Clinical Trials Register

Summary
EudraCT Number:	2016-003126-16
Sponsor's Protocol Code Number:	CANA-1
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-06-08
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

2016-003126-16

A.3

Full title of the trial

A PHASE II, RANDOMIZED, CROSS-OVER, DOUBLE-BLIND, PLACEBO-CONTROLLED, SINGLE CENTER STUDY OF THE EFFECT OF THE ACUTE ADMINISTRATION OF THE SGLT-2 INHIBITOR CANAGLIFLOZIN ON CONTERREGULATORY RESPONSE TO INSULIN-INDUCED HYPOGLYCEMIA

Studio clinico di fase II randomizzato, cross over, in doppio cieco controllato con placebo su singolo centro per valutare l¿effetto acuto della somministrazione dell¿inibitore del SGLT-2 Canagliflozin sulla risposta controregolatoria all¿ipoglicemia indotta dall¿insulina

A.3.1

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

Measurement of the effect of Canagliflozin versus Placebo in type 2 diabetes during insulin-mediated hypoglycemia

Valutazione dell¿effetto di canagliflozin in confronto a placebo in pazienti con diabete di tipo 2 durante l¿ipoglicemia indotta dall¿insulina

A.3.2

Name or abbreviated title of the trial where available

CANA-1

A.4.1

Sponsor's protocol code number

CANA-1

A.5.4

Other Identifiers

Name:

CANA-1

Number:

CANA-1

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 OSPEDALIERO-UNIVERSITARIA PISANA
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	Janssen-Cilag
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	Dip. Univ. Medicina clinica e sperimentale Pisa
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	UO MALATTIE METABOLICHE E DIABETOLOGIA
B.5.2	Functional name of contact point	UO MALATTIE METABOLICHE E DIABETOLO
B.5.3	Address:
B.5.3.1	Street Address	VIA PARADISA 2
B.5.3.2	Town/ city	PISA
B.5.3.3	Post code	56124
B.5.3.4	Country	Italy
B.5.4	Telephone number	050995103
B.5.5	Fax number	050541521
B.5.6	E-mail	stefano.delprato@med.unipi.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	INVOKANA - 300 MG - COMPRESSA RIVESTITA CON FILM - USO ORALE BLISTER (PVC/ALU) - 30 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	JANSSEN-CILAG INTERNATIONAL N.V.
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.3.1	Product name	INVOKANA
D.3.2	Product code	INVOKANA
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CANAGLIFLOZIN
D.3.9.1	CAS number	842133-18-0
D.3.9.2	Current sponsor code	CANAGLIFLOZIN
D.3.9.3	Other descriptive name	CANAGLIFLOZIN
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	300
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	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	Yes
D.2.1.1.1	Trade name	HUMALOG - 100 U/ML SOLUZIONE INIETTABILE 1 FLACONE 10 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	ELI LILLY NEDERLAND BV
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.3.1	Product name	HUMALOG
D.3.2	Product code	HUMALOG
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	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INSULINA LISPRO DA DNA RICOMBINANTE
D.3.9.1	CAS number	133107-64-9
D.3.9.2	Current sponsor code	INSULINA LISPRO DA DNA RICOMBINANTE
D.3.9.3	Other descriptive name	insulin lispro recombinant DNA origin
D.3.10	Strength
D.3.10.1	Concentration unit	U/ml unit(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	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)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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.8.3	Pharmaceutical form of the placebo	Capsule, hard
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

Type 2 diabetes

Diabete 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	PT
E.1.2	Classification code	10067585
E.1.2	Term	Type 2 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 test the hypothesis that a single canagliflozin (300 mg) oral administration in subjects with type 2 diabetes affects glucagon response to insulin-induced hypoglycaemia as compared to placebo

Valutare l¿ipotesi che una singola somministrazione per os di Canagliflozin (300 mg) in confronto con placebo moduli la secrezione di glucagone durante l¿ipoglicemia indotta da insulina in pazienti con diabete tipo 2.

