Clinical Trials Register

Summary
EudraCT Number:	2011-003148-39
Sponsor's Protocol Code Number:	NN1250-3561
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-03-07
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2011-003148-39

A.3

Full title of the trial

A 26-week, Multinational, Multi-centre, Open-Labelled, Randomised, Parallel, Efficacy and Safety Comparison of Insulin Degludec and Insulin Detemir in children and adolescents 1 to less than 18 years with type 1 Diabetes Mellitus on a basal-bolus regimen with insulin aspart as bolus insulin.

Una sperimentazione per verificare l'efficacia e la sicurezza dell'insulina degludec in bambini e adolescenti con diabete mellito di tipo 1. Studio internazionale, multicentrico, in aperto, randomizzato a doppio braccio e a gruppi paralleli della durata di 26 settimane che mette a confronto la sicurezza e l'efficacia dell'insulina degludec e dell'insulina detemir come insulina basale in combinazione con l'insulina aspart come insulina rapida in soggetti affetti da diabete di tipo 1 in una fascia d'eta' compresa tra 1 e 17 anni.

A.3.1

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

A trial investigating the efficacy and safety of insulin degludec in children and adolescents with type 1 diabetes mellitus.

Una sperimentazione per verificare l'efficacia e la sicurezza dell'insulina degludec in bambini e adolescenti con diabete mellito di tipo 1.

A.3.2

Name or abbreviated title of the trial where available

BEGIN™: Young 1

A.4.1

Sponsor's protocol code number

NN1250-3561

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1122-4758

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/044/2010

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	NOVO NORDISK
B.1.3.4	Country	Italy
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	Novo Nordisk A/S
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novo Nordisk A/S
B.5.2	Functional name of contact point	Global Clinical Registry (GCR,1452)
B.5.3	Address:
B.5.3.1	Street Address	Vandtaarnsvej 114, VTB
B.5.3.2	Town/ city	Soeborg
B.5.3.3	Post code	DK-2860
B.5.3.4	Country	Denmark
B.5.4	Telephone number	.
B.5.5	Fax number	.
B.5.6	E-mail	clinicatrials@novonordisk.com

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	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	Insulin Degludec
D.3.2	Product code	NA
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Insulin Degludec
D.3.9.1	CAS number	844439-96-9
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	U/ml unit(s)/millilitre
D.3.10.2	Concentration type	up to
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)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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	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	LEVEMIR*PENF 5CART 3ML 100UI/M
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVO NORDISK FARMACEUTICI SpA
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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 injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INSULIN DETEMIR
D.3.9.1	CAS number	169148-63-4
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	SUB02692MIG
D.3.10	Strength
D.3.10.1	Concentration unit	U/ml unit(s)/millilitre
D.3.10.2	Concentration type	up to
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)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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

Diabetes Mellitus, Type 1.

Diabete Mellito di tipo 1.

E.1.1.1

Medical condition in easily understood language

Diabetes Mellitus, Type 1.

Diabete Mellito di tipo 1.

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10045228
E.1.2	Term	Type I diabetes mellitus
E.1.2	System Organ Class	10027433 - Metabolism and nutrition 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 confirm the efficacy of insulin degludec administered once daily plus mealtime insulin aspart in controlling glycaemia with respect to change from baseline in HBA1c after 26 weeks of treatment. This is done by comparing the difference in change in HbA1c between insulin degludec + insulin aspart and insulin detemir + insulin aspart to a non-inferiority limit of 0.4%, and if non-inferiority is confirmed, to a superiority limit of 0%.

Confermare l'efficacia dell'insulina degludec somministrata una volta al giorno con insulina aspart ai pasti nel controllo della glicemia rispetto alla variazione della HbA1c basale dopo 26 settimane di trattamento. Questa conferma si ottiene attraverso il confronto delle differenze di variazione della HbA1c tra l'insulina degludec + insulina aspart e insulina detemir + insulina aspart fino a un limite di non inferiorità dello 0,4% e, se questo limite è confermato, fino a un limite di superiorità dello 0%.

E.2.2

Secondary objectives of the trial

1. To compare the efficacy and safety between the two treatment arms after 26 weeks of treatment in terms of: - Other parameters of glycaemic control - Safety 2. To investigate the pharmacokinetics of insulin degludec and insulin detemir in different age groups using a sparse sampling approach and population PK modelling

Confrontare l'efficacia e la sicurezza tra i due bracci di trattamento dopo 26 settimane di trattamento in termini di: • Altri parametri del controllo glicemico • Sicurezza Verificare le caratteristiche farmacocinetiche dell'insulina degludec e dell'insulina detemir in diversi gruppi d'età utilizzando il metodo di 'sparse sampling'' e un modello farmacocinetico per la popolazione in studio.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Informed consent, and child assent as age-appropriate, obtained before any trial-related activities (Trial-related activities are any procedure that would not have been performed during normal management of the subject). The parents or legal representative of the child must sign and date the Informed Consent Form according to local requirements. The child, if possible, parents or legal representative of the child must sign and date the Child Assent Form according to local requirements. 2) Male or female diagnosed with type 1 diabetes mellitus (T1DM) (based on clinical judgement and supported by laboratory analysis as per local guidelines). 3) Age: 1 to less than 18 years of age at randomisation 4) Ongoing daily treatment with insulin (any regimen) for at least 3 months prior to Visit 1. No OADs are allowed. 5) HbA1c ≤ 11%

