Clinical Trials Register

Summary
EudraCT Number:	2021-000726-10
Sponsor's Protocol Code Number:	ADAPT
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2021-000726-10

A.3

Full title of the trial

Evaluating the short-term renal and systemic effects of Dapagliflozin in non-diabetic patients with stage IV CKD at risk of ESKD because of severe renal insufficiency and persistent proteinuria: A prospective, randomized, double-blind, placebo-controlled, cross-over study

Valutazione degli effetti renali e sistemici a breve termine di Dapagliflozin, in pazienti non diabetici con CKD allo stadio IV a rischio di ESKD per grave insufficienza renale e proteinuria persistente: uno studio prospettico, randomizzato, in doppio cieco, controllato con placebo, con disegno cross-over

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

Dapagliflozin in non-diabetic stage IV CKD

Dapagliflozin in pazienti non diabetici con insufficienza renale cronica al IV stadio

A.4.1

Sponsor's protocol code number

ADAPT

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	IRCCS- ISTITUTO DI RICERCHE FARMACOLOGICHE MARIO NEGRI
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	AstraZeneca
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	Istituto di Ricerche Farmacologiche Mario Negri IRCCS
B.5.2	Functional name of contact point	Lab. Attività Regolatorie Studi Cli
B.5.3	Address:
B.5.3.1	Street Address	Via G.B. Camozzi, 3
B.5.3.2	Town/ city	Ranica - BG
B.5.3.3	Post code	24020
B.5.3.4	Country	Italy
B.5.4	Telephone number	0354535307
B.5.5	Fax number	0354535371
B.5.6	E-mail	paola.boccardo@marionegri.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	FORXIGA - 10 MG - COMPRESSE RIVESTITE CON FILM- USO ORALE - BLISTER CALENDARIZZATO (ALU/ALU) - 28 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	ASTRAZENECA AB
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	dapagliflozin
D.3.2	Product code	[dapagliflozin]
D.3.4	Pharmaceutical form	Film-coated tablet
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	dapagliflozin
D.3.9.1	CAS number	461432-26-8
D.3.9.2	Current sponsor code	BMS-512148-05
D.3.9.3	Other descriptive name	dapagliflozin propanediol
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	10
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.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	Film-coated tablet
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

Non-diabetic stage IV Chronic Kidney Disease (CKD)

Insufficienza renale cronica non diabetica IV stadio

E.1.1.1

Medical condition in easily understood language

Non-diabetic stage IV Chronic Kidney Disease (CKD)

Insufficienza renale cronica non diabetica IV stadio

E.1.1.2

Therapeutic area

Diseases [C] - Male diseases of the urinary and reproductive systems [C12]

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	10009119
E.1.2	Term	Chronic renal failure
E.1.2	System Organ Class	100000004857

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 assess whether:
1. Six-week treatment with 10 mg dapagliflozin daily as compared to six-week treatment with placebo may induce a significant reduction in measured GFR (taken as a marker of amelioration of glomerular hyperfiltration)
2. Amelioration of glomerular hyperfiltration translates into a significant reduction in 24-hour urinary protein excretion (taken as a marker of amelioration of glomerular sieving function).

Valutare se:
1 Un trattamento di sei settimane con 10 mg di dapagliflozin al giorno può indurre una riduzione significativa del GFR misurato (considerato come un marker di miglioramento dell'iperfiltrazione glomerulare) rispetto ad un trattamento di sei settimane con placebo;
2 Il miglioramento dell'iperfiltrazione glomerulare si traduce in una significativa riduzione dell'escrezione urinaria di proteine nelle 24 ore (considerata come un marcatore di miglioramento della funzione di “setaccio” del glomerulo).

E.2.2

Secondary objectives of the trial

To assess treatment effect on renal perfusion, markers of glomerular hemodynamics and tubular function, and clinical and metabolic/ laboratory parameters in the study group as a whole and in patients with or without pre-diabetes (2-hour plasma glucose during 75-gram oral glucose tolerance test (OGTT) > or < 140 mg/dl) considered separately.

