Clavelou P, Vial C, Steck A, Musset L, Marin 
B; RIMAG Study Group (France and Switzerland) Neurology. 2013 Jun 11;80(24):2217-25. doi: 
10.1212/WNL.0b013e318296e92b. Epub 2013 May 10. 
Lunn MPT Cochrane data systematic review 2012;5: CD 002827 Immunotherapy for IgM 
Solari, A.; Laurà, M.; Salsano, E.; Radice, R.; Pareyson, D.; (2007) Reliability of clinical outcome measures in 
Charcot-Marie-Tooth disease; Neuromuscular Disorders, Volume 18, Issue 1, Pages 19-26 
Collins JJ, De Luca CJ. Open-loop and closed-loop control of posture: a random-walk analysis of center-of-
pressure trajectories. Exp Brain Res. 1993;95(2):308-18. 
Aline Herrera-Rangel, Catalina Aranda-Moreno, Teresa Mantilla-Ochoa, Lylia Zainos-Saucedo, and Kathrine 
Jáuregui-Renaud; The Influence of Peripheral Neuropathy, Gender, and Obesity on the Postural Stability of 
Patients with Type 2 Diabetes Mellitus, Journal of Diabetes Research Volume 2014, Article ID 787202, 7 pages 
Kleyweg RP, van der Mechè FGA, Schmitz PIM. Interobserver agreement in the assessment of muscle strength 
and functional abilities in Guillain-Barrè syndrome. Muscle Nerve 1991;14:1103-1109. 
Laughlin, R.S., et al., Incidence and prevalence of CIDP and the association of diabetes mellitus. Neurology, 2009. 
73(1): p. 39-45. 
Mahdi-Rogers, M. and R.A. Hughes, Epidemiology of chronic inflammatory neuropathies in southeast England. 
Eur J Neurol, 2013. 
Joint Task Force of the EFNS and the PNS, European Federation of Neurological Societies/Peripheral Nerve 
Society Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a 
joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society – First 
Revision. Journal of the Peripheral Nervous System, 2010. 15(1): p. 1-9. 
European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of 
paraproteinemic demyelinating neuropathies. Report of a Joint Task Force of the European Federation of 
Neurological Societies and the Peripheral Nerve Society--first revision. J Peripher Nerv Syst, 2010. 15(3): p. 185-
95. 
Latov, N., Pathogenesis and therapy of neuropathies associated with monoclonal gammopathies. Ann Neurol, 
1995. 37 Suppl 1: p. S32-42. 
Eurelings, M., et al., Neuropathy and IgM M-proteins: prognostic value of antibodies to MAG, SGPG, and 
sulfatide. Neurology, 2001. 56(2): p. 228-33. 
 
 

 
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13 APPENDICES 
 
 

 
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Appendix 1: 
Biological testing biotin may interfere with (non-exhaustive list): 
ANAEMIA 
Ferritin 
Folate 
Vitamin B12 
CARDIOLOGY 
CK-MB 
Myoglobin 
Nt-proBNP 2 
Troponin I 
Troponin T 
HORMONES /  
FERTILITY 
ACTH 
AMH 
Cortisol 
C-Peptide  
DHEA-s  
Estradiol 
FSH, LH 
HCG 
hGH 
Insulin 
PAPP-A 
PlGF 
Progesterone 
Prolactin 
SHBG 
Testosterone 
THYROID 
Anti TG 
Anti TPO 
Anti-TSHr 
Calcitonin 
T3, FT3 
T4, FT4 
Tg 
TSH 
T-Uptake 
INFECTIOUS 
Ag HBe 
Ag HBs 
Anti-HAV 
Anti-HBc 
Anti-HBc IgM 
Anti-Hbe 
Anti-HBs 
Anti-HCV 2 
CMV IgG, IgM 
HIV Ag p24 
HIV Ag Confirm. 
HIV Combi PT 
HSV-1/2 IgG 
Rubella IgG, IgM 
Syphilis 
Toxo Avidity 
Toxo IgG, IgM 
DRUGS 
Carbamazepine 
Ciclosporine 
Digitoxine 
Digoxine 
Gentamicine 
Lidocaine 
Lithium 
Mycophenolate 
Phenobarbital 
Phenytoine 
Procainamide 
Sirolimus 
Sodium Valproate 
Tacrolimus 
Theophylline 
Tobramycine 
Vancomycine 
BONE 
METABOLISM 
Anti CCP 
Beta cross Laps 
Osteocalcin 
PTH 
P1NP 
Vitamin D 
ONCOLOGY 
ACE 
AFP 
CA 125 
CA 15-3 
CA 19.9 
CA 72-4 
Cyfra 21-1 
HE4 
HER-2/neu 
NSE 
ProGRP 
PSA 
S100 
sFlt-1 
TPS 
SEPSIS / 
INFLAMMATION 
C3, C4 
CRP 
IgA IgE IgG IgM 
IL6 IL8 IL10 
LBP 
Prealbumin 
Procalcitonin 
TNF-α 
Transferrin 

