Clinical trial NCT02317562
Conditions: Chronic Inflammatory Demyelinating Polyradiculoneuropathy
Keywords: Peripheral neuropathy Disimmune disease Neurology chronic disease Rare disease
Sponsor: Laboratoire français de Fractionnement et de Biotechnologies
Start date: 2015-11-01; Completion date: 2017-07-28
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Primary objective:

To assess the efficacy of I10E administered at a reduced maintenance dose in sustaining CIDP response after an initial 6-month treatment in PRISM study. (I10E-1302).

Secondary objective:

To assess the safety of I10E in this patient population.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: I10E
Intervention descriptions: intervention 1: Patients who met all eligibility criteria will receive 0.5 g/kg of IMP every 3 weeks during 45 weeks.

Protocol documents:
Prot_000.pdf: 
 
COVER PAGE 
 
 
TITLE: International, multicentre, efficacy and safety study of I10E in the maintenance 
treatment of patients with Chronic Inflammatory Demyelinating 
Polyradiculoneuropathy: Extension of PRISM study I10E-1302 
 
NCT Number: NCT02317562 
 
 
DOCUMENT: Protocole (v5.0)  
 
 
VERSION & DATE OF DOCUMENT: Version5.0; May 3, 2017 


CONFIDENTIAL
Effective Date : 04 May 2017
Version : 5.0
File Name : Protocol and amendment - 000235723
Product : I10E
Title : Protocol v5.0
First Author : 
Signatures
Name and Surname
Intention
Date
Management Approval
04 May 2017 09:51:31 GMT




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TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................5
SYNOPSIS.............................................................................................................................8
1.
INTRODUCTION AND BACKGROUND INFORMATION ............................................20
1.1.
Disease and Context............................................................................................................. 20
1.2.
Target ................................................................................................................................... 25
1.3.
Non-Clinical and Clinical Information ................................................................................ 26
1.4.
Rationale of the Study.......................................................................................................... 27
2.
STUDY OBJECTIVES ..................................................................................................31
2.1.
Primary Objective ................................................................................................................ 31
2.2.
Secondary Objective(s)........................................................................................................ 31
2.3.
Exploratory Objective(s)...................................................................................................... 32
3.
STUDY DESIGN...........................................................................................................32
3.1.
Design and Study Periods .................................................................................................... 32
3.2.
Endpoints ............................................................................................................................. 33
3.3.
Study Investigational Sites(s)............................................................................................... 34
3.4
Data and Safety Monitoring Board / Steering Committee................................................... 34
3.5
Scientific Committee............................................................................................................ 35
4.
DURATION AND DATES OF THE STUDY..................................................................35
5.
STUDY POPULATION .................................................................................................35
5.1.
Number of Patients............................................................................................................... 35
5.2.
Eligibility Criteria ................................................................................................................ 35
5.3.
Duration of Patient Participation.......................................................................................... 38
5.4.
Discontinuation Criteria / Stopping Rule(s)......................................................................... 38
6.
STUDY DRUG AND CLINICAL SUPPLIES .................................................................38
6.1.
Study drug............................................................................................................................ 38
6.2.
Medical Device .................................................................................................................... 43
7.
PRIOR AND CONCOMITANT MEDICATION ..............................................................43
7.1.
Prior Medication................................................................................................................... 43
7.2.
Concomitant Medication...................................................................................................... 43
8.
STUDY PLAN...............................................................................................................44
8.1.
Patient recruitment ............................................................................................................... 44
8.2.
Sequence of Study Procedures............................................................................................. 47
8.3.
At any course: ...................................................................................................................... 54
8.4.
Central Biological Handling Sampling................................................................................ 54
8.5.
Ultrasonography (for Italian site only)................................................................................. 54
8.6.
Compliance with the Study Plan.......................................................................................... 55
9.
SAFETY........................................................................................................................55


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9.1.
Reference Safety Information Document............................................................................. 55
9.2.
Benefit / Risk Information ................................................................................................... 55
9.3.
Risk Minimisation Actions Throughout the Protocol.......................................................... 57
9.4.
Alternative Therapeutic Management - Handling Emergencies.......................................... 58
9.5.
Definition and Reporting of (Serious) Adverse Events ....................................................... 58
10.
ASSESSMENT OF EFFICACY AND SAFETY.........................................................63
10.1.
Assessment of Efficacy........................................................................................................ 63
10.2.
Assessment of Safety ........................................................................................................... 63
11.
DATA MANAGEMENT .............................................................................................64
11.1.
eCRF Completion Guidelines .............................................................................................. 64
11.2.
eCRF and Data Handling ..................................................................................................... 66
12.
STATISTICS .............................................................................................................67
12.1.
Trial Objectives and Design................................................................................................. 67
12.2.
Statistical Analysis Plan....................................................................................................... 67
12.3.
Sample Size Determination.................................................................................................. 67
12.4.
Randomisation ..................................................................................................................... 67
12.5.
Protocol Deviations and Analysis Sets ................................................................................ 67
12.6.
General rules for Handling of Missing or Inconsistent Data ............................................... 68
12.7.
Demographic and Baseline Characteristics.......................................................................... 68
12.8.
Study drug and Concomitant Treatments............................................................................. 68
12.9.
Efficacy Analysis ................................................................................................................. 69
12.10.
Safety Analysis ................................................................................................................ 70
12.11.
Exploratory Analysis........................................................................................................ 71
13.
STUDY REPORT ......................................................................................................71
14.
CONFIDENTIALITY AND PUBLICATION................................................................72
14.1.
Patient Confidentiality ......................................................................................................... 72
14.2.
Use of Information............................................................................................................... 72
15.
ARCHIVING ..............................................................................................................72
16.
RESPONSIBILITIES OF PARTICIPANTS................................................................73
16.1.
Responsibilities of the Investigator(s).................................................................................. 73
16.2.
Responsibilities of the Monitor............................................................................................ 75
16.3.
Responsibilities of the Data Manager .................................................................................. 76
17.
ETHICS AND REGULATORY CONSIDERATIONS .................................................76
18.
AUDIT AND INSPECTION........................................................................................77
19.
REFERENCES..........................................................................................................78
20.
APPENDICES...........................................................................................................81
20.1.
Scales / Score Used.............................................................................................................. 81


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LIST OF TABLE
Table 1–1 : Differential diagnosis of CIDP ........................................................................................21
Table 1–2: Diagnostic criteria and diagnostic categories of CIDP.....................................................22
Table 1–3: Diagnostic Categories.......................................................................................................23
Table 1–4: Literature review on CIDP patient follow-up and outcomes............................................25
Table 20–1: INCAT disability scale ...................................................................................................81
Table 20–2: MRC scale.......................................................................................................................83
Table 20–3: Final 24-item of CIDP R-ODS .......................................................................................84
LIST OF FIGURE
Figure 8–1: Sequence of study procedures .........................................................................................46
Figure 20–1: Martin vigorimeter.........................................................................................................87


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
GT
Glutamyl Transferase
Ab
Antibody
ACR
Albumine to Creatinine Ratio
AE
Adverse Event
AER
Albumin Excretion Rate
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase 
AMS
Aseptic Meningitis Syndrome
ANSM
Agence Nationale de Sécurité du Médicament et des produits de santé
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical 
BAFF
B Cell Activating Factor
BMI
Body Mass Index
BPWP
Blood Products Working Party
CGI
Clinical Global Impression
CHMP
Committee for Human Medicinal Product
CI
Confidence Interval
CIDP
Chronic Inflammatory Demyelinating Polyradiculoneuropathy
CKD
Chronic Kidney Disease
CMAP
Compound Muscle Action Potential
CNTN1
Contactin 1
CRO
Contract Research Organization
CSA
Cross Section Area
CSP
Code de la Santé Publique
CV
Curriculum Vitae
DAT
Direct Antiglobulin Test
DCFs
Data Clarification Forms
EC
Ethics Committee
eCRF
Electronic Case Report Form
EFNS
European Federation of Neurological Societies
EMA
European Medicines Agency
EOS
End of Study
EU
European Union
FAS
Full Analysis Set
FcR
FcReceptor


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FDA
Food and Drug Administration
FPI
First Patient In
FU
Follow-up
GBS
Guillain Barré Syndrome
GCP
Good Clinical Practice 
GFR
Glomerular Filtration Rate
HAV
Hepatitis A virus
Hb
Haemoglobin 
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human Immunodeficiency Virus
HLGT
High Level Group Term
ICH
International Conference on Harmonisation
IEC/IRB
Independent Ethics Committee (IEC) / International Review Board (IRB)
Ig
Immunoglobulin
IgA
Immunoglobulin A
IgG
Immunoglobulin G
IMP
Investigational Medicinal Product
INCAT
Inflammatory Neuropathy Course and Treatment 
ITP
Immune ThrombocytoPenia
IVIg
Intravenous Immunoglobulin 
kPa
kiloPascals
LDH
Lactate Dehydrogenase
LFB
Laboratoire Français du Fractionnement et des Biotechnologies 
LLN
Lower Limit of Normal
LLT
Lowest Level Term
LOCF
Last Observation Carried Forward
LPO
Last Patient Out
MAG 
Myelin-Associated Glycoprotein 
MCV
Mean Corpuscular Volume
MDRD
Modified Diet in Renal Disease 
MedDRA
Medical Dictionary for Regulatory Activities
MGUS
Monoclonal Gammopathy of undermined Significance 
MMN
Multifocal Motor Neuropathy
MRC
Medical Research Council 


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NCR
No Carbon Required
NCS
Nerve conduction studies
NF155
Neurofascin 155
NYHA
New York Heart Association
PCR
Protein to Creatinine Ratio
PER
Protein Excretion Rate
PID
Primary Immune Deficiency
PNS
Peripheral Nerve Society
PPS
Per Protocol Set
PT
Preferred Term
RBC
Red Blood Cells
R-ODS
Rasch-built Overall Disability Scale
RR
Relative Risk
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCIg
Sub-Cutaneous Immunoglobulin
SPC
Summary of Product Characteristics
SOC
System Organ Class
SUSAR
Suspected and Unexpected Serious Adverse Reaction
TAAE
Temporally-Associated Adverse Event
TEAE
Treatment-Emergent Adverse Event
TTS
Total Treated Set 
ULN
Upper Limit of Normal
USG
Ultrasonography
WHO
World Health Organisation


























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1. INTRODUCTION AND BACKGROUND INFORMATION
1.1. Disease and Context
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired paralytic illness 
caused by a demyelinating process affecting peripheral nerves. The underlying pathologic 
mechanisms are still unclear. Yet, an autoimmune aetiology is largely thought to be probable. 
CIDP is a rare disease. The various epidemiological studies show that prevalence may vary from 
1.24/100 000 to 8.9/100 000 [1] [2]. Due to the ambiguities of diagnosing CIDP, the true prevalence 
of the disease may be underestimated or overestimated [3].
1.1.1. Diagnostic Criteria for CIDP
Diagnostic criteria for CIDP have been defined by expert groups. These diagnostic criteria sets 
combine clinical, electrophysiological and biological features.
The typical clinical presentation of CIDP includes symmetric sensory and motor symptoms in the 
proximal and distal segments of all four limbs, associated with areflexia and evolving over more 
than 2 months. The disease may show either continuous or stepwise progression over months to 
years or may take a more fluctuating course.
However, clinical features are heterogeneous and there are many borderline clinical forms, such as 
purely motor forms, purely sensory forms or Lewis-Sumner syndrome. Furthermore, frequent 
association with other diseases such as diabetes mellitus, monoclonal gammopathy with or without 
antibodies 
to 
myelin-associated 
glycoprotein, 
connective 
tissue 
diseases 
or 
human 
immunodeficiency virus infection may complicate the diagnosis.
Electrodiagnostic tests are mandatory to confirm the diagnosis of CIDP [4]. Electrodiagnostic 
criteria for CIDP are closely linked to diagnostic criteria of peripheral nerve demyelination. They 
include reduced motor nerve conduction velocity, motor nerve conduction block, abnormal temporal 
dispersion, prolonged motor distal latency and prolonged F wave latency or absent F waves [5].
Cerebrospinal fluid examination may assist the diagnosis. Usually there is an albumino-cytological 
dissociation with an elevated protein level and a leukocyte count 10/mm3.
Nerve biopsy is not often used for the diagnosis as it might cause an unacceptable increase in 
neurological symptoms [6]. However, when an affected portion of nerve is examined, segmental 
demyelinating lesions are found associated with inflammatory signs such as endoneurial oedema and 
infiltration by macrophages and T lymphocytes. The demyelination and re-myelination process often 
produces the so-called "onion bulb" formations. There is usually a superimposed axonal 
degeneration.








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1.1.2. Treatment of CIDP and course of the disease
The spontaneous progression of the disease in the absence of any therapy has not been well 
described in the literature. The effectiveness of treatment with corticosteroids was shown at the time 
chronic polyradiculoneuropathy was first described by Austin in 1958 [8].
Three therapeutic options have proved to be efficacious in CIDP: IVIg, oral corticosteroids and 
plasma exchange. The EFNS/PNS guideline recommends the use of IVIg or corticosteroids as first 
line treatment [4]. Plasma exchange, which is less widely available and less tolerated, is only 
recommended as an alternative in case IVIg and corticosteroids are inadequate [4]. The American 
Academy of Neurology considers that IVIg should be offered for the long-term treatment of CIDP 
(Level A recommendation) [9].
Regarding IVIg, a meta-analysis in a Cochrane review of 5 double-blind placebo-controlled 
randomised trials showed that a significantly higher proportion of patients improved in disability 
within one month after IVIg treatment compared with placebo [10]. Only one study (ICE study) had 
a long-term follow-up [11]; in this study, 57 responder patients were re-randomised for an extension 
24-week phase between either IVIg at 1 g/kg or placebo every 3 weeks. The percentage of relapse 
was 13% with the IVIg and 45% with the placebo (p=0.011) [11].
In a randomised controlled Italian trial, Nobile-Orazio et al. compared the long-term efficacy of 
IVIg (0.5 g/kg/day for 4 consecutive days, every 28 days) versus IV methylprednisolone (0.5 g daily 
for 4 consecutive days, every 28 days) [11]. Both treatments were discontinued after 6 months and 
patients followed up for a further 6 months. During the 6 months after therapy discontinuation, none 
of the 10 patients who improved with IV methylprednisolone worsened and required further therapy, 
whereas 8 (38%) of 21 patients who responded to IVIg worsened (p=0.0317) in 1 to 5 months 
(median 4 months). They all responded to resumed therapy [12]. In an extension to their initial 
study, the authors reported a similar high proportion of patients eventually relapsing: 85.7% of 
patients after IVIg therapy with a median follow-up of 42 months (range 1-57) and 76.9% of
patients treated with IV methylprednisolone with a median follow-up of 43 months (range 7-60; 
p=0.659) [13]. However, median time to relapse was
significantly longer after IV
methylprednisolone [1-31 months (median 14)] than IVIg [1-24 months (median 4.5)] (p= 0.0126) 
[13].




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1.3. Non-Clinical and Clinical Information 
The study drug is I10E, a ready-to-use liquid human normal immunoglobulin preparation for IV 
administration (ATC Code: J06BA02). I10E is manufactured by LFB BIOMEDICAMENTS (see 
Section 6.1.1. Description of study drug). 
Marketing Authorization Application (MAA) was submitted in Intravenous Immunoglobulin (IVIg) 
Core Summary of Product Characteristics (SPC) indications through the Decentralized Procedure 
(DCP) in the following European Union Member States: Austria, Belgium, Czech Republic, 
Denmark, Finland, Germany, Greece, Hungary, Italy, Luxembourg, the Netherlands, Spain, 
Slovakia, Sweden, and the United Kingdom.The first national marketing authorisation was granted 
in the United Kingdom in August 2015, then in Denmark, Germany, Hungary, Belgium and Finland.
I10E MAA dossier was also submitted in Mexico and approved in April 2015 in the core SPC 
indications, multifocal motor neuropathy and Birdshot retinochoroidopathy.
This section summarises the available clinical and non-clinical data of I10E.
1.3.1. Non-Clinical Data
I10E meets specifications of the European Pharmacopoeia Monograph 0918 on IVIg. Non-clinical 
safety studies of I10E were performed in accordance with Good Laboratory Practice. For more 
information, refer to the Investigator’s Brochure.
1.3.2. Clinical Data
As of 08 October 2015, 107 patients have been treated with I10E in open-label clinical studies: 62 
patients with primary immune deficiency (PID) in study I10E-0718 (completed), 38 patients with 
immune thrombocytopenia (ITP) in study I10E-0719 (completed) and 7 patients with chronic 
inflammatory demyelinating polyneuropathy (CIDP) in an ongoing single-arm study I10E-1302 
(PRISM study). In addition, 22 patients with multifocal motor neuropathy (MMN) have been 
enrolled in an ongoing double-blind cross-over randomized study I10E-0901 (LIME study) and at 
least 17 of them were administered with I10E.  
In PID patients, a total of 766 infusions at a dose ranging from 0.22 to 0.97 g/kg were administered. 
I10E has proved to be effective in preventing serious bacterial infections (SBIs) with an annual SBI 
rate below the EMA/FDA requirement of 1/patient. I10E exhibited a PK profile comparable to 
those of other IVIgs with a mean terminal half-life of 33.6 days.
In chronic primary ITP patients, a total of 73 infusions were administered at a median dose of 
1.0 g/kg on one day, 70 of them being administered on 2 consecutive days. I10E was effective in 
increasing rapidly the platelet count and reducing and preventing bleedings with a response rate of 
63.2% of patients using the stringent definition of response of the revised EMA guideline on the 
clinical investigation of IVIg and 83.8% using the primary efficacy endpoint of the previous EMA 
guideline. 
Monitoring of adverse events (AEs), vital signs, ECG and laboratory parameters showed a safety 
profile comparable to that of other IVIg in patients with PID or chronic ITP. 


