Clinical Trials Register

Summary
EudraCT Number:	2012-001995-12
Sponsor's Protocol Code Number:	I10E-0901
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-07-12
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

Spain - AEMPS

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

Estudio europeo aleatorizado, doble ciego, controlado con tratamiento comparador activo y de diseño cruzado que evalúa la seguridad y eficacia de una nueva formulación líquida y lista para usar de inmunoglobulina intravenosa humana al 10 % (I10E) en comparación con Kiovig® en pacientes con neuropatía motora multifocal

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	ZA de Courtaboeuf, 3, avenue des Tropiques
B.5.3.2	Town/ city	Les Ulis Cedex
B.5.3.3	Post code	91940
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)

Neuropatía motora multifocal (NMM)

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).

Es una enfermedad crónica adquirida, probablemente autoinmune, desmielinizante, neuropatía motora. Se trata de una enfermedad rara. La edad media de inicio es de 40 años (rango 20-70 años).

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	16.0
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.

El primer objetivo del estudio es evaluar la eficacia y la seguridad de I10E en comparación con Kiovig® para el tratamiento de mantenimiento de la NMM en un estudio aleatorizado, doble ciego, de diseño cruzado con tratamiento comparador activo.

E.2.2

Secondary objectives of the trial

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

El objetivo secundario del estudio es evaluar la seguridad.

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 (without any change in doses > or < 15% ) of any brand of IVIG (Kiovig excluded) at 1 g/kg body weight every 4-week intervals up to 2 g/kg body weight every 4-week to 8-week intervals 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.

Se podrá incluir a un paciente en el estudio si se cumplen todos los criterios siguientes:
1.Varones o mujeres de entre 18 y 80 años.
2. Obtención del consentimiento informado por escrito antes de que se realice cualquier procedimiento relacionado con el estudio.
3. Diagnóstico de NMM demostrada o probable según las directrices del EFNS/PNS de 2010, Primera revisión realizada por especialistas en enfermedades neuromusculares con experiencia específica en electrodiagnóstico.
4. Pacientes tratados con una dosis de mantenimiento estable (sin ninguna modificación de la dosis > o < 15 %) de cualquier tipo de IGIV (excepto Kiovig®) de entre 1 g/kg de peso corporal en intervalos de 4 semanas y 2 g/kg de peso corporal en intervalos de 4 a 8 semanas, según las directrices del EFNS/PNS de 2010, primera revisión, durante al menos los 3 meses previos a la inclusión.
5. Pacientes con cobertura en el sistema nacional de salud, si lo requiere la normativa local.

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 disease that may cause neuropathy or may interfere with outcome assessments, such as diabetes, vasculitis, or systemic lupus erythematosus.

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. History of Kiovig® use.

7. History of IgA deficiency, except if the absence of anti-IgA antibodies is documented.

8. Patient infected with hepatitis B virus (HBV) and/or hepatitis C virus (HCV), or human immunodeficiency virus (HIV).

9. Protein-losing enteropathy characterised by serum protein levels <60 g/l and serum albumin levels <30 g/l or nephrotic syndrome characterised by proteinuria ?3.5 g /24 hours, serum protein levels <60 g/l and serum albumin levels <30 g/l.

10. History of cardiac insufficiency (New York Heart Association (NYHA) III/IV) or uncontrolled severe hypertension.

11. History of thrombotic episodes (including deep vein thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular accident).

12. Glomerular filtration rate <80 ml/min/1.73m2 measured according to the Modified Diet in Renal Disease (MDRD) calculation.

13. Serum levels of AST, ALT and/or ALP >2 times upper limit of normal range.

14. Patient treated with immunomodulator/immunosuppressor (e.g. cyclophosphamide, cyclosporine or interferon), except use at the same dose of: methotrexate, mycophenolate mofetil, or azathioprine for at least 6 months before the inclusion visit.

15. Treatment with an anti-CD20 antibody within the 12 previous months.

16. Administration of another investigational product within the last month prior to inclusion.

17. Exposure to blood products or derivatives other than commercial IgG, within 3 months prior to inclusion.

18. Positive results of pregnancy blood test or breast-feeding woman, or woman of childbearing potential without effective contraception for the duration of the study.

19. Any serious medical condition that would interfere with the clinical assessment of I10E or prevent the patient from complying with the protocol requirements.