 
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Appendix 2 
Medical Research Council (MRC) sum score 
The total MRC sum score ranges from 0 (total paralysis) to 60 (normal strength). The score is 
the sum of the MRC score of 6 muscles (3 at the upper and 3 at the lower limbs) on both sides, 
each muscle graded from 0 to 5. The following muscles are examined: 
 Deltoid 
 Biceps 
 Wrist extensor 
 Ileopsoas 
 Quadriceps femoris 
 Tibialis anterior  
MRC-Muscle Grading Scale 
Grade 
Degree of Strength 
5 
Normal Strength 
4 
Ability to resist against moderate pressure throughout range of motion 
3 
Ability to move through full range of motion against gravity. If a subject has a 
contracture that limits joint movement, the mechanical range will be to the point 
at which the contracture causes joint restriction 
2 
Ability to move through full range of motion with gravity eliminated 
1 
A flicker of motion is seen or felt in the muscle 
0 
No movement 
Kleyweg RP, van der Mechè FGA, Schmitz PIM. Interobserver agreement in the assessment of 
muscle strength and functional abilities in Guillain-Barrè syndrome. Muscle Nerve 
1991;14:1103-1109. 
 
 

 
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Medical Research Council sum Score: Grille d’évaluation 
Coter chaque muscle des deux côtés selon la règle suivante: 
Grade 
Force 
5 
Force normale 
4 
Mouvement possible contre résistance modérée 
3 
Mouvement possible contre gravité. L’étendue du mouvement s’entend jusqu’au 
point où une contracture bloque l’articulation. 
2 
Mouvement possible si la gravité est neutralisée. 
1 
Ebauche de mouvement vue ou palpable dans le muscle 
0 
Aucun mouvement 
 
 
Grade 
Muscle 
Droit 
Gauche 
Deltoide 
 
 
Biceps 
 
 
Extenseurs du poignet 
 
 
Psoas 
 
 
Quadriceps 
 
 
Jambier anterieur 
 
 
Total 
 
 
SOMME DES SCORES 
 
 
 
 

 
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Appendix 
INCAT Sensory Sum Score (ISS). The ISS ranges from 0 (normal sensation) to 20 (most severe 
sensory deficit) and is composed of the summation of the following sensation qualities: 
 Pinprick arm grade (range 0-4) 
 Vibration arm grade (range 0-4) 
 Pinprick leg grade (range 0-4) 
 Vibration leg grade (range 0-4) 
 Two-point discrimination grade (range 0-4) 
Pinprick is tested with the sharp end of an esthesiometer, subjects indicate normal or abnormal. 
Paresthesia, dysesthesia or hyperesthesia are to be scored as abnormal. Normal reference point: 
face. 
Vibration sense is tested using the graduated Rydel-Seiffer tuning fork, measures obtained are 
compared with the reported normative threshold values. 
Pinprick and vibration sense examination take place distal to proximal and only the highest 
extension of dysfunction of the most affected arm and leg are recorded separately for both 
qualities. 
 
