Clinical Trials Register

Summary
EudraCT Number:	2010-023883-42
Sponsor's Protocol Code Number:	IGD002
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2012-03-08
Trial 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

Italy - Italian Medicines Agency

A.2

EudraCT number

2010-023883-42

A.3

Full title of the trial

Randomized, double-blind, placebo controlled trial to evaluate the efficacy of high dose intravenous immunoglobulins in diabetic painful polyneuropaty (DPNP)resistant to conventional therapies

Studio randomizzato, controllato in doppio cieco per valutare l'efficacia delle immunoglobuline ad alte dosi nel trattamento della polineuropatia diabetica dolorosa resistente alle terapie convenzionali

A.3.1

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

Study to assess the effectiveness of high doses of immunoglobulin in the treatment of polyneuropathy painful diabetic resistant to conventional therapies

Studio per valutare l'efficacia delle immunoglobuline ad alte dosi nel trattamento della polineuropatia diabetica dolorosa resistente alle terapie convenzionali

A.3.2

Name or abbreviated title of the trial where available

IGD002

A.4.1

Sponsor's protocol code number

IGD002

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	AZIENDA OSPEDALIERA OSPEDALE NIGUARDA CA' GRANDA (A.O. DI RILIEVO NAZIONALE)
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	GRIFOLS
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	A.O. NIGUARDA CA' GRANDA
B.5.2	Functional name of contact point	DIPARTIMENTO DI NEUROSCIENZE
B.5.3	Address:
B.5.3.1	Street Address	piazza Ospedale Maggiore 3
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20162
B.5.3.4	Country	Italy
B.5.4	Telephone number	0264442348
B.5.5	Fax number	0264442819
B.5.6	E-mail	neurologia@ospedaleniguarda.it

D. IMP Identification
D.IMP: 1
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	Yes
D.2.1.1.1	Trade name	FLEBOGAMMA DIF
D.2.1.1.2	Name of the Marketing Authorisation holder	ISTITUTO GRIFOLOS SA
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.4	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.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	SUB14196MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5000
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)	No
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

painful diabetic polyneuropathy resistant to conventional therapies

Polineuropatia Diabetica Dolorosa resistente alle terapie convenzionali

E.1.1.1

Medical condition in easily understood language

The painful diabetic polyneuropathy is chronic and disabling is a complication of diabetes.

La Polineuropatia diabetica dolorosa è è una complicanza cronica ed invalidante del diabete.

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	14.1
E.1.2	Level	SOC
E.1.2	Classification code	10029205
E.1.2	Term	Nervous system disorders
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the efficacy of IVIg in reducing the intensity of neuropathic pain in a population of patients with painful diabetic polyneuropathy resistant to conventional treatments

Valutare l'efficacia delle IVIg nella riduzione dell’intensità del dolore neuropatico, in una popolazione di pazienti affetti da polineuropatia diabetica dolorosa resistente ai trattamenti convenzionali.

E.2.2

Secondary objectives of the trial

To evaluate the tolerability of IVIg in patients under study and changes in Quality of Life

Valutare la tollerabilità delle IVIg nei pazienti in studio ed i cambiamenti nella Qualità della Vita

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients males and females, age> 18 years; Outpatients; Diagnosis of painful diabetic polyneuropathy for at least 6 months up to a maximum of 5 years, confirmed according to the criteria of the Expert Group Toronto Diabetic Neuropathy; intensity of pain > 60 units in the visual-analogue scale (VAS) at baseline; DN4 questionnaire to score ≥ 4; Prior treatment with NSAIDs, tricyclic antidepressants and anticonvulsants, and unsatisfactory results despite the achievement of therapeutic doses (pain reduction less than 30% to rating scale) or who have failed to take prescribed treatments for intolerable side effects, patients who have given written informed consent. Second phase of inclusion: Average pain assessment ≥ 60 mm in the VAS during the 7 days after baseline. At least 50% of the diary must be completed to assess the patient's inclusion in the study.

Pazienti maschi e femmine; Età > 18 anni; Pazienti ambulatoriali; Diagnosi di polineuropatia diabetica dolorosa da almeno 6 mesi fino ad un massimo di 5 anni, confermata secondo i criteri del Toronto Diabetic Neuropathy Expert Group; Intensità del dolore > 60 unità alla scala visuo-analogica (VAS) alla visita basale; Punteggio al Questionario DN4 ≥ 4; Precedenti trattamenti con FANS, antidepressivi triciclici ed antiepilettici, e risultati insoddisfacenti nonostante il raggiungimento di dosaggi terapeutici (riduzione del dolore inferiore al 30% alla scala di valutazione); o che non siano riusciti ad assumere le terapie prescritte per intollerabili effetti collaterali; Pazienti che abbiano dato il proprio consenso informato scritto. Seconda fase di inclusione: media della valutazione del dolore ≥60 mm nella scala VAS durante i 7 giorni successivi alla visita basale. Al meno 50% del diario deve essere compilato per poter valutare l’inclusione del paziente nello studio.