Valutare l'effetto del trattamento sulla perfusione renale, sui marcatori dell'emodinamica glomerulare e della funzione tubulare e sui parametri clinici e metabolici/di laboratorio, sia nel gruppo di studio nel suo complesso che nei pazienti in presenza o in assenza di condizione pre-diabetica, (valori di glucosio plasmatico 2 ore dopo test da carico orale con 75 grammi di glucosio > o <140 mg/dl, rispettivamente) considerati separatamente.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1 Provision of informed consent prior to any study specific procedures
2 Male or female more than 18 year old
3 Non-diabetic Stage-IV CKD
4 Fasting blood glucose = 125 mg (= 6.9 mmol/l) and HbA1C =6.4% (= 47 mmol/mol)58 without treatment with oral blood glucose lowering medications and/or insulin
5 Two-hour plasma glucose <200 mg/dl during 75-g oral glucose tolerance test (OGTT)58
6 Persistent proteinuria (24-hour urinary protein excretion = 0.5 grams in at least two consecutive evaluations >1 week apart) despite RAS inhibitor therapy with ACE inhibitors and/or ARBs (or without RAS inhibitors in patients with specific contraindications to these medications)
7 eGFR 15 to 30 ml/min/1.73 m2 by CKD-Epi equation
8 Blood pressure <150/90 mmHg without changes in blood pressure lowering medications over the last four weeks before the randomization
9 Negative pregnancy test (urine or serum) for female subjects of childbearing potential.
10 Female subjects must be 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception (an acceptable method of contraception is defined as a barrier method in conjunction with a spermicide) for the duration of the study (from the time they sign consent) and for 3 months after the last dose of dapagliflozin\placebo to prevent pregnancy. In addition, oral contraceptives, approved contraceptive implant, long-term injectable contraception, intrauterine device, or tubal ligation are allowed. Oral contraception alone is not acceptable; additional barrier methods in conjunction with spermicide must be used.
11 Male subjects must be surgically sterile or using an acceptable method of contraception (defined as barrier methods in conjunction with spermicides) for the duration of the study (from the time they sign consent) and for 3 months after the last dose of IMP to prevent pregnancy in a partner.
12 Subjects who are blood donors should not donate blood during the study and for 3 months following their last dose of dapagliflozin\placebo.

1. Consenso informato prima di qualsiasi procedura specifica dello studio
2. Maschi e femmine di età superiore a 18 anni
3. CKD non-diabetica allo stadio IV
4. Glicemia a digiuno = 125 mg (= 6.9 mmol/l) e HbA1C =6.4% (= 47 mmol/mol), in assenza di trattamento con farmaci ipoglicemizzanti orali e/o insulina
5. Glicemia <200 mg/dl 2 ore dopo test da carico orale (OGTT) con 75-g di glucosio
6. Proteinuria persistente (escrezione urinaria di proteine nelle 24 ore = 0.5 grammi in almeno due misurazioni consecutive a distanza di 1 settimana), nonostante terapia anti-RAS con ACE inibitori e/o ARBs (oppure con farmaci non inibitori RAS in pazienti con specifiche controindicazioni a questi farmaci)
7. eGFR compreso tra 15 e 30 ml/min/1.73m2, calcolato con l’equazione CKD-Epi
8. Pressione sanguigna <150/90 mmHg, e nessuna modifica alla terapia antipertensiva nelle 4 settimane antecedenti la randomizzazione
9. Test di gravidanza negativo (urine o siero) per soggetti di sesso femminile in età fertile
10. I soggetti di sesso femminile devono essere in post-menopausa da 1 anno, chirurgicamente sterili o devono utilizzare un metodo contraccettivo accettabile (definito come una combinazione di un metodo di barriera con uno spermicida) per tutta la durata dello studio (da quando viene firmato il consenso) e per i 3 mesi successivi all'ultima somministrazione di dapagliflozin/placebo per prevenire la gravidanza. Inoltre, sono consentiti contraccettivi orali, impianti contraccettivi approvati, contraccezione iniettabile a lungo termine, dispositivi intrauterini o legatura delle tube. La contraccezione orale da sola non è accettabile; devono essere utilizzati metodi di barriera aggiuntivi in combinazione con uno spermicida.
11. I soggetti di sesso maschile devono essere chirurgicamente sterili o utilizzare un metodo contraccettivo accettabile (definito come una combinazione di metodi di barriera con spermicidi) per tutta la durata dello studio (da quando viene firmato il consenso) e per i 3 mesi successivi all'ultima somministrazione di IMP per prevenire la gravidanza nel partner.
12. I soggetti donatori di sangue devono evitare di donare il sangue per tutta la durata dello studio e per i 3 mesi successivi all‘ultima somministrazione di dapagliflozin/placebo.

