Clinical Trials Register

Summary
EudraCT Number:	2017-004641-25
Sponsor's Protocol Code Number:	2017.12.001
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:	2020-11-04
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

2017-004641-25

A.3

Full title of the trial

Rotation for Optimal Targeting of Albuminuria and Treatment Evaluation (ROTATE-3)

ROTAZIONE DI DIVERSI FARMACI PER LA VALUTAZIONE DEL FARMACO OTTIMALE PER LA RIDUZIONE DELL`ALBUMINURIA (ROTATE 3)

A.3.1

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

A rotation study of different albuminuria lowering drug classes to study individual drug response in diabetic and non diabetic CKD

Rotazione di diversi farmaci che riducono le proteine nelle urine per valutare la risposta nel singolo pazient

A.3.2

Name or abbreviated title of the trial where available

ROTATE-3

A.4.1

Sponsor's protocol code number

2017.12.001

A.5.4

Other Identifiers

Name:

ROTATE-3

Number:

ROTATE-3

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	UNIVERSITY MEDICAL CENTER GRONINGEN
B.1.3.4	Country	Netherlands
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	University Medical Center Groningen
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AOU "Luigi Vanvitelli"
B.5.2	Functional name of contact point	Struttura Complessa Nefrologia e Di
B.5.3	Address:
B.5.3.1	Street Address	Via Maria Longo, n° 50
B.5.3.2	Town/ city	Napoli
B.5.3.3	Post code	80138
B.5.3.4	Country	Italy
B.5.4	Telephone number	0812549409
B.5.5	Fax number	0812549409
B.5.6	E-mail	luca.denicola@unicampania.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) - 30X1 COMPRESSA (DOSE UNITARIA)
D.2.1.1.2	Name of the Marketing Authorisation holder	BRISTOL- MYERS SQUIBB/ASTRAZENECA EEIG
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	Forxiga
D.3.2	Product code	[na]
D.3.4	Pharmaceutical form	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	na
D.3.9.3	Other descriptive name	DAPAGLIFLOZIN
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.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	EPLERENONE PFIZER - "50 MG COMPRESSE RIVESTITE CON FILM " 10X1 COMPRESSE IN BLISTER PVC/AL MONODOSE
D.2.1.1.2	Name of the Marketing Authorisation holder	PFIZER ITALIA S.R.L.
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	Eplerenone
D.3.2	Product code	[na]
D.3.4	Pharmaceutical form	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	EPLERENONE
D.3.9.1	CAS number	107724-20-9
D.3.9.2	Current sponsor code	na
D.3.9.3	Other descriptive name	EPLERENONE
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	50
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Chronic Kidney Disease

Insufficienza renale cronica

E.1.1.1

Medical condition in easily understood language

Presence of a reduction in kidney function

Presenza di una riduzione della funzionalità renale

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	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 determine the correlation between individual albuminuria lowering responses of the MRA eplerenone, SGLT2 inhibitor dapagliflozin and their combination in patients with chronic kidney disease

Determinare la correlazione tra le singole risposte di riduzione dell'albuminuria all'eperenone, l'inibitore di SGLT2 dapagliflozin e la loro associazione in pazienti con iinsufficienza renale cronica

E.2.2

Secondary objectives of the trial

To determine the correlation between office/home blood pressure-lowering responses of eplerenone, dapaglifozin and their combination.
To determine which patients characteristics predict the albuminuria and blood pressure response to eplerenone, dapagliflozin and their combination

Determinare la correlazione tra le risposte di riduzione della pressione arteriosa ambulatoriale/ domiciliare all'eplerenone, al dapaglifozin e alla loro combinazione.

Determinare quali caratteristiche dei pazienti predicono la risposta antialbuminurica e antiipertensiva all'eplerenone, al dapagliflozin e alla loro combinazione

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

eGFR > 30 and < 90 ml/min/1.73m2
Albuminuria = 100 mg/24 hour and = 3500 mg/24 hour
Serum potassium = 5.0 mmol/L
Treatment with ACEi or ARB
Age = 18 years
Written informed consent

eGFR > 30 e < 90 ml/min/1.73m2
Albuminuria = 100 mg/24 ore e = 3500 mg/24 ore
Potassio sierico = 5.0 mmol/L
Trattamento con un ACEi o un ARB
Età = 18 anni
Consenso informato del paziente

E.4

Principal exclusion criteria

Diagnosis of type 1 diabetes mellitus

Urinary protein excretion > 3500 mg/24 hour

Autosomal dominant polycystic kidney disease or autosomal recessive polycystic kidney disease, lupus nephritis, or ANCA-associated vasculitis

Indication for immunosuppressants as per the treating physician’s judgment.

Receiving cytotoxic therapy, immunosuppressive therapy, or other immunotherapy for primary or secondary renal disease within 6 months prior to enrolment.

Active malignancy aside from treated squamous cell or basal cell carcinoma of the skin.

Diabetes type 2 patients with recent (last 6 months) of hyperosmolar hyperglicemic state who are prone to development redistributive hyperkalemia (movement of potassium out of the cells)

Pregnant women and women of child-bearing potential who are not using reliable contraception

Cardiovascular disease: myocardial infarction, angina pectoris, percutanous transluminal coronary angioplasty, coronary artery bypass grafting, stroke, heart failure (NYHA I-IV) < 6 months before inclusion

Uncontrolled blood pressure (office blood pressure > 160 / 100 mmHg)

History of autonomic dysfunction (e.g. history of fainting or clinically significant orthostatic hypotension)

History of amputations

eGFR change > 30% in the last six months before study randomization

Current therapy with renin inhibitor or MRA

Concomitant treatment with ACEi and ARB

Intolerance or contraindications to drugs inhibiting the Renin-Angiotensin-Aldosterone System (RAAS). Cyclosporine A, tacrolimus, trimethoprim due to increased risk of hyperkalemia in combination with eplerenone. Ketoconazole, itraconazole, ritonavir, nelfinavir, clarithromycin, telithromycin and nefazadone, lithium, amiodarone, diltiazem, verapamil due to increase in toxicity when combined with eplerenone. Rifampicin, carbamazepine, phenytoin, phenobarbital due the risk of decreased eplerenone efficacy.