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In MMN patients, the ongoing study I10E-0901 (LIME study) compares I10E to Kiovig® 
maintenance therapy at a dose of 1.0 g/kg every 4 weeks up to 2.0 g/kg every 4 to 8 weeks for 
approximately one year. The enrolment in the study is completed.
In CIDP patients, the study I10E-1302 (PRISM study) aims at evaluating the safety and efficacy of 
one dose of 2.0 g/kg of I10E followed by 7 doses of 1.0 g/kg every 3 weeks. A total of 42 patients 
are planned to be enrolled in the study.
As of 08 October 2015, no serious adverse reactions were reported in both study I10E-0901 and 
study I10E-1302. 
An extension of study I10E-1302, namely study I10E-1306 (PRISM-2 study) has been initiated to 
assess the efficacy and safety of a reduced maintenance dose of I10E in responder patients at the end 
of study I10E-1302. For more information, refer to the Investigator’s Brochure.
The dose of I10E recommended in this protocol will not exceed the doses used in current practice in 
patients with CIDP as well as in other indications of immunomodulation.
This section is not intended to be all inclusive regarding risks and benefits. The investigator must 
become familiar with all sections of the I10E Clinical Investigator's Brochure.
1.4. Rationale of the Study
LFB BIOTECHNOLOGIES wishes to develop the CIDP indication for I10E. As required by the 
European Guideline EMA/CHMP/BPWP/94033/2007 rev.2 [17], confirmatory data of I10E in CIDP
patients should be provided to Health Authorities in order to file the indication. Published literature 
already indicates a beneficial effect of IVIg in CIDP.
A clinical trial (PRISM I10E-1302 study) has already been set-up in CIDP patients with the 
objective of providing confirmation data on the efficacy of I10E in the initial and maintenance 
treatment phases of CIDP and on the safety of I10E. An improvement of the neurological status – as 
assessed by neurological scales – is expected after treatment with I10E in both immunoglobulin (Ig)-
naive patients and relapsing Ig-pretreated patients. Both types of CIDP patients were eligible in the 
study. They both received one dose of I10E at 2 g/kg over 2-5 days. Three weeks later, they received 
7 doses of I10E at 1g/kg over 1-2 day(s) each, every 3 weeks. The total treatment period was of 21 
weeks +/- 7 days as recommended in the EFNS/PNS guideline [4]. The primary efficacy endpoint 
was the responder rate at the EOS visit. Responders were defined as patients with a decrease of ≥1 
point in the adjusted INCAT disability score between baseline and the EOS visit.
The EFNS/PNS guideline states that “if the first-line treatment is effective, continuation should be 
considered until the maximum benefit has been achieved and then the dose reduced to find the 
lowest effective maintenance dose” [4]. Indeed, majority of neurologists apply dose reduction 
schemes for CIDP patients. However, these schemes vary between practitioners by lack of evidence-
based medicine recommendation.
ICE study showed a reduced probability of relapse in patients receiving IVIg at a maintenance dose 
of 1 g/kg during its extension phase compared to placebo [11]. All other studies only assessed long-
term outcome after IVIg discontinuation. Following EFNS/PNS guideline recommendation to 
reduce IVIg doses on the long term, a reduced dose (0.5g/kg) will be assessed in this study in order 
to document the effect on the relapse rate in CIDP patients.


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The current study is an extension of PRISM I10E-1302 study. The primary objective is to assess the 
efficacy of I10E administered at a reduced maintenance dose, in sustaining CIDP response by using 
the same outcome measures than in PRISM I10E-1302. 
The secondary objective is to further assess safety of I10E in this patient population. 
As it was the case in PRISM I10E-1302 study, exploratory objectives are i) to assess a potential 
relationship between serum total IgG trough levels, biomarkers levels and clinical response assessed 
by neurological scales, and ii) to assess a potential relationship between ultrasonography (USG) 
coupled to neurophysiology analysis of nerves and clinical changes as assessed by neurological 
scales (ancillary study in Italy).
1.4.1. Disability and impairment scales
In 2013, Els K. Vanhoutte, Catherina G. Faber and Ingemar S.J. Merkies published outcome 
measures in inflammatory peripheral neuropathies on behalf of the PeriNomS study group the 196th
ENMC international workshop. Their recommendations on the most relevant scales for CIDP have 
been included in the current protocol. The following scales will therefore be assessed at 24 weeks 
(V9) and EOS visit as part of secondary endpoints:
Adjusted INCAT disability score;
Grip strength with the Martin vigorimeter in both hands, Rasch-built Overall Disability Scale (R-
ODS); 
Patient and Investigator Clinical Global Impression (CGI): Severity (CGI-S), Efficacy (CGI-E) 
and Improvement (CGI-I);
Medical Research Council (MRC) 12 muscles sum score (0 to 5) and Rasch-modified MRC (0 to 
3); 
1.4.2. Immunological Background and Biomarkers
The pathogenesis of CIDP is not fully understood. T cells, B cells, macrophages, cytokines and 
chemokines, autoantibodies and complement are the main effectors involved in the pathogenesis of 
CIDP and are therefore the main targets of therapies. Immune cells and soluble mediators are 
regulated by IVIg and this regulation is correlated in many instances with IVIg response. Numerous 
biomarkers have been proposed in CIDP but none seems to predict the response to IVIg accurately. 
This trial gives the opportunity to assess specific biomarkers, their modulation by IVIg treatment 
and their correlation with clinical response.
IVIg seems to work by a direct competition and quantitative blockade of autoantibody action by 
different mechanisms. 
In 2013 Professor Isabel Illa highlighted IgG4 anti-contactin1 and NF155 autoantibodies as poor 
prognostic factors after IVIg therapy: in her series, the presence of at least one of these 
autoantibodies identified a lack of response to IVIg [18]. Anti-contactin 1 (CNTN1) and anti-
neurofascin 155 (NF155) antibodies were associated to small subgroups of CIDP patients with 
specific phenotypic features. 
Other soluble biomarkers such as BAFF contribute to B-cell homeostasis and autoantibody 
production [19].


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Complement components have been shown to be modulated by IVIg [20] [21]. Scavenging of 
complement fragments is a mechanism believed to be important in the efficacy of IVIg. Binding of 
IgG molecules to potentially harmful complement fragments (C3b, C4b) blocks deposition of these 
fragments onto their target and the formation of amplification convertases, decreasing activation of 
C5 and deposition of the C5b-C9 membrane attack complex.
The modulation of the complement pathway following IVIg treatment can be monitored by the 
combined dosage of CH50 (ELISA-based assay) for the quantitative determination of functional 
classical, mannose binding lectin and alternative complement pathways, and the quantitative dosage 
of C3 and C4 proteins (routinely perform by nephelometry) in serum samples. 
Serum concentrations of these markers will be measured in order to document their modulation after 
I10E therapy.
Analyses of these biomarkers should advance understanding of immune modulation and mechanism 
of action of IVIg in CIDP.
1.4.3. Neurophysiological Examination (Ancillary study; Italian sites only)
Monolateral nerve conduction studies (NCS) will be performed through the following minimum 
neurophysiological protocol. Local laboratory standards will be employed.
Motor nerve conduction studies will be performed in the following nerves:

median nerve: the motor response will be recorded with surface electrodes over the 
abductor pollicis brevis muscle and the sites of stimulation will be at the wrist (1 cm 
proximal volar wrist fold) and at the elbow;

ulnar nerve: the motor response will be recorded with surface electrodes over the 
abductor digiti minimi muscle and the stimulation site will be at the wrist, above and 
below elbow (3 cm above and below elbow) and axilla;

deep fibular nerve: the motor response will be recorded with surface electrodes over the 
extensor digitorum communis and the sites of stimulation will be proximal to the 
anterior tarsal tunnel, 2 cm distal the proximal margin of fibular head and in the popliteal 
fossa.
Motor nerve conduction velocities, distal latencies, and amplitude of the negative phase of 
compound muscle action potentials will be measured.
F wave studies will be performed in the ulnar nerve with measurement of mean F latency and 
frequency of F response.
Sensory nerve conduction studies:

orthodromic sensory NCS of the median nerve will be recorded at the wrist and the 
stimulation with ring electrodes will be at digit III;

orthodromic sensory NCS of the ulnar nerve will be recorded at the wrist and the 
stimulation with ring electrodes will be at digit V;

antidromic sensory NCS of the sural nerve will be recorded at posterior-lateral malleolus 
and the site of stimulation will be at the posterior-distal leg with the cathode at 12 cm 
from the active electrode.


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As methods differ from site to site, all participating centers must provide complete information on 
their laboratory's standard NCS protocols.
If clinically indicated, additional studies may be performed at the discretion of the examiner.
1.4.4. Peripheral Nerve Ultrasonography (Ancillary study; Italian sites only)
High-resolution ultrasound (USG) of peripheral nerves is a valuable complement to 
neurophysiology especially in the work-out of mononeuropathies. Less is known on 
polyneuropathies, where the great heterogeneity made difficult the identification of a specific 
alteration pattern. In previous studies in CIDP patients, nerve US showed diffuse enlargement of 
cross sectional area (CSA) of peripheral nerves trunks and cervical roots [22] [23] [24] [25] [26]. 
Recently, US findings in CIDP have been shown not only to contribute to the diagnosis, but also to 
mirror the underlying pathophysiological mechanisms. Nerve enlargement was statistically related 
to disability and muscle strength, and the relationship between duration of symptoms and US classes 
was highly significant [27].
For the nerve US evaluation, US systems equipped with medium (the lowest being around 6 Hz) and 
high-frequency (15-18 MHz) broadband probes will be used. US will be performed in the 
neurophysiologically evaluated side. Additional nerves may be evaluated at the discretion of the 
examiner.
Nerve assessment required and pre-determined site of measurements are:
Median: wrist, mid-forearm, elbow, mid-humerus and axilla
Ulnar: wrist, mid-forearm, elbow, mid-humerus and axilla
Fibular: fibular head and popliteal fossa
Sural: median third of the leg
Optional assessments (for skilled US operators) are: 
Supraclavicular brachial plexus (strongly suggested)
Radial at humeral sulcus
Posterior interosseus nerve under the supinator muscle
C5-C6-C7 cervical roots.
US outcome measures will be: 
1) Maximal/minimal CSA for each nerve along the visible course;
2) Intra-nerve and inter-nerve variability;
3) US immune-related classification.
1) Maximal and minimal CSA
The method to calculate CSA (just inside the hyperechoic rim of the nerve in transversal section) is 
usually the “ellipse method” when applicable (when the nerve in the transverse scan has an elliptical 
or roundish shape) or the “tracing method” when the nerve has an “irregular” shape. Echogenicity 
alteration not associated with CSA alteration will be not considered.
In addition to the pre-determined sites of imaging, maximal (MAX-CSA) and minimal (MIN-CSA) 
CSA enlargement along the visible course will be recorded for each nerve.


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The CSA of whole plexus will be bilaterally measured. Moreover, after identification of the cervical 
spinal root level, CSA of each root (from C5 to C7) are measured just before entering the spine [28]. 
Each centre will use its own previously established CSA normative values. Every participating 
centre has to submit their normative values in advance. If not available, normative values adopted in 
the coordinating site will be used.
2) Intra- and inter-nerve variability
"Intra-nerve CSA variability" (for each nerve: maximal CSA/minimal CSA) and "inter-nerve CSA 
variability" (for each patient: maximal intra-nerve CSA variability/minimal intra-nerve CSA 
variability) will be evaluated [29] [30]. Intra-nerve variability will be evaluated only in ulnar, 
median and fibular nerves, having sural nerve a very short assessable segment (with only a single 
measure taken).
Normal values of upper cut-off of intra-nerve ratio are for median nerve 2.3 and for the ulnar nerve 
2.1. Concerning inter-nerve variability the upper cut-off value is 1.9.
3) US immune-related classification
On the basis of previous US observations [28] US pattern is classified as follows:
Class 1: large nerves, with hypoechoic segments and increased nerve CSA. Enlarged fascicles 
may be seen or the nerve may appear enlarged and hypoechoic without fascicular structure.
Class 2: large nerve, with segments with increased nerve CSA and coexistence of hyper and 
hypoechogenic enlarged (or normal) fascicles (in other words, in the same point we observe 
fascicles with hyperechoic and other fascicles with hypoechoic structure).
Class 3: normal nerve size, but changes in echogenicity (nerve appears hyperechoic with 
reduced CSA). The edge of the nerve and surrounding is not clear. The hyperechoic rim of 
epineurium is not clearly identified. Fascicles are not well visualized.
Only CIDP patients enrolled in Italian centres will undergo US examination coupled with 
neurophysiology, as Italian sites already have nerve examination-trained ultra-sonographers. 
2. STUDY OBJECTIVES
2.1. Primary Objective
To assess the efficacy of I10E administered at a reduced maintenance dose, in sustaining CIDP 
response after an initial 6-month treatment in PRISM study.
2.2. Secondary Objective(s)
To assess the safety of I10E in this patient population.


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2.3. Exploratory Objective(s)
To assess a potential relationship between serum total IgG trough levels, biomarkers levels and 
clinical response, as assessed by neurological scales, in patients with CIDP.
To assess a potential relationship between US coupled to neurophysiology analysis of nerves and 
clinical responses, as assessed by neurological scales, in patients with CIDP (ancillary study in 
Italy only).
3. STUDY DESIGN
3.1. Design and Study Periods
This study is a phase III, international, multicentre, single-arm, open-label, prospective study. It is 
the extension of PRISM study I10E-1302.
Study periods are as follows:
3.1.1. Screening
Responder patients in PRISM I10E-1302 study will be asked to sign an informed consent for
PRISM 2 I10E-1306 study. Inclusion (see below) should occur on the same day or within 72 hours 
of the EOS visit of PRISM I10E-1302 study. 
3.1.2. Baseline
Baseline data are those obtained either during the EOS visit of PRISM I10E-1302 study or during 
the screening period of PRISM 2 I10E-1306 study, before inclusion. If multiple results are available 
for a given assessment, the most recent will be considered.
3.1.3. Inclusion
A patient is considered included once he/she receives first study drug administration in this 
extension study.
3.1.4. Treatment Period
Patients meeting all eligibility criteria will receive 1 dose of study drug at 0.5 g/kg over 1 to 
2 day(s), every 3 weeks (+/- 7 days) for a total of 16 doses. 
Investigators or Study Nurses will call patients 4 days (+/1 day) after the end of each study treatment 
course to document potential AEs and TAAEs (see Section 8.2.2).
Duration of the treatment period will be approximately 45 weeks.
3.1.5. Follow-up and End of Study
Three weeks after visit V16, patients will undergo an EOS visit. This visit corresponds to visit V17 
(Week 48).


