Clinical Trials Register

Summary
EudraCT Number:	2015-003563-10
Sponsor's Protocol Code Number:	NN9924-4221
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:	2019-09-06
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

2015-003563-10

A.3

Full title of the trial

A trial investigating the cardiovascular safety of oral semaglutide in subjects with type 2 diabetes

Uno studio clinico per valutare la sicurezza cardiovascolare di semaglutide orale in soggetti affetti da diabete tipo 2

A.3.1

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

A trial investigating the cardiovascular safety of oral semaglutide in subjects with type 2 diabetes

Uno studio clinico per valutare la sicurezza cardiovascolare di semaglutide orale in soggetti affetti da diabete tipo 2

A.3.2

Name or abbreviated title of the trial where available

PIONEER 6 – Cardiovascular outcomes

PIONEER 6 – Esiti Cardiovascolari

A.4.1

Sponsor's protocol code number

NN9924-4221

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1173-0750

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	NOVO NORDISK. S.P.A.
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	Novo Allé
B.5.3.2	Town/ city	Bagsværd
B.5.3.3	Post code	2880
B.5.3.4	Country	Denmark
B.5.4	Telephone number	N/A
B.5.5	Fax number	N/A
B.5.6	E-mail	clinicaltrials@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	semaglutide 3 mg
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	semaglutide
D.3.9.1	CAS number	910463-68-2
D.3.9.2	Current sponsor code	not applicable
D.3.9.3	Other descriptive name	SEMAGLUTIDE
D.3.9.4	EV Substance Code	SUB32188
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	3
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	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	semaglutide
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Semaglutide
D.3.9.1	CAS number	910463-68-2
D.3.9.2	Current sponsor code	not applicable
D.3.9.3	Other descriptive name	SEMAGLUTIDE
D.3.9.4	EV Substance Code	SUB32188
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	7
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
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: 3
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	semaglutide 14 mg
D.3.2	Product code	not applicable
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Semaglutide
D.3.9.1	CAS number	910463-68-2
D.3.9.2	Current sponsor code	non applicabile
D.3.9.3	Other descriptive name	SEMAGLUTIDE
D.3.9.4	EV Substance Code	SUB32188
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	14
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.4	Route of administration of the placebo	Oral use

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 2

Diabete Mellito, tipo 2

E.1.1.1

Medical condition in easily understood language

Type 2 diabetes

Diabete tipo 2

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10045242
E.1.2	Term	Type II diabetes mellitus
E.1.2	System Organ Class	100000004861

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective is to confirm that treatment with oral semaglutide does not result in an unacceptable increase in cardiovascular risk compared to placebo (rule out 80% excess risk) in subjects with type 2 diabetes at high risk of cardiovascular events

L’obiettivo primario è confermare che il trattamento con semaglutide orale non provochi un aumento inaccettabile del rischio cardiovascolare in confronto al trattamento con placebo (esclusione dell’ 80% di eccesso di rischio), in soggetti affetti da diabete tipo 2 ad alto rischio di eventi cardiovascolari.

E.2.2

Secondary objectives of the trial

The secondary objectives are to compare the efficacy and safety of oral semaglutide versus placebo in subjects with type 2 diabetes at high risk of cardiovascular events

Gli obiettivi secondari consistono nel mettere a confronto l’efficacia e la sicurezza di semaglutide orale rispetto al placebo in soggetti affetti da diabete tipo 2 ad alto rischio di eventi cardiovascolari.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female diagnosed with type 2 diabetes
2. Age ≥ 50 years at screening and presence of cardiovascular disease, or age ≥ 60 years at screening and presence of at least one cardiovascular risk factor

1. Soggetti di sesso maschile o femminile a cui è stato diagnosticato il diabete tipo 2.
2. Età ≥ 50 anni allo screening e di una patologia cardiovascolare, oppure età ≥ 60 anni allo screening e presenza di almeno un fattore di rischio cardiovascolare.