Pinprick sensation 
(sites of examination and 
corresponding grades) 
Vibration sensation 
(sites of examination and 
corresponding grades) 
Two-point discrimination 
(sites of examination and 
corresponding grades) 
Arms 
Legs 
Arms 
Legs 
Index finger K 
Normal sense 
0, at index fingerA 
Normal sense 
0, at halluxF 
Normal sense 
0, at index fingerA 
Normal sense 
0, at halluxF 
Normal sense 
0, < 4 mm 
Abnormal sense Abnormal sense Abnormal sense Abnormal sense 
Abnormal sense 
1, at index 
fingerB 
1, at halluxG 
1, at index 
fingerB 
1, at halluxG 
1, 5-9 mm 
2, at wristC 
2, at ankleH 
2, at wristC 
2, at ankleH 
2, 10-14 mm 
3, at elbowD 
3, at kneeI 
3, at elbowD 
3, at kneeI 
3, 15-19 mm 
4, at shoulderE 
4, at groinJ 
4, at shoulderE 
4, at groinJ 
4, > 20 mm 
A,B: index fìnger (dorsum distal interphalangeal joint); C: ulnar styloid process; D: medial 
humerus epicondyle; E: acromioclavicular joint; F,G: hallux (dorsum inter-phalangeal joint); 
H: medial malleolus; I: patella; J: anterior superior iliac spine; K: index finger (ventral side: 
distal phalanx) 
 

 
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Appendix 
Timed 10-meter walking test: 
- 
The patient should be instructed to walk without assistance 10 meters (32.8 feet) and the time 
is measured for the intermediate 6 meters (19.7 feet) to allow for acceleration and deceleration 
 
start timing when the toes of the leading foot crosses the 2-meter mark 
 
stop timing when the toes of the leading foot crosses the 8-meter mark 
 
assistive devices can be used but should be kept consistent and documented from test to test 
- 
If physical assistance is required to walk, this should not be performed 
- 
The test can be performed at preferred walking speed or fastest speed possible 
- 
The documentation should include the speed tested (preferred vs. fast) 
- 
Three trials have to be performed and the average of the three trials calculated 
Set-up (derived from the reference articles): 
- 
measure and mark a 10-meter walkway 
- 
add a mark at 2-meters 
- 
add a mark at 8-meters 
 
 
 
 
0 m 
2 m 
8 m 
10 m 
 
Patient Instructions (derived from the reference articles): 
Maximum speed trial: “I will say ready, set, go. When I say go, walk as fast as you safely can until I say 
stop” 
Instruction in French: « Je vais vous dire attention, prêt, partez. Lorsque je dis partez, marchez 
prudemment aussi vite que vous pouvez jusqu'à ce que je vous dise stop. » 
 
 

 
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Appendix 
6-minute walking test Detailed instruction for challenge: 
I. GENERAL INSTRUCTIONS 
The Six Minute Walk Test Form is filled out by the study clinician conducting the test. Using a paper 
copy of the form to record the data while the test is in progress is recommended. 
The Six Minute Walk, an assessment of lung function is the Flexible Block A procedure. Usually the 
walk should follow shortly after spirometry since it is performed after bronchodilation (for participants 
with COPD and/or asthma). 
The testing area must be a 30m (100 ft.) segment of straight, unimpeded hallway. 
Prepare the area by applying markers for the endpoints and 3m intervals to the baseboard on one side of 
the hall, with special attention to avoid doorways, etc. 
Use the provided 30m metric tape measure. If a pre-existing 100 ft. (30.48m) course with 10ft. markers 
has been previously laid out, it may be used. 
If available, place the traffic cones at the center of the proximal and distal turn points. Place the turn 
signs at the proximal and distal turn points of the course. 
Have ready the following materials: stopwatch/timer, worksheet for counting laps, oximeter, Borg 
breathlessness and exertion scales, a chair that can be easily moved along the walking course, emergency 
equipment (according to local policy): telephone, sphygmomanometer, oxygen source. 
A “warm-up” period before the test should not be performed. 
Participants should use their usual walking aids during the test (cane, walker, etc.) and be dressed in 
comfortable clothing and walking shoes. 
II. DETAILED INSTRUCTIONS FOR CHALLENGE 
Read the following instructions to the participant: 
“The object of this test is to walk as far as possible for 6 minutes. You will walk back and forth 
in this hallway. Six minutes is a long time to walk, so you will be exerting yourself. You will 
probably get out of breath or become exhausted. You are permitted to slow down, to stop, and 
to rest as necessary. You may lean against the wall while resting, but resume walking as soon 
as you are able. You will be walking back and forth around the cones. You should pivot briskly 
around the cones and continue back the other way without hesitation. Now I’m going to show 
you. Please watch the way I turn without hesitation.” 
Demonstrate by walking one lap yourself. Walk and pivot around a cone briskly. 
Record completed and partial laps on the lap count worksheet. 
Say to the participant: 
“Are you ready to do that? I am going to use this counter to keep track of the number of laps you 
complete. I will click it each time you turn around at this starting line. Remember that the object is to 
walk AS FAR AS POSSIBLE for 6 minutes, but don’t run or jog. Start now, or whenever you are ready.” 
Standardized Encouragement read in a steady voice: 
- 
After the 1st minute: “You are doing well. You have 5 minutes to go.” 
- 
When the timer shows 4 minutes remaining: “Keep up the good work. You have 4 minutes to 
go.” 
- 
When the timer shows 3 minutes remaining: “You are doing well. You are halfway done. 
- 
When the timer shows 2 minutes remaining: “Keep up the good work. You have only 2 minutes 
left. 
- 
When the timer shows 1 minute remaining: “You are doing well. You only have 1 minute to go. 