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In the event of premature discontinuation of the study drug or patient withdrawal from the study, an 
EOS visit will be performed within 7 days and prior to administration of any other treatment for 
CIDP (see Section 8.2.5). The reason for premature study drug discontinuation / study withdrawal 
should be accurately documented, as well as the planned new treatment to be administered if any. 
The total duration of the study for a patient is approximately 48 weeks.
3.1.6. Relapsing Patients
A relapse is defined as one of the following conditions:
▪
Adjusted INCAT disability score increase by 1 point compared to baseline,
AND
Judging on the clinical examination and/or the neurological scales assessments, the 
Investigator considers change in patient's treatment is mandatory: increase in IVIg 
dosage, increase or initiation of a corticotherapy, immunosuppressive therapy, plasma 
exchange.
▪
Adjusted INCAT disability score increase by at least 2 points compared to baseline.
Relapsing patients will undergo the study assessments scheduled at the EOS visit within 7 days and 
prior to the administration of any other CIDP treatment. The patient will be then withdrawn from the 
study and treated at the discretion of his/her physician.
3.2. Endpoints
3.2.1. Primary Efficacy Endpoint:
The primary efficacy endpoint will be the responder rate at EOS visit.
Responders are defined as patients with either:
No change or decrease in the adjusted INCAT disability score and without any change in 
CIDP treatment between baseline and EOS visit. 
or
An increase by 1 point in the adjusted INCAT disability score without requirement of any
change in CIDP treatment between baseline and EOS visit.
3.2.2. Secondary Efficacy Endpoints:
Main secondary efficacy endpoints:
Change from baseline to 24 weeks (Visit V9) and EOS visit in the adjusted INCAT disability 
score.
Responder rate at 24 weeks (visit V9).
Time to relapse. 
Change from baseline to 24 weeks (Visit V9) and EOS visit in the following scores:
▪
Grip strength with the Martin Vigorimeter in both hands;
▪
Rasch-built Overall Disability Scale (R-ODS);


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▪
Medical Research Council (MRC) 12 muscles sum score (0 to 5) and Rasch-modified 
MRC (0 to 3).
Other secondary endpoints:
Percentage of patients at 24 weeks (Visit V9) and EOS visit with no requirement of change 
in CIDP treatment from baseline.
Change from baseline to 24 weeks (Visit V9) and EOS visit in Patient and Investigator 
Clinical Global Impression (CGI).
3.2.3. Safety Endpoints:
Safety will be evaluated by the assessment of treatment-emergent adverse events (TEAEs) and 
temporally-associated AEs (TAAEs) – including SAEs – from first study drug administration to the
EOS visit, as well as by assessment of clinically significant changes from baseline in vital signs and 
laboratory tests.
3.2.4. Exploratory Endpoints:
The following exploratory endpoints will be considered:
Biomarker study:
Anti-CNTN1 and anti-NF155 antibodies titers at EOS visit.
B cell activating factor (BAFF) and complement components (C3 and C4 antigens, CH50) 
at EOS visit.
Serum total IgG trough levels at each visit, within 24 hours prior to study drug
administration.
Ancillary study: Italian sites only:
Change from baseline to EOS visit in nerve conduction velocities, distal latencies, amplitude of 
the negative phase of compound muscle action potentials and F wave for the following peripheral 
nerves: median nerve, ulnar nerve and deep fibular nerve (F wave assessed on ulnar nerve only).
Change from baseline to EOS visit in nerve maximal/minimal cross section area (CSA), intra-
nerve and inter-nerve variability assessed by ultrasonography (USG) and USG immune-related 
classification (see Section 1.4.4. peripheral nerve ultrasonography), in the following peripheral 
nerves: median nerve, ulnar nerve, fibular nerve and sural nerve.
3.3. Study Investigational Sites(s)
This study will be conducted in approximately 22 recognised referral and/or specialist centres and/or 
centres of expertise for neuromuscular diseases or peripheral neuropathies in France, Italy, Spain, 
Tunisia, Turkey, the United Kingdom and Poland. All of them would have participated in PRISM 
I10E-1302 study.
3.4 Data and Safety Monitoring Board / Steering Committee
No DSMB will be set up for this study for the following reasons:


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IVIgs are used in current medical practice in this indication with a favourable benefice-to-
risk ratio. 
Investigators selected in this study have established competence in the treatment of CIDP, 
in particular in the use of IVIg for this indication and work in renowned reference centres.
Previous human experience with I10E showed a comparable safety profile than with other 
IVIgs.
Neither interim analysis nor arbitration on study continuation or early termination or 
redesign is planned. 
3.5 Scientific Committee
A scientific committee will be set up for the following activities:
Protocol review
Participation in the Investigator’s meeting, including training of investigators on specific scales 
and evaluations used in this protocol.
Medical support for medical data review if needed.
Its membership is the following:
Prof. Eduardo Nobile-Orazio, MD, PhD, Prof. of  Neurology (Italy)
Prof. Richard Hughes, MD, FRCP, Emeritus Prof. of  Neurology (United Kingdom)
Prof. Isabel Illa, MD, PhD, Prof. of  Neurology (Spain)
Prof. Jean-Marc Léger, MD, Co-Chair National Referral Center for rare neuromuscular 
diseases (France)
Prof. Jean-Marie Grouin, PhD, Associate Professor in Statistics (France)
Prof. Luca Padua, MD, PhD, Prof of Neurology and Ultrasonography (Italy)
Dr. Ingemar Merkies, MD, PhD, Neurologist- Clinimetrician (The Netherlands)
4. DURATION AND DATES OF THE STUDY
The FPI is planned in Q4 2015 and the LPO is planned in Q4 2018.
5. STUDY POPULATION
5.1. Number of Patients
The target number of included patients in PRISM I10E-1302 study is 42, ensuring 38 evaluable 
patients (around one third of all patients will be either Ig-naïve or relapsing Ig-pretreated).
The number of patients included in this study depends on the number of responders in the I10E-1302 
trial willing to participate in the extension study. Estimated to be between 15 and 30 patients. Thus, 
no formal sample size calculation is done.
5.2. Eligibility Criteria
Before any study-related procedure is undertaken, written informed consent must be obtained (see 
Section 8.1.1)


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A patient is eligible if all the inclusion criteria and none of the exclusion criteria are met.
5.2.1. Inclusion Criteria
1.
Male or female patient aged 18 years or more.
2.
Responder patient who have completed the last visit of PRISM I10E-1302 study defined as 
a patient with a decrease 1 point in the adjusted INCAT disability score between baseline 
and the end-of-study (EOS) visit of PRISM I10E-1302 study.
3.
Covered by national healthcare insurance system as required by local regulations.
4.
Written informed consent obtained prior to any study-related procedures.
5.2.2. Exclusion Criteria
Based on follow-up and results of analyses performed in PRISM I10E-1302 study: 
1. History of severe allergic reaction or serious adverse reaction to any Ig.
2. Known hypersensitivity to human Ig or to any of the excipients of I10E (glycine and 
polysorbate 80).
3. History of cardiac insufficiency (NYHA III/IV), uncontrolled cardiac arrhythmia, unstable 
ischemic heart disease, or uncontrolled hypertension.
4. History of venous thromboembolic disease, myocardial infarction or cerebrovascular 
accident.
5. Risk factor for blood hyperviscosity such as cryoglobulinemia or haematological malignancy 
with monoclonal gammopathy.
6. History of personal or familial congenital thrombophilia or acquired thrombophilia.
7. Factors contributing to venous stasis such as long-term bed confinement.
8. Body Mass Index (BMI) 40 kg/m².
9. Protein-losing enteropathy characterised by total serum protein level 60 g/L and serum 
albumin levels 30 g/L.
10. History of kidney transplantation, nephrotic syndrome (defined as proteinuria 3.5 g per 
24 hours accompanied by hypoalbuminemia and edema), or any acute or chronic kidney 
disease that in the opinion of the investigator and/or nephrologist would preclude the use of 
I10E and/or interfere with the assessment of the safety and efficacy of I10E.
AND/OR
Chronic kidney disease (CKD) for more than 3 months as documented by at least one of the 
following:


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▪
glomerular filtration rate (GFR) 60 mL/min/1.73m2 measured according to the 
Modified Diet in Renal Disease (MDRD) formula
AND/OR
▪
urine protein reagent strip: 2 crosses
AND/OR
▪
urine protein reagent strip: one cross with one of the following:
o
albumin excretion rate (AER) 300 mg/24 hours or protein excretion rate 
(PER) 500 mg/24 hours (24h-urine collection)
OR
o
albumin to creatinine ratio (ACR) 30 mg/mmol or protein to creatinine ratio 
(PCR) 50 mg/mmol (spot urine sample).
11. Serum levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST)
2 times upper limit of normal (ULN) range.
12. Any other ongoing disease that may cause chronic peripheral neuropathy, such as toxin 
exposure, dietary deficiency, uncontrolled diabetes, hyperthyroidism, cancer, systemic lupus 
erythematosus or other connective tissue diseases, infection with HIV, Hepatitis B Virus 
(HBV) or Hepatitis C Virus (HCV), Lyme disease, multiple myeloma, Waldenström's 
macroglobulinaemia, amyloidosis, and hereditary neuropathy.
13. Woman with positive results on a urine pregnancy test or breastfeeding woman or woman of 
childbearing potential without an effective contraception.
Effective contraceptives are injectable, patch or oral combined oestro-progestative or 
progestative contraceptives, Copper T or levonorgest releasing intra-uterine devices, depot 
intramuscular medroxyprogesterone, subcutaneous progestative contraceptive implants, 
condoms or occlusive caps (diaphragm or cervical/vault caps) with spermicide, true 
abstinence (when this is in line with the preferred and usual lifestyle of the patient).
14. Any other serious medical condition that would interfere with the clinical assessment of 
CIDP or use of I10E or prevent the patient from complying with the protocol requirements.
15. Increasing dosage or introduction of a systemic corticosteroids therapy, or corticosteroids 
therapy at a dose higher than 10 mg prednisolone per day, or equivalent within the last 
3 months prior to screening (in I10E-1302 Clinical Study). Topical corticosteroids are 
permitted.
16. Treatment 
within 
12
months 
prior 
to 
screening 
with 
immunomodulatory 
or 
immunosuppressant agents (including but not limited to cyclophosphamide, cyclosporine, 
interferon-, 
interferon-1a, 
anti-CD20, 
alemtuzumab, 
aziathioprine, 
etanercept, 
mycophenolate mofetil and methotrexate) or haemopoetic stem cell transplantation.
17. Plasma exchange, blood products or derivatives administered within the last 3 months prior 
to screening.
18. Drug or alcohol abuse.


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19. Anticipated poor compliance of patient with study procedures.
5.3. Duration of Patient Participation
The total duration of the study for a patient is approximately 48 weeks.
5.4. Discontinuation Criteria / Stopping Rule(s)
All patients are free to withdraw from participation in this study at any time, for any reason, and 
without prejudice. The Investigator must withdraw from the study any patient who requests to stop 
participating in the study. Patients who withdraw their consent will be asked to undergo the study 
assessments scheduled at the EOS visit. They will be advised that participation to the EOS visit is 
voluntary but is their best interest.
The Investigator must discontinue study drug administration to a patient and perform an EOS visit at 
the request of the Sponsor or if the patient:
Experiences an AE - including a clinically significant laboratory abnormality -that justifies study 
drug premature discontinuation.
Undergoes protocol deviation that could endanger the patient safety.
Becomes pregnant.
Relapses.
Relapsing patients will undergo the study assessments scheduled at the EOS visit within 7 days and 
prior to the administration of any other CIDP treatment. The patient will be then withdrawn from the 
study and treated at the discretion of his/her physician.
If a patient is prematurely discontinued, the date, reason of discontinuation and any change in CIDP 
treatment will be documented. 
If a patient is withdrawn because of an AE, he/she will be followed up until complete resolution or 
stabilisation of the AE.
Patients lost to follow-up will be considered as discontinued from the study. A patient will be 
considered as lost to follow-up only after having exhausted all means of contact. Investigators must 
make every effort to contact the patient and/or his/her family or relatives to obtain the maximum of 
the per protocol requested information. All contact attempts should be documented in the patient’s 
medical records
6. STUDY DRUG AND CLINICAL SUPPLIES
6.1. Study drug
6.1.1. Description of Study Drug
The study drug is I10E.
I10E will be supplied, free of charge, by LFB BIOTECHNOLOGIES.


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6.1.1. 1. I10E (Study Drug)
Pharmaceutical form
I10E is a ready-to-use liquid human normal immunoglobulin preparation for IV administration 
(ATC Code: J06BA02). I10E is manufactured by LFB BIOMEDICAMENTS.
I10E contains 10% (100 mg/mL) of proteins, 98% at least of which are IgG. The other ingredients 
are glycine (18.8 mg/mL) and polysorbate 80 (0.05 mg/mL): these excipients have been chosen for 
their stabilising properties and good tolerance. 
I10E is produced by fractioning plasma proteins and then extracting and purifying 
immunoglobulins. 
More information is available in the Investigator’s Brochure of I10E.
6.1.1. 2. Packaging
The primary packaging of I10E is a sterile type-1 glass vial, sealed with a bromobutyl-rubber 
stopper. 
Each I10E box will contain one vial of human normal immunoglobulin 20g/200 mL or 10g/100mL.
6.1.1. 3. Labelling 
The study drug will be labelled individually. A system of tear-off labels will insure traceability. 
Labels will carry the following required regulatory texts. Each vial will be labelled with at least the 
following information:
Study LFB NO.I10E-1306
I10E - Human Normal Immunoglobulin - 100 mg/mL (vial : 20g/200mL or 10g/100mL)
Batch Number CLIXXXX
Use by date : MM/YYYY
Treatment Number: XXXX
Patient N°XX-XX (to be filled)
Investigator name (to be filled)
Infusion date (to be filled)
For intravenous use only
Solution for infusion
Storage requirements: according to the labelling
Protect from light, do not freeze
The standard caution statement:
Medicinal Product derived from human plasma
For clinical use only
For use under medical supervision
LFB BIOTECHNOLOGIES's name, address and phone number
Labels will be adapted to local requirements and translated into the local language when legally 
required.


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6.1.2. Management of Study Drug at Hospital Pharmacy
6.1.2. 1. Shipment and Study Drug Reception
Shipments of study drug to Hospital Pharmacy will be organised by the Sponsor's drug distributor at
controlled temperature according to the labelling.
Upon receipt, the Hospital Pharmacist will inventory the study drugs and complete the 
acknowledgement of receipt form which has to be returned to the drug distributor. Should any 
abnormality of the supply boxes be observed, the Hospital Pharmacist must immediately inform the 
drug distributor. 
Re-supply of the sites with study drug will be organised as necessary by the drug distributor upon 
Pharmacist's request. 
6.1.2. 2. Study Drug Storage
The Hospital Pharmacist will be responsible for the appropriate storage of the study drug at the 
study site.
Study drug must be stored in a safe and locked place according to the storage temperature 
requirements with no access by unauthorized personnel.
I10E must be stored under controlled and monitored temperature. I10E must be protected from light 
(kept in their boxes) and must not be frozen.
The Hospital Pharmacist must immediately inform the Monitor of any non-respect of the required 
storage conditions. Any temperature deviation must be reported within 1 working day to the 
Sponsor, using a temperature deviation form. The official written approval for the use of treatment 
must be obtained from the Sponsor prior to any dispensation/administration. In the meantime, study 
drug under temperature deviation should be placed under quarantine at controlled temperature as per 
the labelling. In case of decision to not use the study drug, the vials will be stored under quarantine 
at ambient temperature until shipment back to the drug distributor.
6.1.2. 3. Preparation of Study Drug and Dispensing
The Investigator will write a prescription sheet (on a quadruplicate No Carbon Required (NCR) 
paper) prior to the first infusion of each treatment course. The original prescription sheet, the 2nd 
and the 3rd NCR copy will be sent to the Hospital Pharmacist. The 4th will be kept in the 
Investigator site file. 
The prescription will give the following information:
Study LFB BIOTECHNOLOGIES I10E-1306
Patient identification: Patient number 
Patient weight (in kg)
Infusion dosage (in mL)
Planned infusion(s) date(s).


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The Hospital Pharmacist will prepare the study drug for the infusions, according to the infusion 
dosage indicated in the prescription. The product should be at room or body temperature before it is 
administered to the patient. Prior to transfer, study drug will be checked for cloudiness, colour, 
soapy solution or deposits. If it does not conform to the description, the study drug must not be 
dispensed and the Hospital Pharmacist should immediately alert the Monitor.
For each study vial that is to be dispensed for infusion, the Hospital Pharmacist will stick one tear-
off label on the prescription sheet (original), which will be filled in the Pharmacy study file for 
traceability purposes.
6.1.2. 4. Study Drug Return, Destruction and Recall
When closing the investigational site, all used and unused study drug vials, including empty vials, 
must be returned to the Sponsor's drug distributor except in case of specific local regulatory 
requirements.
The Pharmacist must not destroy the used/unused study drugs without written authorisation from the 
Sponsor.
6.1.2. 4.1. Return
The return preparation of used/unused study drugs will be performed by the Hospital Pharmacist and 
the Monitor.
For French sites only, return will be organised by Sponsor's drug distributor. The person in charge of 
study drug at site level should fill in and send (e-mail or fax) to drug distributor the "Study Return 
Request Form" in which the Hospital Pharmacist will set a date and time for courier pick up. The 
Hospital Pharmacist or a delegate should be available at the predetermined date and time when the 
boxes will be collected from the investigational site.
For other countries, return will be arranged via the Monitors after obtaining the import authorisation 
from the French Competent Authority (ANSM). The Pharmacist should inform the Sponsor's drug 
distributor of the expected receipt date through "IMP Return Notification Form".
6.1.2. 4.2. Destruction
After complete reconciliation, consolidated destruction of returned and stored vials will be 
performed by drug distributor upon Sponsor's request.
In case of any on-site destruction required, site must obtain from LFB BIOTECHNOLOGIES a 
written authorisation for destruction which will be filed along with the certificate of destruction in 
the IMP section of the Pharmacy site file.
Destruction of infusion lines will be carried out by the centre under Investigator's responsibilities.
6.1.2. 4.3. Recall
The Sponsor or its representative and the Investigator/Hospital Pharmacist will inform each other of 
any suspected or identified study drug defect. Study drug must immediately be put in quarantine as 
per the storage temperature requirements and no further administration of the concerned batch(es) 
must be done until Sponsor’s instructions.