E.4

Principal exclusion criteria

Any condition that, in the opinion of the investigator, may affect the patient's participation in the study, presence of other types of pain that may confound the assessment of painful polyneuropathy, patients treated with IVIg for six months at study Patients with Serum IgA <70 mg / dL; Cardiovascular disease failure, or uncontrolled by drug therapy, renal failure, liver failure, severe alterations of the Peripheral blood counts (leukopenia, thrombocytopenia, pancytopenia), psychiatric disease, amputations, pregnancy and lactation; Participation in clinical trials in the 30 days preceding the beginning of this study. Second phase inclusion Media> 60 mm in the VAS during the 7 days after baseline. At least 50% of the diary must be completed to assess the patient's inclusion in the study.

Qualunque condizione che, a giudizio dello sperimentatore, possa inficiare la partecipazione del paziente allo studio; Presenza di altro tipo di dolore che possa confondere la valutazione della polineuropatia dolorosa; Pazienti trattati con IVIg nei sei mesi precedenti all'ingresso nello studio Pazienti con dosaggio serico di IgA < a 70 mg/dL; Patologia cardiovascolare scompensata o non controllata farmacologicamente, insufficienza renale, insufficienza epatica, gravi alterazioni della crasi ematica (leucopenia, trombocitopenia, pancitopenia), malattie psichiatriche; Amputazioni; Gravidanza e allattamento; Partecipazione a studi clinici nei 30 giorni precedenti all’inizio del presente studio. Seconda fase di inclusione Media > 60 mm nella scala VAS durante i 7 giorni successivi alla visita basale. Al meno 50% del diario deve essere compilato per poter valutare l’inclusione del paziente nello studio.

E.5 End points

E.5.1

Primary end point(s)

Evaluate the intensity of pain measured by VAS scale and reported in the patient diary. Will be compared to the last seven days prior to Visit 4 with values reported in the patient diary VAS before treatment.

Valutare l'intensità del dolore misurato con la scala VAS e riportato nel diario del paziente. Saranno confrontati gli ultimi sette giorni prima della Visita 4 con i valori della VAS riportati nel diario del paziente prima del trattamento.

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary efficacy endpoint of the study is at least 50% reduction in pain compared to baseline values between patients treated with IVIg compared with a reduction of 25% in the placebo group. These changes in pain relief will be assessed by the average of the last 7 in the VAS values reported in the patient diary prior to V4 than the average VAS values recorded before treatment.

L’end-point primario d’efficacia dello studio è la riduzione di almeno 50% del dolore rispetto ai valori della basale tra i paziente trattati con IVIg rispetto ad una riduzione del 25% nel gruppo trattato con placebo. Questi cambiamenti nella riduzione del dolore saranno valutati dalla media degli ultimi 7 valori nella scala VAS riportati nel diario del paziente prima della V4 rispetto alla media dei valori VAS registrati prima del trattamento.

E.5.2

Secondary end point(s)

Evaluate the intensity of pain measured by VAS scale is the diary that assessed the value of VAS at the time of the visit, the quality of life measured by SF36 questionnaire, and the type of pain NPSI identified with the questionnaire and the clinical global is expressed by the physician through the CGI-C scale only by the patient through the PGI-C.

Valutare l’intensità del dolore misurato con la scala VAS sia con il diario che il valore della scala VAS valutata al momento della visita, la qualità della vita misurata con questionario SF36; il tipo di dolore identificato con questionario NPSI e lo stato clinico globale, sia espresso dal medico mediante la scala CGI-C, che dal paziente mediante la scala PGI-C.

E.5.2.1

Timepoint(s) of evaluation of this end point

The VAS scale for assessing pain reduction by comparing the average of VAS values reported in the patient diary every week and after the end of treatment than the average VAS values recorded before treatment. The VAS scale for the assessment of pain relief assessed by comparison of VAS values at each visit with the value measured immediately before treatment VAS  The SF-36 questionnaire for assessing quality of life of patients by comparing the values obtained each visit with the value recorded immediately before treatment. The NPSI questionnaire for assessing the type of pain by comparing the values obtained at each visit with the value recorded immediately before treatment.

La scala VAS per la valutazione della riduzione del dolore tramite comparazione della media dei valori VAS riportati nel diario del paziente ad ogni settimana e dopo la fine del trattamento rispetto alla media dei valori VAS registrati prima del trattamento. La scala VAS per la valutazione della riduzione del dolore tramite comparazione dei valori VAS valutati al momento di ogni visita con il valore VAS valutato immediatamente prima del trattamento  Il questionario SF-36 per la valutazione della qualità della vita del paziente tramite comparazione dei valori ottenuti ad ogni visita con il valore registrato immediatamente prima del trattamento.

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

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

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

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1

Number of subjects for this age range:

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2012-03-08.

Yes

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.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)

NON APPLICABILE

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

2012-03-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-09-16

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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