 
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- 
With 15 seconds to go: “In a moment I’m going to tell you to stop. When I do, just stop right 
where you are and I will come to you.” 
- 
At 6 minutes: “Stop” 
If the participant stops at any time prior, you can say: “You can lean against the wall if you would like; 
then continue walking whenever you feel able.” 
Do not use other words of encouragement (or body language) to influence the patient’s walking speed. 
Accompany the participant along the walking course, but keep just behind them. Do not lead them. 
III. DETAILED INSTRUCTIONS FOR EACH ITEM 
Before starting: 
Item 1. Pulse: Record beats per minute. 
Starting test: 
Item 2. Start of 6-minute walk: Record time in hours and minutes. Choose AM or PM. 
Immediately following 6MW: Record the following: 
Item 3. Pulse: Record beats per minute. 
Item 4. Breathlessness: Record participant’s response from 0-10 on the Modified Borg Scale 
(0=no breathlessness, nothing at all, 0.5=very, very slight, 1=very slight, 2=slight 
breathlessness, 3=moderate, 4=somewhat severe, 5=severe breathlessness,6=is between severe 
breathlessness and very severe breathlessness, 7=very severe breathlessness, 8=between very 
severe breathlessness and very,very severe breathlessness, 9=very, very severe breathlessness, 
10=maximum breathlessness.) 
Item 5. Exertion: Record participant’s response from Scale of Perceived Exertion (0=none, 
2=very,very light, 3=very light, 4=fairly light, 5=somewhat hard, 6=hard, 7=very hard, 
8=very,very hard. 
Item 6. Type of course used: Select the type of course used. Record 1 for 30 meters x 2 lengths, 
2 for 100 feet x 2 lengths, or 3 for other. If Other, specify in the space provided. 
Item 7. Record the number of completed laps 
Item 8. Record the distance walked the final partial lap in meters. 
Item 9. Stopped before 6 minutes: Record Y for Yes or N for No. If No skip out of form. If Yes 
answer Item 10 and 11. 
Item 10. Duration: Record in minutes and seconds. 
Item 11. Reason for stopping: Record one response 1-5. (1=desaturation <80%, 2=foot, knee, 
hip or other 48rthopaedic pain, 3=muscle fatigue or pain, 4=breathlessness, 5=adverse event) 
Item 12. If response to Item 11=5, select all that apply. (a=angina, b=lightheadedness, 
c=intolerable dyspnea, d=leg cramps, e=staggering, f=diaphoresis, g=pale or ashen appearance, 
h=mental confusion or headache, i=other). If other is selected, please explain. 
 
 

 
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Appendix