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The Monitor or the drug distributor will organize with the Investigator/Hospital Pharmacist the 
return of the concerned batch(es) as per the Sponsor return procedure. Depending on the study 
status, new batch(es) may be sent to the investigational site.
6.1.3. Administration of study drug to Patients
6.1.3. 1. Study drug dosage and Treatment Schedule
Patients will receive 16 doses of study drug at 0.5 g/kg over 1 to 2 day(s), every 3 weeks 
First course (visit 1) will take place on the same visit, or at least within 72 hours of PRISM I10E-
1302 study EOS visit (right after).
6.1.3. 2. Method of administration 
Before administration to a patient, the Investigator will check that the label corresponds to his/her 
prescription for the patient (study number, patient number, study drug dose). 
Study drug will be administered with an infusion pump. 
The infusion flow rate must be compliant with the Investigator’s Brochure of I10E.
For the first day of any study drug course, the initial flow rate will not exceed 0.5 mL/kg/h during 
the first 30 minutes. If well tolerated, the rate of administration may be increased up to 1 mL/kg/h 
during 30 minutes, then, at the Investigator's discretion, gradually increased up to 2, 4 and 
6 mL/kg/h as a maximum flow rate. In patients older than 65 years, the maximum infusion flow rate 
should be 2 mL/kg/h.
On the subsequent days of any study drug course, the flow rate is at the Investigator's discretion (up 
to 6 mL/kg/h except for patients older than 65 years for whom the maximum infusion flow rate 
should be 2 mL/kg/h).
6.1.3. 3. Traceability, Accountability and Documentation
Each study drug course should be documented in the patient's medical file, including doses, time and 
flow rate changes.
The prescribed dose, the date and time of administration and the exact dose administered will be 
recorded in the eCRF.
The Sponsor will provide specific forms for IMP accountability, which will be kept up-to-date by 
the Hospital Pharmacist throughout the study. At the end of the study, it must be possible to 
reconcile the number of study drugs sent by the drug distributor with the number of study drugs
delivered to patients and the number of unused study drugs.
6.1.3. 4. Compliance
Compliance with treatment is defined as dose(s) administered within 20% of the prescribed dose(s). 
Both prescribed and administered doses will be recorded in the eCRF.


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As the study drug will be administered only under the direct supervision of a physician familiar with 
the requirements of the study protocol, compliance should not be an issue. Nevertheless, the reason 
for any non-compliance must be recorded in the eCRF.
6.2. Medical Device
Infusion pump and perfusion lines will be provided by the Sponsor. 
7. PRIOR AND CONCOMITANT MEDICATION
7.1. Prior Medication
The term ‘prior medication’ refers to any medication given up to 8 months before study entry, i.e. 
2 months before informed consent is signed.
All relevant prior medications taken within 8 months prior to the study entry must be recorded in the 
patient’s medical file and documented on the appropriate pages of the CRF. Moreover, any prior 
medication taken more than 8 months prior to the study which is, in the opinion of the investigator, 
clinically relevant to the patient's condition will also be recorded.
The following prior medications are not allowed before patient inclusion because they could 
interfere with the assessment of study drug efficacy: 
Any other investigational product administered within a month prior to screening of PRISM 
I10E-1302 study.
Exposure to blood products or derivatives within 3 months prior to screening of PRISM I10E-
1302 study 
Immunomodulators/immunosuppressors agents (including but not limiting to cyclophosphamide, 
cyclosporine, interferon-, interferon-1a, anti-CD20, alemtuzumab, aziathioprine, etanercept, 
mycophenolate mofetil and methotrexate) or haemopoetic stem cell transplantation. administered
during the last 12 months prior to screening of PRISM I10E-1302 study.
Systemic corticosteroids therapy, if administered with an increasing dosage or introduced, or 
administered at a dose higher than 10 mg prednisolone per day, or equivalent within the last 3 
months prior to screening of PRISM I10E-1302 study. Topical corticosteroids are permitted. 
Loop diuretics administered during the last 24 hours hours before IVIg infusion planned date. In 
this case, the study drug infusion date will have to be postponed.
Study drug at another dosage than planned in this study: 0.5 g/kg.
7.2. Concomitant Medication
The term ‘concomitant medication’ refers to any medication that the patient receives at any time 
during the study, i.e. from screening to EOS visit. This includes the screening/baseline period, 
treatment period and follow-up as defined in the protocol. At each visit, the Investigator will ask the 
patient about any medication taken since the last visit. All concomitant medication must be recorded 
in the patient’s medical file and documented on the appropriate pages of the eCRF. 
Treatments not allowed during the study are the following:
Plasma exchange, blood products or derivatives other than the study drug.


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Immunomodulators/immunosuppressors 
agents 
(e.g. 
including
but 
not 
limited 
to 
cyclophosphamide, cyclosporine, interferon-, interferon-1a, anti-CD20, alemtuzumab, 
aziathioprine, etanercept, mycophenolate mofetil, methotrexate and haemotopoeitic stem cell 
transplantation).
Introduction or increasing dose of systemic corticosteroids therapy, and/or systemic 
corticosteroids therapy at a dose higher than 10 mg prednisolone per day, or equivalent. Topical 
corticosteroids are permitted.
Loop diuretics administered during the last 24 hours hours before IVIg infusion planned date. In 
this case, the study drug infusion date will have to be postponed.
Routine pre-medication (to prevent known drug related adverse reaction) are not recommended to 
avoid masking potential AEs. However, patients who have routinely been receiving pre-medication
with previous Ig treatments may continue to receive the same pre-medication. 
Other medications which are necessary for the patient’s welfare or well-being may be given at the 
discretion of the Investigator.
All concomitant medications must be recorded in the patient’s medical records and documented on 
the appropriate pages of the eCRF.
8. STUDY PLAN
The method for assessing each study parameter is described in Section 10.
See also table 1: flow chart.
8.1. Patient recruitment
8.1.1. Informed Consent
The Investigator provides each patient with relevant, comprehensive, verbal and written information 
regarding the objectives and procedures of the study, as well as the possible risks involved. A patient 
information sheet will be given to the patient.
The patient should have enough time and opportunity to inquire about study details. All his/her 
questions should be answered in a satisfactory manner. The patient must be informed about his/her 
right to withdraw from the study at any time. 
Signed informed consent must be obtained from the patient prior to undertaking any study-related 
procedure and before a blood sample is taken for the screening tests. 
One original of the informed consent form, signed and dated by both the patient and the Investigator, 
will be given to the patient. A second original is filed at the Investigator’s site. The process of 
obtaining consent will be documented in the patient’s file. 


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8.1.2. Screening
Patients who have completed PRISM I10E-1302 study (i.e. responders, defined as patients with a 
decrease 1 point in the adjusted INCAT disability score between baseline and EOS visit) will be 
invited to participate in PRISM 2 I10E-1306 study and asked to sign an informed consent. Inclusion 
(see below) should occur on the same day, or at least within 72 hours of the EOS visit of PRISM 
I10E-1302 study. 
8.1.3. Patient Allocation
Patient numbers will be composed of 4 digits numbers as shown here below:
|__|__| - |__|__| 
Site        - screeningI10E-1302 -
Patients will keep the same patient number they had in PRISM-I10E1302 study.
Assigned by the 
Investigator
Assigned by 
the Sponsor


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Figure 8–1: Sequence of study procedures
* ultrasonography coupled to electrophysiology (only for italian sites).


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8.2. Sequence of Study Procedures
8.2.1. Visit 1: Week 0 (first study drug course) 
Visit 1 will occur on the same day of inclusion, which is on the same day of the last visit of PRISM 
I10E-1302 study or at least within 72h of the last visit of PRISM-I10E study.
The following study procedure will be carried out at the 1st Study drug course:
Before the 1st study drug course (within 24 hours before study drug course)
The following assessments may be performed as part of the visit of PRISM study.
Informed consent signature
Check of inclusion and exclusion criteria.
Demographic and biometric information (gender, age, weight, BMI).
Relevant medical history and ongoing concomitant diseases.
Listing of prior medications.
Complete physical examination.
Vital signs: temperature, heart rate, systolic and diastolic blood pressure.
Neurological status assessment: 
▪
INCAT disability score (adjusted INCAT disability score will be deduced from reported 
values).
▪
Patient and Investigator Clinical Global Impression-Severity (CGI-S), Clinical Global 
Impression-Efficacy (CGI-E) and Clinical Global Impression-Improvement (CGI-I).
▪
MRC sum score. 
▪
Rasch-modified MRC sum score.
▪
R-ODS.
▪
Grip strength with Martin vigorimeter in both hands.
Biological tests in local laboratory:
▪
Haematology: 
▪
Complete blood count + differentials, haemoglobin (Hb), mean corpuscular volume 
(MCV), platelets count.
▪
Haptoglobin.
▪
Reticulocytes, direct Coombs test.

Biochemistry:
▪
Creatininemia, glomerular filtration rate according to MDRD.
▪
LDH.
▪
Total and free bilirubin. (total bilirubin in all patients; if total bilirubin >ULN, free 
bilirubin will be assessed from the same blood sample, as total bilirubin).
▪
AST, ALT, ALP, GT.
▪
Total serum protein level
▪
C3 and C4 antigens.
▪
Serum total IgG trough levels 
▪
HBs Ag, anti HBs & anti HBc antibodies, HIV, HCV tests.


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▪
Serum reference sample for long term storage.
▪
Urine protein reagent strip test [to be performed in patients who at screening in the I10E-
1302 Clinical Study tested for urine protein reagent strip result "1 cross 1 (+)" and/or 
had GFR in the range of  60-80 mL/min/1.73m2]:
If urine protein reagent strip test result
= Negative or Trace
Action: No further urine test required
If urine protein reagent strip test result
= 1 cross (1 +) or more
Action: Assess either AER or PER from a 24h-urine collection sampled at least 7 days 
after the end of the previous study drug course
or assess ACR or PCR from a spot urine sample immediately following the urine 
protein reagent strip test (i.e. urine obtained before study drug administration).
The Investigator must review these results in time prior to the study drug 
administration and consider if any of the Early Discontinuation Criteria / Stopping 
Rules (see Section 5.4) apply.
▪
Urine pregnancy test for female patients of child bearing potential.

Analysis at centralised laboratory: 
▪
BAFF.
▪
CH50.
▪
Anti-contactin 1 (CNTN1), anti-neurofascin (NF155) antibodies.

Ultrasonography coupled to neurophysiology (for Italian sites only)

AEs assessment.

Listing of concomitant treatments.

Delivery of Patient diary with instructions for use. The patient should document in the diary 
any AE that occurs outside of hospital (including start and end date and time) and any 
medication taken during the study. The patient should come back at each visit with the diary 
and the Investigator should assess and evaluate patient information recorded in the diary and 
report appropriate relevant information in the eCRF.
Abnormal findings at V1 physical and biological tests should be reported as baseline 
findings in patient medical history. All clinical or laboratory abnormalities other than those 
found on mandatory study screening tests should be reported as an adverse event if clinically 
significant.
During the course of study drug infusion:
▪
Collection of infusion parameters.
▪
Vital signs measured 30-45 min and 60-75 min after the beginning of the infusion: 
temperature, heart rate, systolic and diastolic blood pressure.
▪
Listing of concomitant medication if applicable.
▪
AE assessment.
30-45 min after the end of study drug infusion:
▪
Vital signs: temperature, heart rate, systolic and diastolic blood pressure.
▪
Listing of concomitant medication if applicable.
▪
AE assessment.


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Four days after the end of study drug administration (+/-1 day): the Investigator or the Study Nurse 
will call the patient in order to collect information about the possible occurrence of AEs after the 
patient has left the hospital. 
8.2.2. Visits 2 to 8: Weeks 3 to 21 (+/- 7 days)
The following study procedure will be carried out:
Before study drug course (within 24 hours before study drug course)
Clinical examination focused on arterial or venous thrombo-embolic signs.
Biometric information (weight).
Vital signs: temperature, heart rate, systolic and diastolic blood pressure.
Neurological status assessment: 
INCAT disability score (adjusted INCAT disability score will be deduced from reported 
values).
Biological tests in local laboratory:
Haematology: 
▪
Complete blood count + differentials, Hb, MCV, platelets count.
▪
Haptoglobin.
Biochemistry:
▪
Creatininemia, glomerular filtration rate according to MDRD.
▪
LDH.
▪
Total and free bilirubin (total bilirubin in all patients; if total bilirubin ULN, free 
bilirubin will be assessed from the same blood sample, as total bilirubin).
Serum total IgG trough levels 
Urine protein reagent strip test [to be performed in patients who at screening in the I10E-
1302 Clinical Study tested for urine protein reagent strip result "1 cross 1 (+)" and/or had 
GFR in the range of 60-80 mL/min/1.73m2]:
If urine protein reagent strip test result
= Negative or Trace
Action: No further urine test required
If urine protein reagent strip test result
= 1 cross (1 +) or more
Action: Assess either AER or PER from a 24h-urine collection sampled at least 7 days 
after the end of the previous study drug course
or assess ACR or PCR from a spot urine sample immediately following the urine 
protein reagent strip test (i.e. urine obtained before study drug administration).
The Investigator must review these results in time prior to the study drug 
administration and consider if any of the Early Discontinuation Criteria / Stopping 
Rules (see Section 5.4) apply.
AEs assessment.
Listing of concomitant treatments.
Patient diary verification. If information on the patient’s diary is not clear, the Investigator will 
ask the patient questions. The Investigator may annotate the patient’s diary but must date 
and sign the annotations.


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During the course of study drug infusion:
▪
Collection of infusion parameters.
▪
Vital signs measured 30-45 min and 60-75 min after the beginning of the infusion:
temperature, heart rate, systolic and diastolic blood pressure.
▪
Listing of concomitant medication if applicable.
▪
AE assessment.
30-45 min after the end of study drug infusion:
▪
Vital signs: temperature, heart rate, systolic and diastolic blood pressure.
▪
Listing of concomitant medication if applicable.
▪
AE assessment.
Four days after the end of study drug administration (+/- 1 day): the Investigator or the Study Nurse 
will call the patient in order to collect information about the possible occurrence of AEs after the 
patient has left the hospital. 
8.2.3. Visits 9: Weeks 24 (+/- 7 days)
The following study procedure will be carried out:
Before study drug course (within 24 hours before study drug course)
Complete physical examination.
Biometric information (weight).
Vital signs: temperature, heart rate, systolic and diastolic blood pressure.
Neurological status assessment: 
▪
INCAT disability score (adjusted INCAT disability score will be deduced from reported 
values).
▪
Patient and Investigator Clinical Global Impression-Severity (CGI-S), Clinical Global 
Impression-Efficacy (CGI-E) and Clinical Global Impression-Improvement (CGI-I).
▪
MRC sum score.
▪
Rasch-modified MRC sum score.
▪
R-ODS.
▪
Grip strength with Martin vigorimeter in both hands.
Biological tests in local laboratory:
Haematology: 
▪
Complete blood count + differentials, haemoglobin (Hb), mean corpuscular volume 
(MCV), platelets count.
▪
Haptoglobin.
▪
Reticulocytes, direct Coombs test.
Biochemistry:
▪
Creatininemia, glomerular filtration rate according to MDRD.
▪
LDH.
▪
Total and free bilirubin (total and free bilirubin (total bilirubin in all patients; if total 
bilirubin ULN, free bilirubin will be assessed from the same blood sample, as total 
bilirubin).


