Clinical Trials Register

Summary
EudraCT Number:	2014-001838-29
Sponsor's Protocol Code Number:	TEATE
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:	2014-07-04
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

2014-001838-29

A.3

Full title of the trial

PrevenTion of contrast‐inducEd nephroAThy with urinE alkalinization: the TEATE study

Prevenzione della nefropatia indotta da mezzo di contrasto con alcalinizzazione delle urine: studio TEATE

A.3.1

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

Prevention of renal insufficiency caused by contrast medium

prevenzione dell’insufficienza renale causata da mezzo di contrasto

A.4.1

Sponsor's protocol code number

TEATE

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	"G. d'Annunzio" University
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	"G. d'Annunzio" University Chieti, Department of Neuroscience and Imaging
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	"G. d'Annunzio" University
B.5.2	Functional name of contact point	Dept. of Neuroscience and Imaging
B.5.3	Address:
B.5.3.1	Street Address	via dei Vestini, 31
B.5.3.2	Town/ city	Chieti
B.5.3.3	Post code	66100
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390871358622
B.5.5	Fax number	00390871402817
B.5.6	E-mail	rdecater@unich.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.2.1.2	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	sodium bicarbonate 1.4% i.v.
D.3.4	Pharmaceutical form	Solution for infusion
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	sodium bicarbonate 14.0 g
D.3.9.1	CAS number	144-55-8
D.3.9.2	Current sponsor code	sodium bicarbonate 1.4% i.v.
D.3.9.3	Other descriptive name	SODIUM HYDROGEN CARBONATE
D.3.9.4	EV Substance Code	SUB12290MIG
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1.4
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	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	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	Yes
D.3.11.13.1	Other medicinal product type	sodium bicarbonate 1.4%
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.2.1.2	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	sodium bicarbonate oral
D.3.4	Pharmaceutical form	Powder for oral solution
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	SODIUM HYDROGEN CARBONATE
D.3.9.1	CAS number	144-55-8
D.3.9.2	Current sponsor code	sodium bicarbonate oral
D.3.9.3	Other descriptive name	SODIUM HYDROGEN CARBONATE
D.3.9.4	EV Substance Code	SUB12290MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	4
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	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	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	Yes
D.3.11.13.1	Other medicinal product type	sodium bicarbonate oral
D.IMP: 3
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	Sodio cloruro 0,9% Baxter
D.2.1.1.2	Name of the Marketing Authorisation holder	Baxter S.p.A.
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	Sodio cloruro 0,9% Baxter
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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	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	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	Yes
D.3.11.13.1	Other medicinal product type	sodium chloride

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

contrast‐induced nephroathy

nefropatia da mezzo di contrasto

E.1.1.1

Medical condition in easily understood language

renal insufficiency caused by contrast medium

insufficienza renale causata da mezzo di contrasto

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	17.0
E.1.2	Level	PT
E.1.2	Classification code	10010836
E.1.2	Term	Contrast media reaction
E.1.2	System Organ Class	10022117 - Injury, poisoning and procedural complications

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	PT
E.1.2	Classification code	10029155
E.1.2	Term	Nephropathy toxic
E.1.2	System Organ Class	10038359 - Renal and urinary 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

We will test the hypothesis that both oral and i.v. bicarbonate are adequate strategies for Contrast Induced Nephropathy (CIN) prevention in patients after coronary angiography. Comparing the incidence of CIN according to urine pH achieved immediately before angiography, we aim at demonstrating that urine alkalinization is the real goal, and that results are here largely independent from the strategy adopted to achieve this goal. We will therefore compare the efficacy in alkalinizing urine and preventing CIN of three different strategies: hydration alone; hydration plus i.v. sodium bicarbonate; and hydration plus oral bicarbonate.

Testare l’ipotesi secondo cui l’alcalinizzazione urinaria, ottenuta con bicarbonato e.v. o bicarbonato per os rispetto alla sola idratazione, sia il principale determinante nel prevenire la nefropatia indotta da mezzo di contrasto (CIN). Confrontando l'incidenza della CIN con il ph urinario, ottenuto immediatamente prima dell'esame contrastografico, il nostro scopo è dimostrare che l'alcalinizzazione urinaria è il principale obiettivo e il risultato è indipendente dala strategia adottata. Confronteremo l'alcalinizzazione delle urine e la prevenzione della CIN tra tre strategie differenti: idratazione, idratazione più sodio bicarbonato e.v. e idratazione più sodio bicarbonato per os.

E.2.2

Secondary objectives of the trial

non‐inferiority results of the oral group compared to i.v. bicarbonate group in alkalinizing urine and preventing CIN

non inferiorità tra il bicarbonato per os e il bicarbonato e.v. nella capacità di alcalinizzazione urinaria e nell’incidenza di CIN

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Consecutive patients scheduled for coronary angiography and/or angioplasty will be considered for enrollment. Patients will be considered eligible if having:
• age ≥18 years;
• eGFR <60 mL/min/1.73 m2, but >15 mL/min/1.73 m2 (MDRD formula).

pazienti consecutivi da sottoporre a coronarografia e/o angioplastica con:
• età ≥18 anni;
• filtrato glomerulare stimato (eGFR) <60 mL/min/1.73 m2 (formula MDRD).

