Clinical Trials Register

Summary
EudraCT Number:	2012-001995-12
Sponsor's Protocol Code Number:	I10E-0901
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-06-03
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2012-001995-12

A.3

Full title of the trial

A European, randomised, double-blind, active comparator-controlled, cross-over, efficacy and safety study of a new 10% ready-to-use liquid human intravenous immunoglobulin (I10E) versus Kiovig® in patients with Multifocal Motor Neuropathy

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A.4.1

Sponsor's protocol code number

I10E-0901

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	LFB BIOTECHNOLOGIES
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	LFB BIOTECHNOLOGIES
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	LFB BIOTECHNOLOGIES
B.5.2	Functional name of contact point	Clinical trial information desk
B.5.3	Address:
B.5.3.1	Street Address	3, avenue des Tropiques, ZA de Courtaboeuf BP 40305
B.5.3.2	Town/ city	Les Ulis Cedex
B.5.3.3	Post code	91958
B.5.3.4	Country	France
B.5.4	Telephone number	+33169 82 70 10
B.5.5	Fax number	+33169 82 72 72

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	KIOVIG
D.2.1.1.2	Name of the Marketing Authorisation holder	Baxter AG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	KIOVIG
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	HUMAN NORMAL IMMUNOGLOBULIN
D.3.9.3	Other descriptive name	HUMAN NORMAL IMMUNOGLOBULIN (IV)
D.3.9.4	EV Substance Code	SUB12041MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	Yes
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	human normal immunoglobulin for intravenous administration
D.3.2	Product code	I10E
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	HUMAN NORMAL IMMUNOGLOBULIN
D.3.9.2	Current sponsor code	I10E
D.3.9.3	Other descriptive name	HUMAN NORMAL IMMUNOGLOBULIN (IV)
D.3.9.4	EV Substance Code	SUB12041MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	Yes
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Multifocal motor neuropathy (MMN)

E.1.1.1

Medical condition in easily understood language

Multifocal motor neuropathy (MMN) is a chronic acquired, probably autoimmune, demyelinating, motor neuropathy. It is a rare disease. The mean age at onset is 40 years (range 20-70 years).

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	PT
E.1.2	Classification code	10065579
E.1.2	Term	Multifocal motor neuropathy
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to evaluate the efficacy of I10E compared to Kiovig® for maintenance treatment of patients with MMN in a randomised, double-blind, active comparator-controlled, cross-over design.

E.2.2

Secondary objectives of the trial

The secondary objective of this study is to assess the safety.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

A patient may be included in the study if all of the following criteria are fulfilled:
1. Male or female patient aged 18 to 80 years.
2. Written informed consent obtained prior to any study-related procedures.
3. Diagnosis of definite or probable MMN according to the EFNS/PNS Guideline 2010, First revision made by neuromuscular disease specialists with specific electrodiagnostic expertise.
4. Patients treated with a stable maintenance dose within 15% of any brand of IVIG (Kiovig excluded) at 1 g/kg for 1-3 days up to 2 g/kg for 2-5 days every 4 to 8 weels (+/-7 days), according to the EFNS/PNS Guideline 2010, First revision for at least 3 months prior to enrolment.
5. Covered by national health care insurance system if required by local regulations.

E.4

Principal exclusion criteria

A patient may be included in the study if none of the following criteria is met:
1. Upper motor neuron, bulbar, cranial nerve or significant sensory deficit.
2. CSF protein >100 mg/dL (if available and done as part of a previous evaluation).
3. 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 diseases, infection with HIV, hepatitis B virus (HBV), or
hepatitis C (HCV), Lyme disease, multiple myeloma, Waldenström's macroglobulinaemia, amyloid, and hereditary neuropathy.
4. BMI ≥ 40 kg/m2.
5. Known hypersensitivity to the active substance or to any of the excipients of I10E (glycine and polysorbate 80) or Kiovig® (glycine).
6. Patients who have been treated with Kiovig® shall not have received Kiovig® during the last 6 months prior to enrolment.
7. History of IgA deficiency, except if the absence of anti-IgA antibodies is documented.
8. Protein-losing enteropathy characterised by serum protein levels <60 g/l and serum albumin levels <30 g/l .
9. History of cardiac insufficiency (New York Heart Association (NYHA)III/IV) , uncontrolled cardiac arrhythmia, unstable ischemic heart disease, or uncontrolled hypertension.
10. History of venous thrombo-embolic disease, myocardial infarction or cerebrovascular accident.
11. Risk factor for blood hyperviscosity such as cryoglobulinemia or haematological malignancy with monoclonal gammopathy.
12. 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:
- 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:
*albumin excretion rate (AER) >300 mg/24 hours or protein excretion
rate (PER) >500 mg/24 hours (24h-urine collection)
OR
*albumin to creatinine ratio (ACR) >30 mg/mmol or protein to creatinine ratio (PCR) >50 mg/mmol (spot urine sample).
13. Serum levels of AST, or ALT and/or ALP >2 times upper limit of normal range.
14. Treatment within 12 months prior to screening with immunomodulatory or immunosuppressant agents (including but not limited to cyclophosphamide, cyclosporine, interferon-a, interferon-β 1a, anti-CD20, alemtuzumab, azathioprine, etanercept, mycophenolate mofetil, methotrexate and haematopoietic stem cell transplantation).
15. Administration of another investigational product within the last month prior to inclusion.
16. Plasma exchange, blood products or derivatives administered with the last 3 months prior to screening.
17. Woman with positive results on a pregnancy test or breastfeeding woman or woman of childbearing potential without an effective contraception. Effective contraception are injectable, patch or 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).
18. Any serious medical condition that would interfere with the clinical assessment of I10E or prevent the patient from complying with the protocol requirements.
19. Anticipated poor compliance of patient with study procedures during the 12 month duration of the study.
20. Drug or alcohol abuse.

E.5 End points

E.5.1

Primary end point(s)

Difference between I10E and Kiovig® in the mean assessments of the original MMRC 10 sum score (10 muscles on both sides see Table 20.1) described by Cats 2008 during the evaluation period (i.e. 13 weeks after the initiation of either I10E or Kiovig® until the end of the respective treatment period).

E.5.1.1

Timepoint(s) of evaluation of this end point

- Before the course
- During the evaluation period (i.e. 13 weeks after the initiation of either I10E or Kiovig® until the end of the respective treatment period).

E.5.2

Secondary end point(s)

Difference between I10E and Kiovig® in the mean assessments of the following parameters during the evaluation period (i.e. 13 weeks after the initiation of either I10E or Kiovig® until the end of the respective treatment period):
• MMRC 10 new sum score (10 slightly different muscles on both sides chosen because they are expected to be more relevant and responsive to change; see Table 20.1)
• Rasch built MMRC sum score (based on the 10 muscles in the MMRC sum score described by Cats 2008)
• MMRC 14 sum score (14 muscles on both sides)
• Grip strength with dynamometer in the most affected hand
• Need for change of the IVIG dose or frequency due to a worsening of the patient's neurological status with IMPs during the respective treatment period.
• Change of Clinical Global Impression (CGI) during respective treatment periods.
• Discontinuation of study treatment during the respective treatment period.
• INCAT: upper and lower limbs

E.5.2.1

Timepoint(s) of evaluation of this end point

- Before the course
- During the evaluation period (i.e. 13 weeks after the initiation of either I10E or Kiovig® until the end of the respective treatment period).

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Active comparator

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

At the last visit patients will be switched to the normal standard of care for the condition.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-06-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-08-01

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-07-01

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