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Serum total IgG trough levels 
Urine protein reagent strip test [to be performed in patients who at screening in the I10E-
1302 Clinical Study tested for urine protein reagent strip result "1 cross 1 (+)" and/or had 
GFR in the range of 60-80 mL/min/1.73m2]:
If urine protein reagent strip test result
= Negative or Trace
Action: No further urine test required
If urine protein reagent strip test result
= 1 cross (1 +) or more
Action: Assess either AER or PER from a 24h-urine collection sampled at least 7 days 
after the end of the previous study drug course
or assess ACR or PCR from a spot urine sample immediately following the urine 
protein reagent strip test (i.e. urine obtained before study drug administration).
The Investigator must review these results in time prior to the study drug 
administration and consider if any of the Early Discontinuation Criteria / Stopping 
Rules (see Section 5.4) apply.
AEs assessment.
Listing of concomitant treatments.
Patient diary verification. If information on the patient’s diary is not clear, the Investigator will 
ask the patient questions. The Investigator may annotate the patient’s diary but must date and 
sign the annotations.
During the course of study drugs infusion:
▪
Collection of infusion parameters.
▪
Vital signs measured 30-45 min and 60-75 min after the beginning of the infusion: 
temperature, heart rate, systolic and diastolic blood pressure.
▪
Listing of concomitant medication if applicable.
▪
AE assessment.
30-45 min after the end of study drug infusion:
▪
Vital signs: temperature, heart rate, systolic and diastolic blood pressure.
▪
Listing of concomitant medication if applicable.
▪
AE assessment.
Four days after the end of studyr drug administration (+/- 1 day): the Investigator or the Study Nurse 
will call the patient in order to collect information about the possible occurrence of AEs after the 
patient has left the hospital. 
8.2.4. Visit 10 to 16: Weeks 27 to 45 (+/- 7 days)
The following study procedure will be carried out:
Before study drug course (within 24 hours before study drug course)
Clinical examination focused on arterial or venous thrombo-embolic signs.
Biometric information (weight).
Vital signs: temperature, heart rate, systolic and diastolic blood pressure.
Neurological status assessment: 


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▪
INCAT disability score (adjusted INCAT disability score will be deduced from reported 
values).
Biological tests in local laboratory:
Haematology: 
▪
Complete blood count + differentials, Hb, MCV, platelets count.
▪
Haptoglobin.
Biochemistry:
▪
Creatininemia, glomerular filtration rate according to MDRD.
▪
LDH.
▪
Total and free bilirubin (total and free bilirubin (total bilirubin in all patients; if total 
bilirubin ULN, free bilirubin will be assessed from the same blood sample, as total 
bilirubin).
Serum total IgG trough levels.
Urine protein reagent strip test [to be performed in patients who at screening in I10E-1302 
Clinical Study tested for urine protein reagent strip result "1 cross 1 (+)" and/or had GFR in 
the range of 60-80 mL/min/1.73m2]:
If urine protein reagent strip test result
= Negative or Trace
Action: No further urine test required
If urine protein reagent strip test result
= 1 cross (1 +) or more
Action: Assess either AER or PER from a 24h-urine collection sampled at least 7 days 
after the end of the previous study drug course
or assess ACR or PCR from a spot urine sample immediately following the urine 
protein reagent strip test (i.e. urine obtained before study drug administration).
The Investigator must review these results in time prior to the study drug 
administration and consider if any of the Early Discontinuation Criteria / Stopping 
Rules (see Section 5.4) apply.
AEs assessment.
Listing of concomitant treatments.
Patient diary verification. If information on the patient’s diary is not clear, the Investigator will 
ask the patient questions. The Investigator may annotate the patient’s diary but must date 
and sign the annotations.
During the course of study drug infusion:
▪
Collection of infusion parameters.
▪
Vital signs measured 30-45 min and 60-75 min after the beginning fo the infusion:
temperature, heart rate, systolic and diastolic blood pressure.
▪
Listing of concomitant medication if applicable.
▪
AE assessment.
30-45 min after the end of study drug infusion:
▪
Vital signs: temperature, heart rate, systolic and diastolic blood pressure.
▪
Listing of concomitant medication if applicable.
▪
AE assessment.


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Four days after the end of study drug administration (+/- 1 day): the Investigator or the Study Nurse 
will call the patient in order to collect information about the possible occurrence of AEs after the 
patient has left the hospital. 
8.2.5. Visit 17: Week 48 (+/- 7 days) – End of study visit
At the end of the follow-up period, patients undergo an end of study visit evaluation. In the event of 
premature discontinuation from the study drug or patient withdrawal from the study, an end of study 
visit is performed anyway within 72 hours.
The end of study assessment should be performed before any other treatment including Igs is 
administered.
The reason for premature studyr drug discontinuation / study withdrawal should be accurately 
assessed and entered into the eCRF.
The following study procedure will be carried out:
Complete physical examination.
Vital signs: temperature, heart rate, systolic and diastolic blood pressure.
Neurological status assessment: 
▪
INCAT disability score (adjusted INCAT disability score will be deduced from reported 
values).
▪
Patient and Investigator Clinical Global Impression-Severity (CGI-S), Clinical Global 
Impression-Efficacy (CGI-E) and Clinical Global Impression-Improvement (CGI-I).
▪
MRC sum score. 
▪
Rasch-modified MRC sum score.
▪
R-ODS.
▪
Grip strength with Martin vigorimeter in both hands.
Biological tests in local laboratory:
Haematology: 
▪
Complete blood count + differentials, haemoglobin (Hb), mean corpuscular volume 
(MCV), platelets count.
▪
Haptoglobin.
▪
Reticulocytes, direct Coombs test.
Biochemistry:
▪
Creatininemia, glomerular filtration rate according to MDRD.
▪
LDH.
▪
Total and free bilirubin (total bilirubin in all patients; if total bilirubin ULN, free 
bilirubin will be assessed from the same blood sample, as total bilirubin).
▪
AST, ALT, ALP, GT.
▪
Total serum protein level
C3 and C4 antigens.
Total serum IgG trough levels 


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HBs Ag, anti HBs & anti HBc antibodies, HIV, HCV tests.
▪
Serum reference sample for long term storage.
Urine protein reagent strip test [to be performed in patients who at screening in I10E-1302 
Clinical Study tested for urine protein reagent strip result "1 cross 1 (+)" and/or had GFR in 
the range of 60-80 mL/min/1.73m2]:
If urine protein reagent strip test result
= Negative or Trace
Action: No further urine test required
If urine protein reagent strip test result
= 1 cross (1 +) or more
Action: Assess either AER or PER from a 24h-urine collection sampled at least 7 days 
after the end of the previous study drug course
or assess ACR or PCR from a spot urine sample immediately following the urine 
protein reagent strip test (i.e. urine obtained before study drug administration).
Analysis at centralised laboratory: 
▪
BAFF.
▪
CH50.
▪
Anti-contactin 1 (CNTN1), anti-neurofascin (NF155) antibodies.
Ultrasonography coupled to neurophysiology (for Italian sites only)
AEs assessment.
Listing of concomitant treatments.
Patient diary verification. If information on the patient’s diary is not clear, the Investigator will 
ask the patient questions. The Investigator may annotate the patient’s diary but must date and 
sign the annotations.
8.3. At any course:
In case of suspected thrombus: D-Dimers testing will be performed.
In case of suspected haemolysis based on biological tests [Hb, haptoglobin, LDH, total and free 
bilirubin levels (total bilirubin in all patients; if total bilirubin ULN, free bilirubin will be assessed 
from the same blood sample, as total bilirubin)]: Reticulocytes and direct Coombs test will be 
performed.
8.4. Central Biological Handling Sampling
Details for blood sampling performed for the biomarkers (anti-CNTN1, anti-NF155 antibodies, 
BAFF, CH50), storage and shipment to the central laboratory are described in the laboratory 
manual.
8.5. Ultrasonography (for Italian site only)
Details for ultrasonography coupled to neurophysiology examination are described in the 
ultrasonography manual.


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8.6. Compliance with the Study Plan
The Investigator should make every effort to comply with the study plan. If the Investigator 
encounters difficulties in complying with the study plan, e.g. with regard to the schedule of visits or 
the required procedures, he/she must alert the Sponsor. The Sponsor may consider it relevant to 
generate an amendment. 
The Investigator should make every effort to avoid the occurrence of deviations from the study plan. 
If deviations occur or if the Investigator knows that a deviation will occur, he/she must promptly 
inform the Sponsor to determine how to manage the deviation.
9. SAFETY
9.1. Reference Safety Information Document
The current version of the Investigator Brochure of I10E, will be the Reference Safety Information 
document to assess the expectedness of AEs. 
9.2. Benefit / Risk Information
9.2.1. Potential Risk(s) Related to the Study Drug
Common and important adverse reactions associated with IVIg administration are described in the 
European Guideline EMA/CHMP/BPWP/94038/2007 rev.4 of IVIg [18].
Adverse reactions such as chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, 
arthralgia, low blood pressure and moderate low back pain may occur occasionally with IVIg.
Rarely human normal Ig may cause a sudden fall in blood pressure and, in isolated cases, 
anaphylactic reaction, even when the patient has shown no hypersensitivity to previous 
administration.
Cases of reversible aseptic meningitis and rare cases of transient cutaneous reactions have been 
observed with human normal immunoglobulin. Reversible haemolytic reactions have been observed 
in patients, especially those with blood groups A, B, and AB. Rarely, haemolytic anaemia requiring 
transfusion may develop after high dose IVIg treatment.
Increase in serum creatinine level and/or acute renal failure have been observed.
Very rarely, thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, 
deep vein thromboses have been described.
Important potential risks that could be anticipated with I10E administration are those known with 
IVIg preparations:
Hypersensitivity
True hypersensitivity reactions are rare. They can occur in patients with anti-IgA antibodies.


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Rarely, human normal immunoglobulins can induce a fall in blood pressure with anaphylactic 
reaction, even in patients who had tolerated previous treatment with human normal 
immunoglobulins.
To minimize risk of anaphylactic reactions, patients with IgA deficiency will be excluded, except if 
the absence of anti-IgA antibodies is documented. The patients with a known hypersensitivity to the 
active substance or to any of the excipients of I10E will be excluded. 
Thromboembolism
There is clinical evidence of an association between IVIg administration and thromboembolic events 
such as myocardial infarction, cerebral vascular accident (including stroke), pulmonary embolism 
and deep vein thromboses. Such an association is assumed to be related to a relative increase in 
blood viscosity through the high influx of immunoglobulins in at-risk patients. 
To minimize the risk of thrombo-embolic events, patients with a history of venous thrombo-embolic 
disease, myocardial infarction or cerebrovascular accident will be excluded. As well, patients with 
uncontrolled cardiac arrhythmia and patients with unstable ischemic heart disease will not be 
allowed to participate to the study.
Acute renal failure
Cases of acute renal failure have been reported in patients receiving IVIg therapy. In most cases, risk
factors have been identified. These included pre-existing renal insufficiency, diabetes mellitus, 
hypovolaemia, overweight, concomitant nephrotoxic medicinal products and age over 65.
To minimize the risk of acute renal failure, patients with a chronic kidney disease (CKD) defined as 
abnormalities of kidney structure or function, present for 3 months, with implications for health, 
i.e. patients with persistent albuminuria category A3 and/or GFR 60 mL/min/1.73m2 (measured 
according to the MDRD calculation) [31] will be excluded. 
The use of loop diuretics is also not allowed if used within 24 hours prior to study drug
administration. 
Aseptic meningitis syndrome (AMS)
Aseptic meningitis syndrome has been reported to occur in association with IVIg treatment.
Discontinuation of IVIg treatment has resulted in remission of AMS within several days without 
sequelae. AMS may occur more frequently in association with high-dose of IVIgs.
Haemolytic anaemia
IVIg products can contain blood group antibodies which may act as haemolysins and induce in vivo 
coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction 
(Coombs’ test) and, rarely, haemolysis. Haemolytic anaemia can develop subsequent to IVIg 
therapy due to enhanced red blood cells (RBC) sequestration. 
Haptoglobin and LDH levels in patients will be assessed at every visit.
Interference with serological testing
After injection of immunoglobulin the transitory rise of various passively transferred antibodies in 
the patient’s blood may result in misleading positive results in serological testing.
Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D may interfere with some 
serological tests for red cell antibodies for example the direct antiglobulin test (DAT), direct 
Coombs’ test.


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Interaction with other medicinal products
I10E may impair the efficacy of live attenuated virus vaccines for a period of up to 3 months. In the 
case of measles, this impairment may persist for up to 1 year.
Transmissible agents
Despite dedicated effective measures to prevent infections resulting from the use of plasma-derived 
products including selection of donors, screening of individual donations and plasma pools, as well 
as effective manufacturing steps for the inactivation/removal of viruses, the risk of transmitting 
infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and 
other pathogens.
Patient serum reference samples will be drawn at the beginning and at the end of the study, and will
be kept for long term storage.
9.2.2. Potential Risks Related to the Study Procedures
Blood sampling will be performed during this study in order to monitor the safety. Although this 
procedure represents an inconvenience for the patient, it does not constitute an additional significant 
risk.
There is a minor risk of haematoma from intravenous infusion of the study drug and from drawing 
blood. Slight pain at the injection site, feeling light-headed, bruising and, exceptionally, infection as 
well as bleeding from the site of the puncture may occur.
9.3. Risk Minimisation Actions Throughout the Protocol
Some adverse drug reactions may be related to the infusion flow rate. Patients will be closely 
monitored and carefully observed for any symptoms throughout the infusion periods. In the case of 
AE, the infusion rate may be reduced or even stopped. Standard medical care should be 
implemented as necessary.
Potential complications will be avoided by ensuring that patients: 
have an adequate hydration status prior to infusions of the study drug;
are not sensitive to human normal Ig by initially infusing the product slowly, starting at 
0.5 mL/kg/h during the first 30 minutes;
are carefully monitored for any symptoms throughout the infusion period and 30-45 minutes after 
the end of each infusion. An additional phone call at 4 days (+/- 1 day) from the Investigator or 
the Study Nurse to the patient is planned to ask if AEs or TAAEs are reported within 72 hours 
after the end of each course;
Close Monitoring (vital signs, biological tests, haematological tests, physical examinations 
planed for each course to minimise these risks);
D-Dimers, in case of suspected thrombus;
Reticulocytes and Direct Coombs test, in case of haemolysis based on biological tests [Hb, 
haptoglobin, LDH, total and free bilirubin levels (total bilirubin in all patients; if total bilirubin 
ULN, free bilirubin will be assessed from the same blood sample, as total bilirubin)]. 


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9.3.1. Benefit/Risk Balance
I10E have been developed by LFB and manufactured from plasma pools which are EMA certified.
Marketing Authorization Application (MAA) was submitted in Intravenous Immunoglobulin (IVIg) 
Core Summary of Product Characteristics (SPC) indications through the Decentralized Procedure 
(DCP) in the following European Union Member States: Austria, Belgium, Czech Republic, 
Denmark, Finland, Germany, Greece, Hungary, Italy, Luxembourg, the Netherlands, Spain, 
Slovakia, Sweden, and the United Kingdom. The marketing authorization was obtained in the 
United Kingdom in August 2015, then in Denmark, Hungary, Germany, Belgium and Finland.
This study is designed according to the currently accepted scheme of the standard of care of CIDP, 
based on the clinical guideline (EFNS/PNS CIDP Guideline 2010, First revision) which is in line 
with European countries’ recommendations and the recommendations of EMA. IVIg are used in 
CIDP patients and have shown a favorable benefit/risk balance. I10E has already been assessed in 
two pivotal studies: I10E-0718 and I10E-0719, respectively in PID and ITP, in 100 patients. Both 
studies concluded to a comparable safety profile with IVIg preparation. The I10E doses 
recommended in this protocol will not exceed those used in current medical practice in this 
indication, in the before-mentioned clinical trials. Participation in the study is not expected to induce 
significant additional risk for patients. 
9.4. Alternative Therapeutic Management - Handling Emergencies
If allergic or anaphylactic-type reactions occur, the infusion must be stopped immediately and 
standard medical treatment must be implemented.
In case of misuse and/or overdose, appropriate corrective actions should be promptly undertaken
when possible. The patient should be followed-up until the assurance that no AE occurs is 
obtained.
9.5. Definition and Reporting of (Serious) Adverse Events
9.5.1. Definition of Adverse Event and Serious Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject to whom a 
medicinal product is administered. The occurrence does not have necessarily a causal relationship 
with the treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), any symptom or disease, whether new or exacerbated, 
temporally associated with the use of a medicinal product, whether or not related to the 
investigational drug product.
An AE, whether or not considered to be causally related to the investigational drug product, may be:
The deterioration of a pre-existing chronic disease or aggravation of a symptom or disease that 
was present at inclusion of the patient in the study.
A symptom or disease discovered after the start of the study even if it was probably present prior 
to the patient's inclusion.
Abnormal laboratory findings when they are considered as clinically significant by the 
Investigator. 