20. Anticipated poor compliance of patient with study procedures during the 12 month duration of the study.

21. Drug or alcohol abuse.

Se podrá incluir a un paciente en el estudio si no cumple ninguno de los siguientes criterios:
1.Déficit de la neurona motora superior, bulbar, del nervio craneal o déficit sensorial significativo.
2.Proteínas en el LCR > 100 mg/dl (si se dispone de esta información, obtenida como parte de una evaluación previa).
3.Cualquier enfermedad que pueda provocar neuropatía o pueda interferir con el resultado de las evaluaciones, tales como diabetes, vasculitis o lupus eritematoso sistémico.
4.IMC ? 40 kg/m2.
5.Hipersensibilidad conocida al principio activo o a alguno de los excipientes de I10E (glicina y polisorbato 80) o Kiovig® (glicina).
6.Antecedentes de tratamiento con Kiovig®.
7.Antecedentes de deficiencia de IgA, excepto si se ha documentado ausencia de anticuerpos anti-IgA.
8.Paciente con infección por el virus de la hepatitis B (VHB) y/o hepatitis C (VHC), o virus de la inmunodeficiencia humana (VIH).
9.Enteropatía perdedora de proteínas caracterizada por niveles de proteína sérica < 60 g/l y niveles de albúmina sérica < 30 g/l o síndrome nefrótico caracterizado por proteinuria igual o mayor a 3,5 h/24 horas, niveles de proteína sérica < 60 g/l y niveles de albúmina sérica < 30 g/l.
10.Antecedentes de insuficiencia cardíaca (Grado III/IV de la New York Heart Association (NYHA)) o hipertensión grave no controlada.
11.Antecedentes de episodios trombóticos (incluidos trombosis venosa profunda, embolia pulmonar, infarto de miocardio y accidente cerebrovascular).
12.Tasa de filtración glomerular < 80 ml/min/1,73m2 determinada con el cálculo de la dieta modificada en la enfermedad renal (MDRD).
13.Niveles de AST, ALT y/o FA > 2 veces el límite superior de normalidad.
14.Pacientes tratados con inmunomoduladores/inmunosupresores (p. ej., ciclofosfamida, ciclosporina o interferón), excepto si se han usado a la misma dosis que metotrexato, micofenolato mofetilo o azatioprina durante al menos los 6 meses anteriores a la visita de inclusión.
15.Tratamiento con un anticuerpo anti-CD20 en los 12 meses previos.
16.Administración de otro producto en investigación en el mes previo a la inclusión.
17.Exposición en los 3 meses previos a la inclusión a otros productos sanguíneos o hemoderivados diferentes de la IgG comercializada.
18.Resultados positivos en una prueba de embarazo en sangre o mujeres en periodo de lactancia o en edad fértil que no utilicen un método anticonceptivo eficaz durante todo el estudio.
19.Cualquier enfermedad grave que pudiera interferir en la evaluación clínica de I10E o impedir que el paciente cumpla los requisitos del protocolo.
20.Previsión de incumplimiento del paciente de los procedimientos del estudio durante los 12 meses del estudio.
21.Alcoholismo o toxicomanía.

E.5 End points

E.5.1

Primary end point(s)

Difference between I10E and Kiovig® in the original MMRC 10 sum score (10 muscles on both sides see Table 20.1) described by Cats 2008

Diferencia entre I10E y Kiovig® en la puntuación total de la escala modificada 10 del MRC (10 músculos en ambos lados, véase la Tabla 20.1) descrita por Cats 2008

E.5.1.1

Timepoint(s) of evaluation of this end point

- Before the course

- Efficacy assessments between 13 and 25 weeks for each period and depending on courses frequencies

- End of study visit

- Antes del curso

- Las evaluaciones de eficacia entre semanas 13 y 25 para cada periodo y dependiendo de las frecuencias de los cursos

- Fin de la visita de estudio

E.5.2

Secondary end point(s)

Difference between I10E and Kiovig® in:
? 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.
? Change of Clinical Global Impression (CGI)
? Discontinuation of study treatment
? INCAT: upper and lower limbs

Diferencia entre I10E y Kiovig® en:
?Nueva puntuación total en la escala modificada 10 del MRC (elección de 10 músculos ligeramente diferentes en ambos lados porque se espera que sean más importantes y respondedores al cambio; véase la Tabla 20.1)

?Puntuación total en la escala modificada del MRC mediante el análisis de Rasch (basada en los 10 músculos de la puntuación total de la escala modificada del MRC, descrita por Cats 2008)

?Puntuación total en la escala modificada 14 del MRC (14 músculos en ambos lados)

?Fuerza de presión determinada con un dinamómetro en la mano más afectada
?Necesidad de modificación de la dosis o de la frecuencia de administración de la IGIV debido a un empeoramiento del estado neurológico del paciente con los PEI.
?Cambio en la Impresión Clínica Global (CGI)
?Suspensión del tratamiento del estudio
?INCAT: extremidades superiores e inferiores

E.5.2.1

Timepoint(s) of evaluation of this end point

- Before the course

- End of study visit

- For INCAT: assessments between 13 and 25 weeks for each period and depending on courses frequencies

- For Grip strength: 2 weeks (15-18 days) after the last course of each period

- Antes del curso

- Fin de la visita de estudio

- Para INCAT: evaluaciones entre la semana 13 y 25 para cada periodo y dependiendo de la frecuencia de los cursos

- Para la fuerza de presión: 2 semanas (15-18 días) después del último curso de cada período

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.

Al finalizar el estudio, los pacientes serán tratados según la práctica clínica habitual.

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

2013-07-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-05-15

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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