E.4

Principal exclusion criteria

• acute renal insufficiency;
• emergency catheterization (e.g., STEMI patients) preventing the possibility of pretreatments;
• a history of adverse reactions to contrast media;
• use of potentially nephrotoxic drugs (non‐steroidal anti‐inflammatory drugs, aminoglycosides, sulphonamides, ciclosporin, tacrolimus, methotrexate or platinum complexes) from 48 hours before to 24 hours after the procedure, but allowing drugs deemed essential for cardiovascular therapy (diuretics, acetylsalicylic acid, angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers or aliskiren);
• pulmonary edema;
• multiple myeloma and other monoclonal gammopathies;
• factors predisposing to kidney injury: diarrhea, vomiting, dehydration or bleeding;
• exposure to contrast media within 7 days before the procedure;
• pregnancy;
• use of N‐acetyl cysteine, teophylline, dopamine, fenoldopam, mannitol, citrate or bicarbonate within 48 hours before coronary angiography;
• urinary tract infection.

• insufficienza renale acuta;
• cateterizzazione in emergenza (ad es. pazienti con STEMI);
• pregresse reazioni avverse al mezzo di contrasto;
• uso di farmaci nefrotossici (anti‐infiammatori non steroidei, aminoglicosidi, sulfonamidi, ciclosporina, tacrolimus, metotrexate o composti del platino) da 48 ore prima fino a 24 ore dopo la procedura, consentendo l’uso di farmaci considerati essenziali nella terapia cardiovascolare (diuretici, acido acetilsalicilico, ACE‐inibitori, sartani o aliskiren);
• edema polmonare;
• mieloma multiplo o altre gammopatie monoclonali;
• fattori predisponenti al danno renale: diarrea, vomito, disidratazione o emorragia;
• esposizione al mezzo di contrasto entro i 7 giorni precedenti la procedura;
• gravidanza in atto;
• utilizzo di N‐acetil cisteina, teofillina, dopamina, fenoldopam, mannitolo, citrato o bicarbonato nelle 48 ore precedenti la coronarografia;
• infezione delle vie urinarie.

E.5 End points

E.5.1

Primary end point(s)

The incidence of CIN, according to urine alkalinization achieved immediately before angiography (cut‐off pH >6). Our primary hypothesis is that the incidence of CIN according to the above definition is significantly different in patients achieving urine alkalinization compared with patients not achieving it.

Incidenza di CIN, in accordo al grado di alcalinizzazione urinaria raggiunto prima dell’angiografia (cut‐off pH >6). La nostra ipotesi primaria è che l’incidenza di CIN sia significativamente differente nei pazienti che raggiungono adeguata alcalinizzazione urinaria rispetto a chi mantiene un pH <6.

E.5.1.1

Timepoint(s) of evaluation of this end point

48 hours

48 ore

E.5.2

Secondary end point(s)

- the mean change of urine pH from hospital admission to the time of coronary angiography, to compare the capability of the three strategies to alkalinize urine. Our hypothesis is that the proportion of patients achieving urine alkalinization (pH>6) will be greater in patientsallocated to the sodium bicarbonate group or oral sodium/potassium citrate group compared to control group;
- the incidence of CIN in three treatment groups. Our hypothesis is that the proportion of patients that develop a CIN will be greater in patients allocated to control group respect to patients assigned to other groups;
- non‐inferiority comparison between oral sodium bicarbonate group and i.v. sodium bicarbonate group. The non‐inferiority of oral bicarbonate group respect to i.v. sodium bicarbonate group will be evaluated in term of incidence of CIN and proportion of patients achieving urine alkalinization.

- variazione del pH urinario dall’ospedalizzazione all’angiografia, per confrontare la capacità di alcalinizzazione urinaria delle tre strategie preventive impiegate. La nostra ipotesi è che la proporzione di pazienti che raggiungono adeguata alcalinizzazione (pH >6) sarà maggiore nei gruppi trattati con bicarbonato rispetto al gruppo di controllo
- valutazione dell’incidenza di CIN nei tre gruppi di trattamento. La nostra ipotesi è che la proporzione di pazienti che sviluppano CIN sarà maggiore nel gruppo di controllo rispetto agli altri gruppi
- confronto di non‐inferiorità tra il gruppo bicarbonato e.v ed il gruppo bicarbonato per os, sia in termini di incidenza di CIN che di capacità di indurre adeguata alcalinizzazione

E.5.2.1

Timepoint(s) of evaluation of this end point

48 hours

48 ore

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

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

Yes

E.8.4

The trial involves multiple sites in the 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

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

ultima visita dell'ultimo soggetto

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

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:

100

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

140

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2014-07-04.

Yes

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

240

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)

usual care

secondo la pratica clinica

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

2014-10-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-01-08

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

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