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In case a vital sign shows a clinically significant abnormality, an AE should be reported (or the 
abnormal vital sign should be linked to an already reported AE). A serious AE is an AE that, at any 
time, fulfils one or more of the following criteria:
results in death,
is life threatening (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 it were more severe),
requires in-patient hospitalisation or prolongation of existing hospitalisation - hospitalisation 
required by the study will not be considered as an AE,
results in persistent or significant disability/incapacity (substantial disruption of a person’s ability 
to carry out normal life functions),
is a congenital anomaly/birth defect,
is any important medical event that may not be immediately life threatening or result in death or 
hospitalisation but, based upon appropriate medical judgment, may endanger the patient or may 
require intervention to prevent one of the other outcomes listed in the definition above, and 
should also be reported in the same way as an SAE. Examples of such events are invasive or 
malignant cancers, intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation; or 
development of drug dependency or drug abuse.
Distinction should be made between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is based on the outcome or the action criteria described above, for example, 
nausea that persists for several hours may be considered as severe, but not as an SAE. On the 
contrary, a cardiovascular event that causes limited degree of disability may be considered as not 
severe but would be recorded as an SAE.
Events initially reported as an AE may become serious. For example, diarrhoea may become 
debilitating and require hospitalisation or prolongation of hospitalisation and is then reported as 
an SAE. 
Surgical intervention is not to be considered as a SAE but the medical condition requiring the 
surgery is to be reported as such.
If a medical condition known before the start of study treatment requires hospitalisation for 
planned surgical measures, it should not be considered as an AE. However, the medical condition 
should be reported in the medical history.
Occurrence of study drug misuse/abuse, overdose or drug dependency, whether or not associated 
to an adverse event, must be recorded, reported immediately to the Sponsor. 
9.5.2. Definition of Specific Events in the Study (if applicable) 
A worsening of the CIDP will not be regarded as an AE (or a SAE) and will be recorded in specific 
eCRF forms. These data will be analysed as part as the efficacy assessment.
9.5.3. Adverse Event Recording and Reporting
Period of (Serious) Adverse Event Data Collection:
In order to ensure complete safety data collection, recording and reporting, all (S)AEs occurring 
during the study, i.e. after signature of the Informed Consent, must be recorded, even if no study 
drug was administered. These include all AEs occurring, recurring, or worsening after the signature 


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of the informed consent. The period of observation for the study is from the screening visit to the
visit.
An AE occurring between signature of PRISM 2 Informed consent and first study drug 
administration will be considered as TEAE of PRISM - I10E-1302.
If the Investigator becomes aware, after that period, of any unusual safety information or any safety 
information that appears to be drug related involving a patient who had participated in the study, 
even after the patient completes the study, he/she should contact the sponsor to determine how it 
should be documented and reported.
Recording and Description of (Serious) Adverse Event:
All AEs occurring after signature of the informed consent until the visit will be recorded in the 
appropriate pages of eCRF, including AEs occurring during the screening period and before the first 
administration of study drug, other than baseline findings which will be recorded as medical history. 
Each individual AE is to be listed as a separate entry on the AE e-CRF form. The Investigator will 
provide information on dates of onset and resolution, seriousness, severity, frequency, action(s) 
taken with regard to corrective therapy or to the study drug, outcome and relationship to the study 
drug. The Investigator must report to the Sponsor or its designee all AEs that occur during the study 
from the time the written informed consent is given until the EOS visit or premature termination, 
regardless of their relationship to the study drug. Apart from AEs clinically observed by the 
Investigator, the patient will be given the opportunity to report AEs spontaneously. A general 
prompt will also be given to detect AEs, e.g. “Did you experience any illness or unusual symptom
since your last visit?”
Follow-up of Adverse Events:
All AEs or SAEs assessed as not related to study medication, including clinically significant 
laboratory tests or physical examination findings, must be followed until the event resolves, the 
condition stabilizes, the event is otherwise explained, or the final study visit occurs, whichever 
comes first. 
AEs or SAEs assessed as related to study drug will be followed for as long as necessary to 
adequately evaluate the subject’s safety, or until the event stabilizes, or the subject is lost to follow 
up. If resolved, a resolution date should be provided. 
The Investigator is responsible for ensuring that follow-up includes any supplemental investigations 
indicated to elucidate the nature and/or causality of the AE. This may include additional clinical 
laboratory testing or investigations, histopathological examinations, or consultation with other health 
care professionals as is practical.
If a patient is withdrawn from study due to safety reasons, he/she should be followed until the event 
disappears, is otherwise explained or the patient’s condition has stabilised.
Any patient who voluntarily withdraws from the study should be carefully questioned for the 
possible occurrence of an adverse event. Whenever possible, a patient should be followed through 
the last scheduled visit.


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If no follow-up information can be provided after all efforts and attempts, the Investigator must 
document the outcome as “unknown” and provide a justification.
9.5.4. Procedures for Reporting Serious Adverse Events, Pregnancy and
Overdose/Abuse/Misuse
9.5.4. 1. SAE
The Sponsor or its representative must be informed immediately, and no later than 24 hours, of 
receipt of the SAE information by the site.
If one or more seriousness criteria is fulfilled, the Investigator must promptly forward to the Sponsor 
or its representative a duly completed “SERIOUS ADVERSE EVENT NOTIFICATION FORM” 
provided by the Sponsor, even if the data are incomplete or if it is obvious that more data will be 
needed in order to draw any conclusions, but as soon as the minimum of following information is 
present: 
identification of the notifying person,
identification of the clinical study, 
identification of a patient (patient number and/or initials),
description of the SAE and relationship to the study drug.
After the initial SAE report, the Investigator is required to proactively follow each patient and to 
provide further information on the patient’s condition. The Investigator will ensure that follow-up 
includes any further investigations as may be indicated to elucidate the nature or the causality of the 
SAE. 
Supporting documentation (discharge summaries, all examinations carried out, etc.) will not be sent 
systematically, as all relevant information must appear and be summarized in the narrative of the 
SAE report. However, if judged important, the Investigator could send these documents or LFB 
could request them (all documents must be blinded with respect to the subject’s name). Any follow-
up information must be reported within the same timelines.
TIMEFRAME
“Initial” SAE form
“Follow-up” SAE form
IMMEDIATELY
and no later than 24 hours
as of awareness of the SAE
IMMEDIATELY
and no later than 24 hours
as of availability of essential follow-up information
FAX TRANSMISSION
The SAE reports should be faxed to the following fax number: +44 (1)7 92 52 57 20. The sites in 
Tunisia can use the e-mail address: MHGSafety@prahs.com.
In rare circumstances, when fax transmission is not possible, reporting by telephone is acceptable, 
but this should be followed with a completed “SERIOUS ADVERSE EVENT FORM” signed and 
faxed by the Investigator as soon as possible. 




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Clinical Research Physician
Witold MALYSZCZAK, MD
Phone number
+33 (0)1 69 82 17 14
E-mail address
malyszczakw@lfb.fr
Clinical Research Physician
Alain SADOUN, MD
Phone number
+33 (0)1 69 82 56 12
E-mail address
sadoun@lfb.fr
Location
LFB BIOTECHNOLOGIES
3, avenue des Tropiques, BP 40305
91958 Courtaboeuf Cedex
FRANCE 
10.
ASSESSMENT OF EFFICACY AND SAFETY
10.1.
Assessment of Efficacy
10.1.1.Primary Assessment
The INCAT disability score will be assessed by the Investigator at every visit throughout the study.
The adjusted INCAT disability score will be deduced from the reported values.
The INCAT disability score measures the disability of both upper and lower limbs, each with a score 
from 0 (normal) to 5 (maximal disability) [32]. The total score may vary from 0 to 10. The adjusted 
and original INCAT disability scales are presented in Appendices 20.1.1.and 20.1.2. 
10.1.2.Secondary Efficacy Assessments
Secondary assessments are:
▪
Grip strength with the Martin Vigorimeter in both hands;
▪
Rasch-built Overall Disability Scale (R-ODS);
▪
Medical Research Council (MRC) 12 muscles sum score (0 to 5) and Rasch-modified 
MRC (0 to 3).
▪
Patient and Investigator Clinical Global Impression (CGI).
Analyses and time of assessments are described in Section 12.9 Efficacy Analysis.
10.2.
Assessment of Safety
The Investigator will ensure that all the AEs occurring during the study are identified and 
documented in the eCRF. The identification of AEs may come from various sources:
The Investigator or nurse may clinically observe an AE in the patient at hospital.
The patient may spontaneously report an AE to Investigator or Nurse.


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From Baseline to EOS, the patient will have to document on a patient diary any AE that occurs 
outside the hospital. This diary will be verified at each visit by the investigator. The patient will 
be sensibilised to report carefully day and time of TAAEs.
At each visit the patient will be given a general prompt, e.g. “Did you experience any illness or 
unusual sign or symptom since your last visit?” in order to ensure that no AE has been forgotten.
Vitals signs, including systolic and diastolic blood pressures (mmHg), heart rate (beats/minute), 
and body temperature (°C) will be measured before each infusion, during infusion (30-45 min 
and 60-75 min after the infusion start) and 30-45 minutes after the end of infusion and will be 
recorded in the eCRF. Weight will also be recorded before each study drug course, as it is used to 
calculate the quantity of study drug to be infused. 
Biological tests will be performed at every visit. Clinically significant abnormality in physical 
examination or biological tests performed at the screening as per study protocol will be regarded 
as a medical history. 
The Investigator or a Study Nurse will call the patient 4 days after each treatment course in order 
to collect information about the possible occurrence of an AE after the patient has left the 
hospital. The purpose of this phone call is to ensure that all the temporally associated AEs 
(TAAEs) are tracked.
If a TAAE is reported by the patient during the phone call, the Investigator will ask the patient 
additional information at the next visit. If relevant; the Investigator will report the TAAE in the 
eCRF.
It is the responsibility of the Investigator to collect all the relevant information regarding identified 
AEs.
11.
DATA MANAGEMENT
11.1.
eCRF Completion Guidelines
The following is a general description of the eCRF completion guidelines for this study. For 
complete details please refer to the eCRF completion guidelines included in the eCRF.
11.1.1.Introduction
All of the information required to be reported to the Sponsor as per protocol will be transcribed in 
the eCRFs for each study patient. The eCRFs will be completed by the Investigator or any study 
centre staff designated by the Investigator. The access to the data at the clinical site will be restricted 
and monitored through the system software with its required log-in security procedures. The 
Investigator will be responsible for ensuring that data recorded in the eCRFs are complete, accurate 
and legible. All eCRFs should be filled in before review by the Monitor.
11.1.2.General Instructions
11.1.2. 1.Overview
eCRFs should be completed in English.


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All data will be recorded in the eCRFs. The eCRF is a web based application linked to a 
computerized system that allows creating, modifying, maintaining, archiving, retrieving, or 
transmitting data. 
Access to the eCRF must be limited to authorised individuals. In this way, each Investigator and 
each person, authorised to have access to the eCRF, will receive an individual user login and a 
unique password before the study start and after having completed a specific training. Different 
accesses will be limited according to individual profiles. Therefore individuals must only work 
under their own logins and passwords, and must not share these with others. The attributed password 
should be changed at the first log in.
Individual training:
It will be the responsibility of the Sponsor to organize an individual training and certification for all 
persons who will use the computerised system. In order to have their login and password, each 
person should perform this training.
All data in the eCRFs must come from and be consistent with the source documents - i.e. patient’s 
file or medical records - except the neurological scales which are performed for the specific purpose 
of the study and for which source data worsheets will be provided as source documents.
Source documents may therefore be:
The patient’s medical file
The nurse’s sheets
Laboratories results sheets
The patient’s diary
Specific worksheets provided for neurological scales assessment
Any other document issued in the routine practice of healthcare and providing information on the 
medical status of the patient.
Any discrepancy between data in the eCRF and those in the source documents should be 
documented by the Investigator through a query.
11.1.2. 2.Patient Identification
Patients will be identified on each page of the eCRF by their patient number: patient number will be 
composed of 4 digit numbers (see Section 8.1.3 Patient allocation). Patients with screening failure 
will have an eCRF completed.
11.1.2. 3.Confidentiality
Patient identity must be kept confidential and should not appear on any eCRF form or study-specific 
documents.
11.1.2. 4. eCRF Completion 
The Investigators should complete the eCRF as soon as possible (within 5 days) after each patient’s 
visit. The Investigator or the delegated study site staff will complete all applicable forms in the 
eCRF. All data should be completed and missing data will be documented.


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Specific instructions for completing the eCRF will be detailed in a specific guide.
11.1.2. 5. eCRF Completion in Case of Screening Failure or Premature Withdrawal
In case of a screening failure, the Investigator will complete the relevant forms of the eCRF, 
including AE page and concomitant medication page if applicable.
In case of a premature withdrawal after the first study drug course, all study data available up to the 
point of withdrawal must be recorded on the eCRF, as well as any new AE or modifications to 
existing AEs and/or concomitant medications. The assessment will also be completed.
11.1.2. 6. eCRF Corrections
To ensure and to protect the authenticity, the integrity and the confidentiality of electronic records 
an audit trail will be integrated to the eCRF. All entries and all changes will be tracked in an audit 
trail. The audit trail is a secure, computer-generated, time-stamped system which independently 
records the date and time of operator entries and actions that create, modify or delete electronic 
records.
11.2.
eCRF and Data Handling
Data management will be carried out by a Contract Research Organisation (CRO) from electronic-
based CRF and in accordance with Good Clinical Practices (GCP see ICH-E6).
Throughout the study, the data will be stored in servers located in the United States of America. All 
transfers will be validated. 
Helpdesk services for all investigators and staff will be available 16/24 hours and 5/7 days. Training 
will be provided to the investigators and staff.
The data handling documents, e.g. annotated eCRF, database structure, data entry manual, coding 
rules and computerized validation system, are defined in a Data Management Plan. 
The database and data entry screens will be created in software specifically designed for clinical 
data management in compliance with ICH-E6 requirements.
The tracking of the eCRF will be integrated to the computerized system. As soon as a patient has 
signed his informed consent, the Investigator will create the patient in the e-CRF and will complete 
the appropriate form(s).
The consistency of data will be checked by computerised programs and related queries will be 
generated for resolution by the Investigator. In case of abnormality, Electronic Data Clarification 
Forms (DCFs) will be generated through the eCRF platform for resolution by the Investigator.
Medical coding will be done using Medical Dictionary of Regulatory Activities (MedDRA) for all 
medical terms (medical history, AEs) and World Health Organisation (WHO) drug for all drug 
names (prior and concomitant medications).


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Quality controls to ensure the overall quality and consistency of the database and reconciliation of 
SAE reports with the Pharmacovigilance database will also be carried out.
At the end of the data handling process, a final data review meeting will be held in order to prepare 
the database lock. After database lock, data will be transferred into SAS format for the production of 
statistical analyses.
Data processing, from data capture through database lock, will be carried out in accordance with 
GCP-ICH-E6.
12.
STATISTICS
12.1.
Trial Objectives and Design
The design is an extension of PRISM-I10E-1302 study, phase III, International, multicentre, 
randomised, open study, prospective and descriptive study. The main objective is to assess the 
efficacy of I10E administered at a reduced maintenance dose, in sustaining CIDP patient’s response.
12.2.
Statistical Analysis Plan
The material of this section is the basis for the Statistical Analysis Plan (SAP) of the study. 
The detailed technical aspects of the statistical analyses will be provided in the SAP. The SAP will 
possibly take protocol amendments into account and adapt to unexpected issues raised by the trial 
running and/or data that affect planned analyses in the protocol. 
Any changes from the protocol will be discussed in the study report.
Prior to locking the database, a data review meeting will be planned in order to review individual 
data and validate the SAP.
12.3.
Sample Size Determination
The number of patients included in this study depends on the number of responders in PRISM-I10E-
1302 study willing to participate in the extension study. Estimated to be between 15 and 30 patients. 
Thus, no formal sample size calculation is done.
12.4.
Randomisation
Not applicable
12.5.
Protocol Deviations and Analysis Sets
All deviations from protocol definitions will be listed and defined as major or minor deviations in 
the SAP.
The definition of analysis sets is as follows:
Total Treated Set (TTS): all patients who received at least one administration of study drug. 