E.2.2

Secondary objectives of the trial

To test the hypothesis that a single canagliflozin (300 mg) oral administration in subjects with type 2 diabetes affects during hypoglycaemia as compared to placebo:
- Endogenous glucose production
- FFA, lactate, alanine, glycerol.
- Insulin
- C-peptide, cortisol, growth hormone
- Adrenaline and noradrenaline
- Hypoglycemic symptom score with the Edinburgh Hypoglycemia Symptom Scale, a subjective, validated questionnaire that measures the intensity of commonly experienced hypoglycemic symptoms on a 7-point Likert scale (1 = not present, 7 = very intense) (Performed by Dr. Angela Dardano).
- Cognitive function measured by Mini Mental State Examination (MMSE) and Mental
Deterioration Battery (modified version) (MDB) (Performed by Dr. Angela Dardano).
- Change in area under the curve of glucose infusion rate as average amount of glucose infused.

Valutare l¿ipotesi che una singola somministrazione per os di Canagliflozin (300 mg) in confronto con placebo moduli in pazienti con diabete tipo 2 durante l'ipoglicemia:
- Produzione endogena di glucosio (EGP)
- Acidi grassi liberi (FFA), lattato, alanina, glicerolo
- Insulina
- C-peptide, cortisolo, ormone della crescita
- Adrenalina e noradrenalina
- Score associato ai sintomi di ipoglicemia mediante l¿Edinburgh Hypoglycemia Symptom Scale, un questionario soggettivo e validato che misura l¿intensit¿ dei sintomi associati all¿ipoglicemia in base a una scala Likert a 7 punti (1= non presente: 7=molto intenso) (sar¿ eseguito dalla Dr.ssa Angela Dardano).
- Funzione cognitiva studiata mediante il Mini Mental State Examination (MMSE) e il Mental Deterioration Battery (modified version) (MDB) (sar¿ eseguito dalla Dr.ssa Angela Dardano)
- Variazione dell¿area sotto la curva della velocita¿ di infusione del glucosio che rappresenta la quantita¿ totale di glucosio somministrata.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Males and females
2. Age = 30-60 years
3. BMI= = 35 Kg/m2 and stable weight (± 3 lbs) over the preceding three months
4. Type 2 diabetes (HbA1c > 7 % and < 9.5 %)
5. Drug naive or metformin on stable dose more than 3 months
6. Subjects who are women of childbearing potential must agree to utilize a highly effective contraceptive measure throughout the
course of the study for the entire duration of the trial and the subsequent 30-day follow-up
7. Subjects are capable of giving informed consent

1. Uomo o Donna
2. Eta’= 30-60 anni
3. BMI inferiore o uguale 35 Kg/m2 e peso stabile (± 1.5 Kg) nei precedenti 3 mesi
4. Diabete tipo 2 (HbA1c > 7 % e < 9.5%)
5. Nessun trattamento o trattamento con metformina a dosaggio stabile da piu’ di 3 mesi.
6. Donne in età fertile che accettino di utilizzare metodi contraccettivi altamente efficaci durante il corso dello studio e per i successivi 30 giorni di follow up
7. Soggetti in grado di dare il consenso informato

E.4

Principal exclusion criteria

1. Drugs known to affect glucose metabolism (other than metformin)
2. Known Canagliflozin Excipient Hypersensitivity
3. Liver function enzymes higher more than two times the upper limit
4. Heart Failure (NYHA III-IV)
5. Ongoing urinary tract infection
6. Blood pressure >140/90 mmHg
7. Loop diuretics or thiazide diuretics therapy
8. Hematocrit > 52%
9. Type 1 Diabetes
10. Diabetic Ketoacidosis
11. GFR <60 ml/min/1.73 m2
12. Volume depletion, hypotension or electrolytes imbalance
13. Evidence of proliferative diabetic retinopathy, or 24-hour urinary albumin excretion > 300 mg
14. Donation of blood to a blood bank, blood transfusion, or participation in a clinical study requiring withdrawal of > 400 mL of blood during the 8 weeks prior to the enrollment visit and at least 8 weeks thereafter
15. Women who are pregnant or breastfeeding
16. Patient with a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance which, in the opinion of the investigator or coordinator, might pose an unacceptable risk to the patient or interfere with trial procedures