1)Consenso informato e assenso del minore, appropriato secondo l'età, ottenuto prima di qualsiasi attività correlata allo studio (le attività correlate allo studio sono rappresentate da qualsiasi procedura non richiesta durante la normale gestione del soggetto). I genitori, o il legale rappresentante, del minore devono firmare e datare in Modulo di consenso informato (in base ai requisiti locali). Il minore, se possibile, i genitori, o il legale rappresentante, del minore deve/devono firmare e datare il Modulo di assenso del minore (in base ai requisiti locali) 2)Soggetti di sesso maschile o femminile con diagnosi di T1DM (in base al giudizio clinico e supportati da analisi di laboratorio come dalle linee guida locali) 3)Età: da 1 a meno di 18 anni alla randomizzazione 4)Trattamento giornaliero con insulina in corso (qualsiasi regime) per almeno 3 mesi prima della Visita 1. Non è consentito l'uso di antidiabetici orali (OADs) 5)HbA1c ≤ 11%

E.4

Principal exclusion criteria

1) Known or suspected hypersensitivity to trial product(s) or related products 2) Previous participation in this trial. Participation is defined as randomisation 3) Girls who are pregnant, breastfeeding or intend to become pregnant 4) Girls, who have had menarche and are not using adequate contraceptive measures according to local requirements 5) Known hypoglycaemic unawareness or recurrent severe hypoglycaemic events as judged by the Investigator 6) More than 1 diabetic ketoacidosis requiring hospitalisation within the last 3 months prior to Visit 1 7) Significant concomitant disease, except for conditions associated with type 1 diabetes mellitus, which in the Investigator's opinion could interfere with the trial 8) The receipt of any investigational drug within 1 month prior to Visit 1

1) Ipersensibilità accertata o sospetta al/ai prodotto/i dello studio o ai prodotti correlati 2) Precedente partecipazione a questo studio. La partecipazione è definita come randomizzazione 3)Ragazze in gravidanza, allattamento o che hanno intenzione di intraprendere una gravidanza 4)Ragazze che hanno avuto il menarca e non utilizzano metodi contraccettivi adeguati secondo i requisiti locali 5)Inconsapevolezza nota dello stato di ipoglicemia o eventi di ipoglicemia grave ricorrenti, in base al giudizio del medico 6) 6) Più di una chetoacidosi diabetica che ha richiesto il ricovero in ospedale entro 3 mesi dalla Visita 1 7) 7) Malattia concomitante significativa, eccetto condizioni associate la diabete di tipo 1, che, secondo il parere dello sperimentatore, possa interferire con lo studio 8) Assunzione di qualsiasi farmaco sperimentale entro 1 mese dalla Visita 1

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in HbA1c (%) after 26 weeks of treatment

Variazione della HbA1c basale (%) dopo 26 settimane di trattamento (analizzata dal laboratorio centrale).

E.5.1.1

Timepoint(s) of evaluation of this end point

After 26 weeks of treatment

Dopo 26 settimane

E.5.2

Secondary end point(s)

1. Change from baseline in fasting blood glucose (FPG) after 26 weeks of treatment (analysed by central laboratory) 2. Number of treatment emergent adverse events (TEAEs) 3. Number of hypoglycaemic episodes (severe episodes or episodes with plasma glucose (PG) ≤ 3.9 mmol/L (70 mg/dL) with or without symptoms of hypoglycaemia) during the trial; nocturnal [11 p.m. - 7 a.m./23:00 – 07:00] and over the entire day (24 hours) after 26 weeks of treatment 4. Number of self-measured hyperglycaemia (episodes of PG > 11.1 mmol/L (200 mg/dL)) after 26 weeks of treatment 5. Number of episodes with self monitored blood ketones >1.5 mmol (capillary blood ketone measurement to be performed if self-measured plasma glucose (SMPG) exceeds 14.0 mmol/l (250 mg/dL)) after 26 weeks of treatment 6. Steady-state plasma concentrations of insulin degludec and insulin detemir on three different visits (three different weeks) during the trial

1.Variazione della glicemia a digiuno (FPG) dopo 26 settimane di trattamento (analizzato dal laboratorio centrale).
2.Numero degli eventi avversi relativi al trattamento (TEAE)
3. Numero degli episodi di Ipoglicemia durante lo studio; Numero e severità degli episodi di ipoglicemia (episodi di PG 70 mg/dL con o senza sintomi di ipoglicemia) durante lo studio; notturna [h. 23:00 - 7:00] e per tutto il giorno (24 ore) dopo 26 settimane di trattamento
4.Numero degli episodi di iperglicemia automisurata (episodi di GP > 200 mg/dL) dopo 26 settimane di trattamento 5.Numero di episodi controllati dal paziente di chetoni ematici >1,5 mmol (misurazione dei chetoni ematici capillari da eseguire se l'SMPG eccede i 250 mg/dL) dopo 26 settimane di trattamento 6.Concentrazioni plasmatiche di insulina degludec e insulina detemir a concentrazioni plasmatiche stabili in tre diverse visite (tre diverse settimane) durante lo studio.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. After 26 weeks of treatment 2. After 26 weeks of treatment 3. After 26 weeks of treatment 4. After 26 weeks of treatment 5. After 26 weeks of treatment 6. After 26 weeks of treatment

1.Dopo 26 settimane 2.Dopo 26 settimane 3.Dopo 26 settimane 4.Dopo 26 settimane 5.Dopo 26 settimane 6.Dopo 26 settimane

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

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Japan

Macedonia, the former Yugoslav Republic of

Russian Federation

South Africa

United States

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

Yes

F.1.1

Number of subjects for this age range:

346

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

266

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

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

131

F.4.2.2

In the whole clinical trial

346

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)

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

2012-02-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-02-14

P. End of Trial
P.	End of Trial Status	Completed

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