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Full Analysis Set (FAS): all TTS patients having an available assessment of the primary efficacy 
endpoint.
Per Protocol Set (PPS): all FAS patients without any major deviations from protocol.
The TTS will be used for the analysis of safety data.
The FAS will be used for the primary analysis of  efficacy  data and the PPS to test its robustness.
12.6.
General rules for Handling of Missing or Inconsistent Data
No general rules for the replacement of missing data are planned. Every effort should be made to 
collect the study parameters over the study period.
12.7.
Demographic and Baseline Characteristics
All baseline characteristics and baseline efficacy variables will be summarised using descriptive 
statistics. All summary tables will describe the variables according to their nature: 
Categorical variables (binary, nominal and ordinal) will be summarised by contingency tables 
(frequencies and percentage),
Quantitative variables will be summarised by their mean, standard deviation, median, minimum 
and maximum values.
12.7.1.Previous Treatments
All previous treatments will be classified using the ATC codes and summarised.
12.8.
Study drug and Concomitant Treatments
12.8.1.Extent of Exposure
The duration of treatment exposure will be assessed as from the first day of study drug
administration to the EOS assessment. 
The number of infusions, cumulative dose (g and g/kg), volume infused, duration of infusion and
infusion rate (initial rate and maximum rate) will be described using descriptive statistics. The 
treatment exposure will also be listed for each patient. 
12.8.2.Treatment Compliance
The following compliance criteria will be described:
Prescribed course dosage included in the ranges allowed by the protocol
Course frequency included in the ranges allowed by the protocol
Courses administered at each visit.
Ratio administered dose / prescribed dose within 20%.


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12.8.3.Concomitant Treatment
All concomitant treatments as defined in Section 7.2 Concomitant medication will be classified 
using the ATC codes and summarised. 
12.9.
Efficacy Analysis
12.9.1.Primary Efficacy Variable(s) 
12.9.1. 1.Description of the primary efficacy variable(s)
The primary efficacy endpoint will be the responder rate at EOS visit.
Responders are defined as patients with either:
No change or decrease in the adjusted INCAT disability score and without any change in CIDP 
treatment between baseline and EOS visit. 
or
An increase by 1 point in the adjusted INCAT disability score without requirement of any change 
in CIDP treatment between baseline and EOS visit.
If a patient is treated with a not-allowed treatment during the study period, then all efficacy variables 
measured after the intake of these not-allowed treatments will be censored for the efficacy analyses.
12.9.1. 2.Hypothesis Test and Primary Analysis Model
The responder rate and the exact Clopper-Pearson 95% confidence interval will be presented.
No statistical hypothesis test will be tested.
12.9.1. 3.Handling of Missing Data
The primary analysis of the primary variable will be done using the baseline and last available 
assessment of the adjusted INCAT disability score. If the score at EOS visit is missing, then the Last 
Observation Carried Forward (LOCF) approach will be applied and the last available adjusted 
INCAT disability score will replace the missing value at EOS visit.
12.9.1. 4.Prognostic Factors and Covariates
No prognostic factors will be used in the statistical model.
12.9.1. 5.Other Analyses for the Primary Variable(s)
The analysis of the primary variable will be repeated on the PPS as sensitivity analysis. 
Other sensitivity analyses might be defined in the SAP.


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12.9.2.Secondary Efficacy Variables
12.9.2. 1.Description of Secondary Efficacy Variables
Change from baseline to 24 weeks (Visit V9) and EOS visit in the adjusted INCAT disability 
score.
Responder rate at 24 weeks (visit V9).
Time to relapse. 
Change from baseline to 24 weeks (Visit V9) and EOS visit in the following scores:
▪
Grip strength with the Martin Vigorimeter in both hands;
▪
Rasch-built Overall Disability Scale (R-ODS);
▪
Medical Research Council (MRC) 12 muscles sum score (0 to 5) and Rasch-modified 
MRC (0 to 3).
Percentage of patients at 24 weeks (Visit V9) and EOS visit with no requirement of change in
CIDP treatment from baseline.
Change from baseline to 24 weeks (Visit V9) and EOS visit in Patient and Investigator Clinical 
Global Impression (CGI).
12.9.2. 2.Analysis of Secondary Efficacy Variables
All parameters as well as the change from baseline will be summarised using descriptive statistics at 
each visit.
If a patient is treated with a not-allowed treatment during the study period, then all adjusted INCAT 
disability scores measured after the intake of these not-allowed treatments will be censored for the 
efficacy analyses.
A LOCF approach will be used to handle the missing data of secondary endpoints. All details to 
handling of missing data will be provided in the SAP.
The 24-week and the EOS visit values will be compared to the baseline value.
The adjusted INCAT disability score will additionally be presented graphically over the patients’ 
follow-up during the study. 
12.10. Safety Analysis
12.10.1.
Adverse Events
All AE will be classified using MedDRA including Lowest Level Terms (LLT), Preferred Terms 
(PT) and System Organ Class (SOC).
TEAEs defined as AEs occurring after the start of the 1st study drug administration will be analysed. 
Other AEs will only be listed. An AE occurring between signature of PRISM 2 Informed consent 
and first study drug administration will be considered as TEAE of PRISM - I10E-1302.
The absolute number of TEAEs as well as the number of patients with at least one TEAE will be 
tabulated by SOC and PT. Patients with SAEs, drug-related AEs will be analysed by SOC and PT.


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The duration of the TEAE and the time between the last administration of study drug and the onset 
of the TEAE will be calculated.
TAAEs will be analysed by patients and infusions.
12.10.2.
Vital Signs
Vitals signs, including body temperature (in °C), heart rate (in beats/minute) and systolic and 
diastolic blood pressures (in mmHg) will be measured before each infusion, during infusion 
(30-45 min and 60-75 min after the beginning of infusion) and 30-45 minutes after the end of 
infusion for all visits. Descriptive statistics will be performed.
All abnormalities in vital signs, clinically significant or not, will be listed.  
12.10.3.
Laboratory Data
Laboratory data will be assessed at screening, before each study drug course, after the 1st study drug
course, and at the EOS visit. Shift tables will be produced by study drug courses and baseline. 
Descriptive statistics will be performed. All abnormalities, clinically significant or not, will be 
listed.
12.11. Exploratory Analysis
12.11.1.
Exploratory Variables
The following exploratory endpoints will be analysed:
Anti-CNTN1 and anti-NF155 antibodies titers at EOS visit. 
BAFF and complement components (C3 and C4 antigens, CH50) at EOS visit.
Serum total IgG trough levels at least 24 hours prior each study drug administration.
Change from baseline to EOS visit in nerve conduction velocities, distal latencies, amplitude of 
the negative phase of compound muscle action potentials and F wave for the following peripheral 
nerves: median nerve, ulnar nerve and deep fibular nerve (F wave assessed on ulnar nerve only).
Change from baseline to EOS visit in nerve maximal/minimal cross section area (CSA), intra-
nerve and inter-nerve variability and ultrasound (USG) immune-related classification (see 
Section 1.4.4. Peripheral nerve ultrasonography) in the following peripheral nerves: median 
nerve, ulnar nerve, fibular nerve and sural nerve.
All exploratory variables will be described in summary tables.
12.11.2.
Analysis of Exploratory Variables
All exploratory variables will be presented with descriptive statistics. The analysis of the 
relationship between these variables and clinical response will be detailed in the SAP.
13.
STUDY REPORT
A clinical study report will be prepared in accordance with the ICH-E3 guidelines by the Sponsor.


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Within 1 year after the end of the study, the Sponsor will provide the Health Authorities with the full 
study report or summary. Only the Sponsor is entitled to make the study report available to the 
Authorities.
Neither the complete report nor any part of the study report should be used without the approval of 
the Sponsor.
14.
CONFIDENTIALITY AND PUBLICATION
14.1.
Patient Confidentiality
Patient data will be kept strictly confidential and patient anonymity will be protected by using 
number codes.
The Sponsor or its representative(s) and the Health Authorities are obligated to respect medical 
secrecy and to refrain from divulging any personal patient information they might fortuitously be 
aware of.
14.2.
Use of Information
The Investigator shall not divulge unpublished data or information related to the study provided by 
the Sponsor, including but not limited to the study protocol, eCRFs, assay methods and scientific 
data, to any third party without written approval from the Sponsor.
In addition, any new information that may become available during the course of the study shall be 
considered as confidential and shall not be used for any purpose other than the performance of the 
clinical study.
The study data are the property of the Sponsor. The Investigator and any of the research staff shall 
obtain written approval from the Sponsor prior to the publication/communication of the results of 
any work carried out during or in relation to the study.
Publication and/or communication of the results of the clinical study will be of a cooperative nature 
involving authors representing the Sponsor, the Investigators and the scientific committee.
The Sponsor reserves the right to request modification of the content and/or timing of any 
publication or presentation if a patent application, an existing patent or other proprietary rights may 
be jeopardized.
Authorship of any publication related to the study and the order of presentation of the authors’ 
names shall be approved by the Sponsor. The Sponsor shall not use an Investigator’s name in any 
publication without his/her written permission and vice versa.
15.
ARCHIVING
The Investigators should retain all essential study-related documents, i.e. documents which permit 
evaluation of the conduct of a study and the quality of the data produced, in accordance with the 
applicable regulatory requirements of his/her country. These essential documents include but are not 


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limited to signed protocol, eCRFs, medical records, laboratory reports, informed consent forms, 
drug disposition records, safety reports, information regarding participants who discontinued, and 
other relevant documents and data.
The study-related documents should be kept together in the Investigator site file provided to the 
Investigator by the Sponsor.
Sufficient information about the identity of all study patients, e.g. name, medical records number, 
patient number and study number, should be retained by the Investigator so that any Sponsor 
representatives, auditors or inspectors may access this information when required.
The investigator must retain all records until at least 2 years after the last approval of a marketing 
application in an ICH region for the Study Drug for the indication which is being investigated, or 
40 years after the database locked, whichever is longer, or longer if required by specific local 
requirements. 
The Investigator will contact the Sponsor for authorization prior to the destruction of any study 
records or in the event of accidental loss or destruction of any of them. 
The Investigator will also notify the Sponsor should he/she relocate or move the study-related files 
to a location other than that specified in the Sponsor’s study master file.
All records should be kept in a secure area. However, in the cases of audit or inspection, they should 
be rapidly made available.
16.
RESPONSIBILITIES OF PARTICIPANTS
16.1.
Responsibilities of the Investigator(s)
The Investigators will conduct the study in accordance with Good Clinical Practices, all applicable 
laws in the country where the study is conducted and in accordance with this study protocol.
The responsibilities of the Investigators are summarised below but not limited to:
Patient information and consent
Prior to undertaking any study-related procedure, it is the responsibility of the Investigator, or a 
formal designee, to provide each patient and/or a legal representative/witness, with relevant, 
comprehensive, verbal and written information, including the written information which received 
approval or a favourable opinion from the IEC/IRB and the Health Authorities.
Signed informed consent must be obtained prior to undertaking any study-related procedure. 
Obtaining of consent and how it was obtained must be described and documented in the patient’s 
file.
Information on the overall results of the study
Pursuant to the French “Patient’s rights” law adopted on 9 August 2004, the Investigator must 
provide any patient who so requests it with the overall results of the study, once it is completed. 
The Sponsor will provide the Investigator with the overall results beforehand.


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The Investigator should document in the patient’s file the fact that the information has been 
provided.
Information to other practitioners (if relevant)
In agreement with the patient, the Investigator will formally inform other practitioners of the 
patient’s participation in the study, to avoid any interference or bias in the conduct of the study.
Independent Ethics Committee (IEC)
In accordance with local regulations, the Investigator may be required to interface with the 
IRB/IEC.
Adverse events
The investigator is responsible for ensuring adequate safety monitoring and follow-up of the 
study patients.
The Investigator must report and handle any serious and non-serious adverse event, whether 
clinically observed or spontaneously reported by the patient, using concise medical terminology 
in accordance with Section 9 of the protocol.
Data recording
It is the Investigator’s responsibility to ensure, on an on-going basis, completion and validation of 
all case report forms as well as study-related supportive data. eCRFs must be signed by the 
Investigator. If the Investigator formally delegates completion of the eCRFs, the Investigator 
nevertheless has the final responsibility for signing the eCRFs to certify the accuracy and 
reliability of the data recorded therein.
Record retention
To enable inspections and audits from Health Authorities or the Sponsor, the Investigator agrees 
to keep records, including the identity of all participating patients, i.e. sufficient information to 
link records, all original signed informed consent forms and detailed records of treatment 
disposition. An electronic copy of eCRFs will be provided by the Sponsor to be retained and 
archived at site. The Investigator should maintain a site file with all essential documents.
See also Section 15 Archiving
Use of study-related information
The Investigator is obligated to provide the Sponsor with complete test results and all data 
derived from the study.
Only the Sponsor may make information available to physicians, Health Authorities and/or 
patients enrolled in the study, except as required by local regulations.
Study drug = IMP
Responsibility for IMP accountability at the study centre rests with the Investigator or with the 
institution, depending on local regulations.
Quality control
The Investigator and the relevant personnel should be available during monitoring visits and 
possible audits or inspections and ensure that sufficient time is devoted to the process.


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The Investigator guarantees the Sponsor or its representative and appropriate Health Authorities 
direct access to source documents.
Study discontinuation
Should the Health Authorities or the Sponsor decide to discontinue the study prematurely for any 
reason, the Investigator must promptly, contact all participating patients so they can be 
appropriately followed-up. All study supplies must be collected and all electronic case report 
forms must be completed as fully as possible.
Liability and insurance
Liability and insurance provisions for this study are set out in separate agreements.
Delegation of Investigator duties
The Investigator can delegate tasks to the research team but he/she remains responsible for 
coordinating and informing his/her staff about the protocol and the possible changes made to it.
The Investigator should ensure that all persons assisting with the study are adequately qualified, 
and are informed about the study protocol, any amendments to the protocol, the study treatments, 
and their study-related duties and functions.
The Investigator should maintain a list of appropriately qualified persons to whom significant 
study-related duties will be delegated. The list is to be kept up-to-date.
The Investigator should supply a dated and signed, up-to-date curriculum vitae (CV) in English, 
together with a list of his/her collaborators responsible for the operational conduct of the study. 
These collaborators should also provide a recent dated and signed English version of their CVs.
Study agreement discontinuation
During the study, if events such as retirement, promotion or relocation prevent the Investigator 
from conducting the study as agreed, the Investigator should appropriately transfer his/her 
responsibilities, knowledge and documents to another willing individual, with the agreement of 
the Sponsor. Study specific contracts must be signed between the Sponsor and the newly assigned 
person.
16.2.
Responsibilities of the Monitor
Instructions for monitoring will be developed in a monitoring plan.
The responsibilities of the study Monitor are defined in ICH-E6, Chapter 5. The Monitor, who is 
mandated by the Sponsor, must ensure that the study is conducted in accordance with Good Clinical 
Practice guidelines and all applicable local laws, and that the rights, the security and the well-being 
of the patients are respected.
During the conduct of the study, the Monitor reports any deviations or persistent poor compliance 
with the study requirements and the Sponsor makes decisions about appropriate corrective actions.
Communication
The Monitor is the main line of communication between the Investigator and the Sponsor.
Training


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The Monitor must present the protocol and all procedures related to the study during the study 
set-up visit and provide the Investigator with case report form completion guidelines.
Compliance
During periodic monitoring visits at mutually convenient times, the Monitor has the 
responsibility of assessing the progress of the study, of checking that the informed consent forms 
have been signed, of ensuring adhesion to and compliance with the study protocol and other 
study-related documents, and of ensuring the accuracy and completeness of the eCRFs. 
Inconsistencies in the study records are to be resolved.
Source data verification
The Monitor will perform source document verification and validation and request clarification to 
ensure the accuracy, completeness and reliability of data.
IMP = study drug
The Monitor must ensure that study drug handling is properly carried out and documented.
He/she must ensure that the investigator file is up-to-date with regard to essential documents.
16.3.
Responsibilities of the Data Manager
The LFB Data Manager is responsible for the management of clinical data from data entry to 
database lock.
17.
ETHICS AND REGULATORY CONSIDERATIONS
The current study is to be conducted in accordance with globally accepted standards of Good 
Clinical Practice (ICH-E6), European Directive 2001/20/EC, and the revised version of the 
Declaration of Helsinki set out in the European Directive, as well as with  applicable local 
requirements.
In France, this study will be conducted in accordance with the Code de la Santé Publique CSP. 
The protocol will be submitted to the Health Authorities and a properly constituted Ethics 
Committee (EC) for formal approval of the study conduct in accordance with local regulations. 
The study may not begin until the protocol has received written approval from the Health 
Authorities in accordance with local requirements.
In accordance with specific local requirements, the Investigator may be responsible for submitting 
the protocol and any amendments to the local EC. A copy of the decision letter, a list and versions of 
documents submitted, the list of EC members and their affiliation should be provided by the 
Investigator to the Sponsor.
During the study, the Sponsor should promptly notify the Investigators, Health Authorities and EC 
of any relevant information that could affect the safety of patients and could impact on the conduct 
of the study.
Personal Data Protection


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For biomedical research in France: The Sponsor attests his conformity regarding the Personal Data 
Protection French requirements ("Méthodologie de Réference MR001" updated in October 2010).
Insurance
The Sponsor certifies substracting a contract of public liability insurance to provide patients with 
compensation for any injury, including the consequences of administration of the investigational 
product and of the study procedures.
In case of injury or disability resulting from participation in the study, the patient is requested to 
promptly inform the Investigator responsible for the study.
Indemnity
Participation in this study will not entail any financial compensation to patient.
Changes to the protocol
The Sponsor will not assume any responsibility or liability resulting from implementation of 
unapproved deviations or changes.
The only circumstance in which an amendment may be initiated prior to approval by the Health 
Authorities is where the change is necessary to eliminate apparent immediate hazards to the patients. 
In this event, the Investigator must notify the Sponsor and if applicable the EC, in writing within 5 
working days after implementation.
18.
AUDIT AND INSPECTION
An audit/inspection may be carried out by qualified Sponsor staff, by subcontracted auditors or by 
representatives of national or foreign Health Authorities to ensure that the study is conducted as per 
protocol and in accordance with regulatory requirements, and to ensure the validity of the data.
Participation in this study implies acceptance to cooperate in any potential audit/inspection.
The audit/inspection may consist of an inspection of the premises and equipment together with 
verification of the study documents and data.
The investigational team must be available for inspection or audit.
When the Sponsor or the Investigator is informed that an inspection is to be performed, the other 
party must be informed immediately.
Audits/inspection may take place after the end of the study.