1. Farmaci in grado di alterare il metabolismo del glucosio (diversi da metformina)
2. Ipersensibilita’ nota agli eccipienti di Canagliflozin
3. Alterazione grave della funzione epatica (livelli di AST e ALT superiori di due volte ai limiti normali)
4. Insufficienza cardiaca (classe NYHA III-IV)
5. Infezione in corso delle vie urinarie
6. Pressione arteriosa > 140/90 mmHg
7. Terapia con diuretici dell’ansa o tiazidici
8. Ematocrito > 52%
9. Diabete mellito di tipo I
10. Chetoacidosi diabetica
11. Compromissione renale con GFR < 60 ml/min/1.73 m2
12. Deplezione del volume, Ipotensione e/o sbilanciamento elettrolitico
13. Evidenza di retinopatia proliferativa o escrezione di albumina urinaria (24 ore) maggiore di > 300 mg
14. Donazione di sangue, trasfusione di sangue o partecipazione a studi clinici che hanno richiesto un prelievo di sangue maggiore di 400 ml durante 8 settimane precedenti all’arruolamento
15. Donne in gravidanza o in allattamento
16. Pazienti con storia o evidenza corrente di ogni condizione, terapia, anomalia di laboratorio o altre circostanze che a giudizio dell’investigatore la cui partecipazione allo studio comporta un rischio inaccettabile per il paziente.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the change in plasma glucagon concentration during the hypoglycemic clamp and during the recovery phase with canagliflozin vs. placebo in patients with type 2 diabetes

l’endpoint primario e’ la variazione media della concentrazione di glucagone plasmatico durante il clamp ipoglicemico e la fase di recupero dall’ipoglicemia in risposta a Canagliflozin rispetto al placebo in pazienti con diabete di tipo 2

E.5.1.1

Timepoint(s) of evaluation of this end point

This timepoint will be achieved in a three years study

Questo timepoint sarà raggiunto durante lo studio di tre anni

E.5.2

Secondary end point(s)

The secondary end-points are changes during hypoglycemic clamp and during the recovery phase in:
- Endogenous glucose production
- FFA, lactate, alanine, glycerol.
- Insulin
- C-peptide, cortisol, growth hormone
- Adrenaline and noradrenaline
- Hypoglycemic symptom score with the Edinburgh Hypoglycemia Symptom Scale, a subjective, validated questionnaire that measures the intensity of commonly experienced hypoglycemic symptoms on a 7-point Likert scale (1 = not present, 7 = very intense) (Performed by Dr. Angela Dardano).
- Cognitive function measured by Mini Mental State Examination (MMSE) and Mental
Deterioration Battery (modified version) (MDB) (Performed by Dr. Angela Dardano).
- Change in area under the curve of glucose infusion rate as average amount of glucose infused.

Gli endopoints secondari sono la variazione durante il clamp ipoglicemico e la fase di recupero dall¿ipoglicemia, di:
- Produzione endogena di glucosio
- Acidi grassi liberi (FFA), lattato, alanina, glicerolo
- Insulina
- C-peptide, cortisolo, ormone della crescita
- Adrenalina e noradrenalina
- Score associato ai sintomi di ipoglicemia mediante l¿Edinburgh Hypoglycemia Symptom Scale, un questionario soggettivo e validato che misura l¿intensit¿ dei sintomi associati all¿ipoglicemia in base a una scala Likert a 7 punti (1= non presente: 7=molto intenso) (sar¿ eseguito dalla Dr.ssa Angela Dardano).
- Funzione cognitiva studiata mediante il Mini Mental State Examination (MMSE) e il Mental Deterioration Battery (modified version) (MDB) (sar¿ eseguito dalla Dr.ssa Angela Dardano)
- Variazione dell¿area sotto la curva della velocita¿ di infusione del glucosio che rappresenta la quantita¿ totale di glucosio somministrata.

E.5.2.1

Timepoint(s) of evaluation of this end point

timepoints will be achieved in a three years study

i timepoints saranno raggiunti durante lo studio di tre ann

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

E.6.5

Efficacy

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

Yes

E.6.13.1

Other scope of the trial description

ACUTE EFFECT OF THE SGLT-2 INHIBITOR CANAGLIFLOZIN ON CONTERREGULATORY RESPONSE TO INSULIN-INDUCED HYPOGLYCEMIA

effetto acuto dell¿inibitore del SGLT-2 canagliflozin sulla risposta controregolatoria all¿ipoglicemia indotta dall¿insulina

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

Information not present in EudraCT

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)

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)

The plans for treatment or care after the subject has ended his/her participation will be not affected by this study and they will continue the standard care

I programmi per il trattamento o l'assistenza per i soggetti al termine della loro partecipazione allo studio non saranno influenzati
dallo studio ed essi continueranno lo standard previsto dal centro

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

2016-10-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-10-27

P. End of Trial
P.	End of Trial Status	Ongoing

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