E.4

Principal exclusion criteria

1. Current or previous (within 90 days prior to screening) treatment with any GLP-1 receptor agonist, DPP-4 inhibitor or pramlintide
2. Family or personal history of multiple endocrine neoplasia type 2 (MEN 2) or medullary thyroid carcinoma (MTC)
3. History of pancreatitis (acute or chronic)
4. History of major surgical procedures involving the stomach potentially affecting absorption of trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery)
5. Subjects presently classified as being in New York Heart Association (NYHA) Class IV heart failure
6. Planned coronary, carotid or peripheral artery revascularisation known on the day of screening
7. Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or transient ischaemic attack within the past 60 days prior to screening
8. Chronic or intermittent hemodialysis or peritoneal dialysis or severe renal impairment (corresponding to eGFR <30 mL/min/1.73 m^2)
9. History or presence of malignant neoplasms within the last 5 years (except basal and squamous cell skin cancer and carcinoma in situ)

1. Trattamento attuale o pregresso (entro i 90 giorni precedenti lo screening) con qualsiasi agonista del recettore GLP-1, inibitore di DPP-4 o pramlintide.
2. Storia familiare o personale di neoplasia endocrina multipla di tipo 2 (Multiple Endocrine Neoplasia Type 2, MEN 2) o carcinoma midollare della tiroide (Medullary Thyroids Carcinoma, MTC).
3. Storia di pancreatite (acuta o cronica).
4. Storia di interventi chirurgici maggiori che coinvolgono lo stomaco e che influiscono potenzialmente sull’assorbimento del prodotto sperimentale (ad es. gastrectomia parziale o totale, gastrectomia a manica, intervento di bypass gastrico).
5. Soggetti attualmente classificati con insufficienza cardiaca di Classe IV dalla New York Heart Association (NYHA).
6. Pianificazione di procedure di rivascolarizzazione arteriosa periferica, carotidea o coronarica, note il giorno dello screening.
7. Uno qualsiasi dei seguenti eventi: infarto del miocardio, ictus o ricovero in ospedale per angina instabile o per attacco ischemico transitorio nei 60 giorni precedenti lo screening.
8. Emodialisi continua o intermittente, dialisi peritoneale o grave insufficienza renale
(corrispondente a eGFR <30 ml/min/1,73 m2).
9. Diagnosi o storia medica di neoplasie maligne negli ultimi 5 anni (fatta eccezione per il carcinoma basale e squamoso e per il carcinoma in situ).

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is time from randomisation to first occurrence of a major adverse cardiovascular event (MACE) composite endpoint consisting of: cardiovascular death, non-fatal myocardial infarction or non-fatal stroke.

L’endpoint primario è l’intervallo di tempo che va dalla randomizzazione al verificarsi del primo evento avverso cardiovascolare maggiore (MACE), endpoint composito costituito da: morte cardiovascolare, infarto del miocardio non fatale o ictus non fatale.

E.5.1.1

Timepoint(s) of evaluation of this end point

Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months.

La durata massima del trattamento dipende dal tasso di eventi ed è stata stimata non superiore ai 19 mesi.

E.5.2

Secondary end point(s)

1. Time from randomisation to first occurrence of an expanded
composite cardiovascular endpoint consisting of: cardiovascular death,
non-fatal myocardial infarction, non-fatal stroke, unstable angina
requiring hospitalisation or hospitalisation for heart failure
2. Time from randomisation to first occurrence of each of the individual
components in the expanded composite cardiovascular endpoint
3. Time from randomisation to first occurrence of a composite endpoint
consisting of: all-cause death, non-fatal myocardial infarction or nonfatal
stroke

1 - • L’intervallo di tempo dalla randomizzazione al verificarsi del primo endpoint cardiovascolare composito che include: morte cardiovascolare, infarto del miocardio non fatale o ictus non fatale, angina instabile che richieda il ricovero o ricovero per insufficienza cardiaca
2 - • L’intervallo di tempo dalla randomizzazione al primo verificarsi di ciascuno dei componenti individuali dell’endpoint cardiovascolare composito esteso
3 - • L’intervallo di tempo dalla randomizzazione al primo verificarsi di un endpoint composito costituito da: qualsiasi causa di decesso, infarto del miocardio non fatale o ictus non fatale

E.5.2.1

Timepoint(s) of evaluation of this end point

All endpoints: Maximum treatment duration is dependent on event rates
and is estimated to be no longer than 19 months

Per tutti gli Ednpoints: La durata massima del trattamento dipende dal tasso di eventi ed è stata stimata non superiore ai 19 mesi

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

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

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

Information not present in EudraCT

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

Algeria

Argentina

Brazil

Canada

European Union

India

Israel

Malaysia

Mexico

South Africa

Taiwan

Thailand

Turkey

United States

E.8.7

Trial has a data monitoring committee

Yes

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

Number of subjects for this age range:

F.1.1.1

In Utero

Information not present in EudraCT

F.1.1.2

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

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

1588

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

1588

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

Yes

F.3.3.2

Women of child-bearing potential using contraception

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

100

F.4.2

For a multinational trial

F.4.2.1

In the EEA

780

F.4.2.2

In the whole clinical trial

3176

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)

None

Nessuno

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

2016-05-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-04-07

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

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