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19.
REFERENCES
1
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demyelinating polyradiculoneuropathy: a prevalence study in south east England. J 
Neurol Neurosurg Psychiatry. 1999; 66(5):677-80.
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Laughlin RS, Dyck PJ, Melton LJ 3rd, Leibson C, Ransom J, Dyck PJ. Incidence and 
prevalence of CIDP and the association of diabetes mellitus. Neurology. 2009; 73(1):39-
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Gaebel K, Blackhouse G, Campbell K, Robertson D, Xie F, Assasi N, Chalk C, Levine 
M, Goeree R. Intravenous immunoglobulin for the treatment of chronic inflammatory 
demyelinating polyradiculoneuropathy: A systemic review and meta-analysis. Open 
Medicine. 2010; 4(3):154-166.
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European Federation of Neurological Societies/Peripheral Nerve Society Guideline on 
management of chronic inflammatory demyelinating polyradiculopathy: 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; 15:1-9. 
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Van den Bergh PY, Piéret F. Electrodiagnostic criteria for acute and chronic 
inflammatory demyelinating polyradiculoneuropathy. Muscle Nerve. 2004; 29(4):565-74.
6
Hughes R. Chronic inflammatory demyelinating polyradiculoneuropathy. J Clin 
Immunol. 2010 Apr 15.
7
Vlam L, van der Pol WL, Cats EA, Straver DC, Piepers S, Franssen H, van den Berg LH. 
Multifocal motor neuropathy: diagnosis, pathogenesis and treatment strategies. Nat Rev 
Neurol. 2011 Nov 22; 8(1):48-58. 
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Austin JH. Recurrent polyneuropathies and their corticosteroid treatment; with five-year 
observations of a placebo-controlled case treated with corticotrophin, cortisone, and 
prednisone. Brain. 1958; 81(2):157-92.
9
Patwa HS, Chaudhry V, Katzberg H, Rae-Grant AD, So YT. Evidence-based guideline: 
Intravenous immunoglobulin in the treatment of neuromuscular disorders. Neurology 
2012; 78:1009-1015.
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Eftimov F, Winer JB, Vermeulen M, de Haan R, van Schaik IN. Intravenous 
immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. 
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Hughes RA, Donofrio P, Bril V, Dalakas MC, Deng C, Hanna K, Hartung HP, Latov N, 
Merkies IS, van Doorn PA; ICE Study Group; Intravenous immune globulin (10% 
caprylate-chromatography purified) for the treatment of chronic inflammatory 
demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled 
trial. Lancet Neurol. 2008; 7(2):136-44. Erratum in: Lancet Neurol. 2008; 7(9):771.


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12
Nobile-Orazio E, Cocito D, Jann S, Uncini A, Beghi E, Messina P, Antonini G, Fazio R, 
Gallia F, Schenone A, Francia A, Pareyson D, Santoro L, Tamburin S, Macchia R, 
Cavaletti G, Giannini F, Sabatelli M. «Intravenous immunoglobulin versus intravenous 
methylprednisolone for chronic inflammatory demyelinating polyradiculoneuropathy: a 
randomised controlled trial.» Lancet Neurol, 11 2012: 493-502.
13
Nobile-Orazio E, Cocito D, Jann S, Uncini A, Messina P, Beghi E, Antonini G, Fazio R, 
Gallia F, Schenone A, Francia A, Pareyson D, Santoro L, Tamburin S, Cavaletti G, 
Giannini F, Sabatelli M. «Frequency and time to relapse after discontinuing 6-month 
therapy with intravenous immunoglobulin or methylprednisolone in chronic 
inflammatory demyelinating polyradiculoneuropathy.» American Academy of Neurology 
Conference. 2014.
14
Querol, L., G.Nogales-Gadea, R.Rojas-Garcia, E.Martinez-Hernandez, J.Diaz-Manera, 
X.Suarez-Calvet, M.Navas, J.Araque, E.Gallardo, and I.Illa. 2013. Antibodies to 
contactin-1 in chronic inflammatory demyelinating polyneuropathy. Ann.Neurol. 73:370-
380.
15
Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory 
diseases with intravenous immune globulin. N Engl J Med. 2001; 345:747-755.
16
Tackenberg B, Jelcic I, Baerenwaldt A, Oertel WH, Sommer N, Nimmerjahn F, 
Lünemann JD. Impaired inhibitory Fcgamma receptor IIB expression on B cells in 
chronic inflammatory demyelinating polyneuropathy. Proc Natl Acad Sci U S A. 2009 
Mar 24; 106(12):4788-92.
17
EMA/CHMP/BPWP/94033/2007 rev. 2. Guideline on the clinical investigation of human 
normal immunoglobulin for intravenous administration (IVIg). July 2010.
18
EMA/CHMP/BPWP/94038/2007 rev. 4. Guideline on core SmPC for human normal 
immunoglobulin for intravenous administration (IVIg). European Medicines Agency.
19
Querol, L., G.Nogales-Gadea, R.Rojas-Garcia, E.Martinez-Hernandez, J.Diaz-Manera, 
X.Suarez-Calvet, M.Navas, J.Araque, E.Gallardo, and I.Illa. 2013. Antibodies to 
contactin-1 in chronic inflammatory demyelinating polyneuropathy. Ann.Neurol. 73:370-
380.
20
Bick S., M.Tschernatsch, A.Karg, V.Fuehlhuber, T.E.Trenczek, K.Faltermeier, 
H.Hackstein, M.Kaps, and F.Blaes. 2013. Intravenous immunoglobulin inhibits BAFF 
production in chronic inflammatory demyelinating polyneuropathy - a new mechanism of 
action? J.Neuroimmunol. 256:84-90. 
21
Jacob S. and Y.A.Rajabally. 2009. Current proposed mechanisms of action of 
intravenous immunoglobulins in inflammatory neuropathies. Curr.Neuropharmacol. 
7:337-342. 
22
Durandy A. et al, Intravenous immunoglobulins – understanding properties and 
mechanisms. Clin Exp Immunol. 2009 December; 158(Suppl 1): 2–13.


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23
Goedee HS, Brekelmans GJ, Visser LH. Multifocal enlargement and increased 
vascularization of peripheral nerves detected by sonography in CIDP: A pilot study. Clin 
Neurophysiol 2014; 125:154–159.
24
Imamura K, Tajiri Y, Kowa H, Nakashima K. Peripheral nerve hypertrophy in chronic 
inflammatory demyelinating polyradiculoneuropathy detected by ultrasonography. Intern 
Med 2009; 48:581–582.
25
Zaidman CM, Al-Lozi M, Pestronk A. Peripheral nerve size in normals and patients with 
polyneuropathy: an ultrasound study Muscle Nerve. 2009 Dec;40(6):960-6; Muscle 
Nerve. 2012 Aug;46(2):270-5).
26
Matsuoka N, Kohriyama T, Ochi K, Nishitani M, Sueda Y, Mimori Y, Nakamura S, 
Matsumoto M. Detection of cervical nerve root hypertrophy by ultrasonography in 
chronic inflammatory demyelinating  polyradiculoneuropathy. J Neurol Sci. 2004 Apr 
15;219(1-2):15-21.
27
Taniguchi N, Itoh K, Wang Y, et al. Sonographic detection of diffuse peripheral nerve 
hypertrophy in chronic inflammatory demyelinating polyradiculoneuropathy. J Clin 
Ultrasound 2000; 28:488–491.
28
Padua L, Granata G, Sabatelli M, Inghilleri M, Lucchetta M, Luigetti M, Coraci D, 
Martinoli C, Briani C. Heterogeneity of ultrasound pattern in CIDP patients. Clin 
Neurophysiol. 2014 Jan; 125(1):160-5. doi: 10.1016/j.clinph.2013.07.023. Epub 2013 
Oct 5.
29
Hughes R, Bensa S, Willison H, Van den Bergh P, Comi G, Illa I, Nobile-Orazio E, van 
Doorn P, Dalakas M, Bojar M, Swan A; Inflammatory Neuropathy Cause and Treatment 
(INCAT) Group. Randomised controlled trial of intravenous immunoglobulin versus oral 
Prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann 
Neurol 2001; 50(2):195-201.
30
Van van Nes SI, Vanhoutte EK, van Doorn PA, Hermans M, Bakkers M, Kuitwaard K, 
Faber CG, Merkies IS, on behalf of the PeriNomS study group. Rasch-built Overall 
Disability Scale (R-ODS) for immune-mediated peripheral neuropathies. Neurology 2011 
Jan 25; 76(4):337-45.
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Andrich D, Sheridan B, Luo G – Rasch models for measurement: RUMM2030, ed.R. 
Laboratory 2010, Perth.
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Merkies IS, Schmitz PI, Samijn JP, Meché FG, Toyka KV, van Doorn PA. Assessing 
grip strength in healthy individuals and patients with immune-mediated polyneuropathies
323
Vanhoutte EK, Latov N, Deng C, Hanna K, Hughes RA, Bril V, Dalakas MC, Donofrio 
P, van Doorn PA, Hartung HP, Merkies IS. Vigorimeter grip strength in CIDP: A 
responsive tool that rapidly measure the effect of IVIg – the ICE study. Eur J 
Neurol.2013-may; 20(5):748-55.
34
KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney inter, Suppl. 2012; 
2: 139-274.




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20.1.2.Instructions for the Use of the INCAT Disability Scale
Encourage the patient to answer all the questions by themselves. A carer, relative or friend may help 
if the patient is unsure or has communication difficulties. If the patient does not understand, change 
the question to, “Do you have difficulty doing xxx?” If necessary ask them to demonstrate the task 
required.
If their condition has changed recently ask them to base their answers on the last 24 hours.
ARM GRADE
Ask: 
"Do you have any tingling, numbness, pain or weakness in your hands or arms?" 
Do not include symptoms not due to CIDP.
"Is your ability to do and undo all your buttons and zips affected?" 
If Yes, ask: "Are you able to do and undo all your buttons and zips?"
If the patient can do and undo all buttons and zips but has difficulty, they should be considered as 
affected. If they are not able to do and undo any of their zips and buttons, the activity is prevented. If 
button hooks or adapted zips are used the task is affected. 
"Is your ability to wash or brush your hair affected?"
If Yes, ask: "Are you able to wash and brush your hair?"
If they cannot either wash or brush their hair the task is prevented. If they do not usually wash or 
brush their hair, they should be asked if they think they could, if required. If there is doubt, ask them 
to mime the tasks.
"Is your ability to use a knife and fork (or spoon) together affected?"
If Yes, ask: "Are you able to use a knife and fork (or spoon) together?"
If patients do not use a knife and fork, ask about their usual eating implements (e.g. spoon, 
chopsticks).The task is considered as affected if the patient can use cutlery to eat their food but has 
difficulty. The activity is prevented if the patient cannot use their cutlery to eat. If adapted cutlery is 
used the task should be considered affected. 
"Is your ability to handle small coins affected?"
If Yes ask: "Are you able to handle small coins?"
If there is doubt, ask them to show you how they take coins out of a purse or pocket and put them 
back.
If all the previous activities are prevented, ask: 
"Can you move either hand or arm at all?"
If necessary, ask the patient to show you the movement. Score “Yes” if any voluntary movement is 
observed.
LEG GRADE
Ask: "Do you have difficulty walking?"
Difficulty walking may include difficulty walking long distances, fatigue or unsteadiness.


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If Yes ask: "Do you usually walk outdoors with aid?"
Could be the aid of another person, or the aid of stick(s), crutch(es), arm(s).
If Yes ask:
"Do you usually walk outdoors with unilateral support (stick, single crutch, one arm)?"
"Do you usually walk outdoors with bilateral support (sticks, crutches, frame, two arms)?"
If the patient does not usually walk outdoors (is chairbound), ask:
"Are you able to stand and walk a few steps with help?"
If necessary ask them to show how they stand and walk with help.
20.1.3.Medical Research Council (MRC) Scale and Sum Score
MRS sum score is a scale that assesses motor impairment.
Table 20–2: MRC scale
The patient is investigated in sitting position and/or lying supine.
0 = No visible contraction
1 = Visible contraction without movement of the limb (not existent for hip flexion)
2 = Movement of the limb but not against gravity
3 = Movement against gravity over (almost) the full range*
4 = Movement against gravity and resistance
5 = Normal 
The muscle groups (right and left) assessed in the measurement of the MRC-sum score are the 
following:
Upper limbs:
Shoulder abduction * 
Elbow flexion 
Wrist extension 
Lower limbs: 
Hip flexion
Knee extension 
Ankle dorsal flexion
For each muscle group, a standardised joint / limb position, as well as the point at which counter-
force is administered will be pre-defined and taken when assessing muscle strength. 
This scale yields the so-called ''MRC-sum score", ranging from 0 (paralysis) to 60 (normal strength). 
* For shoulder abduction 90° is considered adequate and for hip flexion 45° to qualify for a score of 3.
20.1.4.RASCH MODIFIED MRC SUM SCORE
The Rasch-modified version of MRC sum score ranges from 0: Total paralysis to 3: Normal 
strength. It assesses the same muscle group (right and left) than the MRC scale. 






LFB Biotechnologies – Protocol I10E-1306-5.0 dated 03 May 2017, incorporated amendment N°2
Page 86/87
CONFIDENTIAL
Efficacy index (CGI-E)
Rate this item on the basis of drug effect only.
Select the terms which best describe the degrees of therapeutic effect and side effects and record the number in 
the box where the two items intersect.
Therapeutic effect
Side effects
None
Do not 
significantly 
interfere with 
patient’s 
functioning
Significantly 
interferes 
with patient’s 
functioning
Outweighs 
therapeutic effect
Marked
Vast improvement. Complete or 
nearly complete remission of all 
symptoms
01
02
03
04
Moderate
Decided improvement. Partial 
remission of symptoms
05
06
07
08
Minimal
Slight which doesn’t alter status 
of care of patient
09
10
11
12
Unchanged or 
worse
13
14
15
16
Not assessed = 
00
20.1.7.Grip Strength
The Martin vigorimeter, a portable dynamometer have been developed to measure grip strength, 
although, strictly speaking, it measures the air pressure in the bulb and not the force. The pressure in 
the bulb is registered on a manometer via a rubber junction tube and expressed in kiloPascals (kPa). 
Reference values for this instrument have been provided for right-handed healthy individuals [33] 
The Vigorimeter has demonstrated good responsiveness, even as early as at 3 weeks of IVIg 
therapies in patient with CIDP [33] [34]
Grip strength measure with the Martin Vigorimeter in both hands will be used to assess the efficacy 
of I10E.



SAP_001.pdf: 
 
COVER PAGE 
 
 
TITLE: International, multicentre, efficacy and safety study of I10E in the maintenance 
treatment of patients with Chronic Inflammatory Demyelinating 
Polyradiculoneuropathy: Extension of PRISM study I10E-1302 
 
NCT Number: NCT02317562 
 
 
DOCUMENT: SAP (v2.0)  
 
 
VERSION & DATE OF DOCUMENT: Version 2.0; October 30, 2017