Participation in any clinical investigation within 3 months prior to initial dosing or longer if required by local regulations, and for any other limitation of participation based on local regulations.

Donation or loss of 400 ml or more of blood within 8 weeks prior to initial dosing

History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during the screening.

Any medication, surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of medications

Diagnosi di diabete mellito tipo 1

Proteinuria > 3500 mg/24 ore

Malattia del rene policistico autosomica dominante o malattia del rene policistico autosomica recessiva, nefrite lupica o vasculite ANCA-associata

Indicazione al trattamento immunosoppressivo secondo il giudizio del medico curante.

terapia citotossica, terapia immunosoppressiva o altra immunoterapia per la malattia renale primitiva o secondaria nei 6 mesi precedenti l'arruolamento.

Neoplasia attiva ad eccezione del carcinoma a cellule squamose o basali della cute precedentemente trattato.

Pazienti con diabete di tipo 2 e recenti episodi (ultimi 6 mesi) di stato iperosmolare iperglicemico che sono inclini a sviluppare iperpotassiemia redistributiva (movimento di potassio fuori dalle cellule)

Donne in gravidanza e donne in età fertile che non usano una contraccezione affidabile

Malattie cardiovascolari: infarto miocardico, angina pectoris, angioplastica coronarica percutanea transluminale, bypass aorto-coronarico, ictus, insufficienza cardiaca (NYHA I-IV) <6 mesi prima dell'inclusione

Pressione arteriosa non controllata (pressione arteriosa ambulatoriale > 160/100 mmHg)

Storia di disfunzione autonomica (per esempio storia di svenimenti o ipotensione ortostatica clinicamente significativi)

Storia di amputazioni

Cambiamento eGFR> 30% negli ultimi sei mesi prima della randomizzazione

Terapia attuale con inibitori della renina o MRA (antagonisti recettoriali dei mineralcorticoidi)

Trattamento concomitante con ACEi e ARB

Intolleranza o controindicazioni ai farmaci che inibiscono il sistema renina-angiotensina-aldosterone (RAAS). Ciclosporina A, tacrolimus, trimethoprim a causa dell'aumentato rischio di iperpotassiemia in combinazione con eplerenone. Ketoconazolo, itraconazolo, ritonavir, nelfinavir, claritromicina, telitromicina e nefazadone, litio, amiodarone, diltiazem, verapamil a causa dell'aumento di tossicità in combinazione con l'eplerenone. Rifampicina, carbamazepina, fenitoina, fenobarbital a causa del rischio di ridotta efficacia dell'eplerenone.

Partecipazione a qualsiasi studio clinico entro 3 mesi prima della somministrazione iniziale o più a lungo se richiesto dalle normative locali e per qualsiasi altra limitazione di partecipazione in base alle normative locali.

Donazione o perdita di 400 ml o più di sangue entro 8 settimane prima della somministrazione iniziale del trattamento di studio

Anamnesi di abuso di droghe o alcol nei 12 mesi precedenti la somministrazione trattamento di studio, o evidenza di tale abuso come indicato dagli esami di laboratorio condotti durante lo screening.

Qualsiasi farmaco, condizione chirurgica o medica che potrebbe alterare in modo significativo l'assorbimento, la distribuzione, il metabolismo o l'escrezione dei farmaci in studio

E.5 End points

E.5.1

Primary end point(s)

Correlation between individual albuminuria response between eplerenone and dapagliflozin.

Correlazione tra la risposta individuale antialbuminurica all'eplerenone e al dapagliflozin

E.5.1.1

Timepoint(s) of evaluation of this end point

24 weeks which corresponds to the sum of the three treatment periods plus the three wash-out periods

24 settimane che corrisponde alla somma dei tre periodi di trattamento più i tre periodi di wash-out

E.5.2

Secondary end point(s)

the degree of correlation in either office or home blood pressure-lowering responses with eplerenone and dapagliflozin
; Correlation between selected biomarkers of interest at baseline such as NT-proBNP and change in albuminuria from baseline during interventions

grado di correlazione di entrambe le risposte di riduzione della pressione arteriosa ambulatoriale e domiciliare al dapaglifozin e all'eplerenone; Correlazione tra i biomarkers di interesse misurati al basale come NT-proBNP ed il cambiamento dell'albuminuria rispetto al basale durante gli interventi farmacologici

E.5.2.1

Timepoint(s) of evaluation of this end point

24 weeks which corresponds to the sum of the three treatment periods plus the three wash-out periods; 24 weeks which corresponds to the sum of the three treatment periods plus the three wash-out periods

24 settimane che corrisponde alla somma dei tre periodi di trattamento più i tre periodi di wash-out; 24 settimane che corrisponde alla somma dei tre periodi di trattamento più i tre periodi di wash-out

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

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

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

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)

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

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

F.3.3.1

Women of childbearing potential not using contraception

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

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)

Patients will receive routine treatment on an outpatient basis

I pazienti riceveranno le cure ordinarie in regime ambulatoriale

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

2018-10-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-07-17

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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