E.4

Principal exclusion criteria

1 Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site)
2 Participation in another clinical study with an investigational product during the last month
3 Ischemic kidney disease (because of possible excess risk of acute kidney injury upon SGLT2-inhibitor associated reduction in sodium pool and kidney perfusion pressure)
4 Rapidly progressive kidney disease (e GFR reduction = 30% over the last three months) and expected risk of progression to end stage kidney failure and need of renal replacement therapy by dialysis or transplantation during the study period.
5 Active systemic autoimmune diseases;
6 Concomitant treatment with steroids or any other immunosuppressive agent
7 Hypersensitivity to the active principle (dapagliflozin) or any of the excipients (e.g. lactose);
8 Severe/unstable heart failure with or without decreased systolic function requiring hospitalization or changes in pharmacological therapy over the last three months
9 Uncontrolled hypertension (BP >150/90 mmHg despite optimized pharmacological treatment and diet or symptomatic hypotension
10 Positive hepatitis C antibody hepatitis B virus surface antigen or hepatitis B virus core antibody, at screening
11 Known to have tested positive for human immunodeficiency virus
12 Drug or alcohol abuse
13 Inability to fully understand the possible risks and benefits related to study participation
14 If female, the subject is pregnant or lactating or intending to become pregnant before, during, or within 90 days after last dose; or intending to donate ova during such time period;
15 If male, the subject intends to donate sperm while on the study this study or for 90 days after last dose;
16 Participation in another interventional clinical trial within the 4 weeks prior to screening.

1. Coinvolgimento nella pianificazione e/o conduzione dello studio;
2. Partecipazione ad un altro studio farmacologico nel mese precedente;
3. Malattia renale ischemica (dovuta al possibile aumento del rischio di insufficienza renale acuta in seguito alla riduzione del pool di sodio e della pressione di perfusione renale associate alla somministrazione di un'inibitore SGLT2)
4. Malattia renale rapidamente progressiva (riduzione del eGFR = 30% negli ultimi 3 mesi) e rischio atteso di progressione verso l'insufficienza renale allo stadio terminale e necessità di terapia renale sostitutiva mediante dialisi o trapianto durante il periodo dello studio.
5. Malattie autoimmuni sistemiche attive
6. Terapia concomitante con steroidi o altri farmaci immunosoppressivi
7. Ipersensibilità al principio attivo (dapagliflozin) o ad uno qualsiasi degli eccipienti (come il lattosio);
8. Insufficienza cardiaca severa/instabile, con o senza riduzione della funzione sistolica, che ha richiesto ospedalizzazione o eventuali modifiche alla terapia farmacologica negli ultimi 3 mesi;
9. Ipertensione incontrollata (BP >150/90 mmHg), nonostante terapia farmacologica/dieta ottimizzate o ipotensione sintomatica;
10. Positività allo screening verso l’anticorpo dell’epatite C, l’antigene di superficie dell’epatite B, o l’anticorpo core dell’epatite B;
11. Positività al virus dell'HIV;
12. Abuso di droga o alcol
13. Incapacità a comprendere pienamente i possibili rischi e benefici legati alla partecipazione allo studio;
14. Paziente di sesso femminile: gravidanza o allattamento, ovvero intenzione di avere un figlio o di donare gli ovuli prima, durante, o nei 90 giorni successivi all’ultima somministrazione del farmaco;
15. Paziente di sesso maschile:, il soggetto intende donare lo sperma nel corso dello studio o nei 90 giorni successivi all’ultima somministrazione del farmaco;
16. Partecipazione ad un altro studio clinico sperimentale nelle 4 settimane antecedenti lo screening.

E.5 End points

E.5.1

Primary end point(s)

1. GFR measured by the Iohexol plasma clearance technique59
2. 24-hour urinary protein excretion (median of three measurements in three consecutive 24-hour urine collections at start and at the end of each Treatment Period with dapagliflozin or placebo)

1 GFR misurato con la tecnica di clearance plasmatica dello ioexolo
2 Escrezione urinaria di proteine nelle 24 ore (mediana di tre misurazioni in tre raccolte consecutive di urine nelle 24 ore all'inizio e alla fine di ciascun periodo di trattamento con dapagliflozin o placebo)

E.5.1.1

Timepoint(s) of evaluation of this end point

In each visit of the study.

In ogni visita dello studio.

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

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)

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.8.6 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)

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)

After a subject has ended his/her participation in the trial he/she will be treated with the best therapy available.

Al termine della loro partecipazione allo studio i pazienti saranno trattati con la migliore terapia disponibile.

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

2021-06-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-04-16

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

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials