Clinical Trials Register

Summary
EudraCT Number:	2012-000776-42
Sponsor's Protocol Code Number:	FLO-01
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:	2012-09-03
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

2012-000776-42

A.3

Full title of the trial

Febuxostat for Tumor Lysis Syndrome Prevention in Hematologic Malignancies: a Randomized, Double Blind, Phase III Study versus Allopurinol

Febuxostat per la prevenzione della sindrome da lisi tumorale nei tumori ematologici: uno studio di fase III in doppio cieco, randomizzato, controllato verso allopurinolo

A.3.1

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

Febuxostat for Tumor Lysis Syndrome Prevention in Hematologic Malignancies

Febuxostat per la prevenzione della sindrome da lisi tumorale nei tumori ematologici

A.3.2

Name or abbreviated title of the trial where available

FLORENCE

A.4.1

Sponsor's protocol code number

FLO-01

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	MENARINI RICERCHE 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	Menarini Ricerche S.p.A
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	Menarini Ricerche S.p.A
B.5.2	Functional name of contact point	Direzione Ricerca Clinica
B.5.3	Address:
B.5.3.1	Street Address	Via Sette Santi, 1
B.5.3.2	Town/ city	Firenze
B.5.3.3	Post code	50131
B.5.3.4	Country	Italy
B.5.4	Telephone number	+39 055 5680 9933
B.5.5	Fax number	+39 055 5680 597
B.5.6	E-mail	ACapriati@menarini-ricerche.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	Adenuric® 120 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Menarini International Operations Luxembourg S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	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	FEBUXOSTAT
D.3.9.1	CAS number	144060-53-7
D.3.9.4	EV Substance Code	SUB25382
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	120
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	No
D.IMP: 2
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	Zyloric® 100 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	mibe GmbH Arzneimittel
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	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	Allopurinolo
D.3.9.1	CAS number	315-30-0
D.3.9.4	EV Substance Code	SUB05338MIG
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	100
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	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
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

Tumor Lysis Syndrome

Sindrome da Lisi Tumorale

E.1.1.1

Medical condition in easily understood language

Tumor Lysis Sindrome results from the rapid killing of a large quantity of tumor cells which occurs most often after the start of chemotherapy in patients with hematologic cancers.

La Sindrome da Lisi Tumorale è causata della rottura di una grande quantità di cellule tumorali; ciò può verificarsi all'inizio della chemioterapia in pazienti con neoplasie ematologiche.

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	15.0
E.1.2	Level	SOC
E.1.2	Classification code	10027433
E.1.2	Term	Metabolism and nutrition disorders
E.1.2	System Organ Class	10027433 - Metabolism and nutrition disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.0
E.1.2	Level	PT
E.1.2	Classification code	10045170
E.1.2	Term	Tumour lysis syndrome
E.1.2	System Organ Class	10027433 - Metabolism and nutrition disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.0
E.1.2	Level	LLT
E.1.2	Classification code	10045152
E.1.2	Term	Tumor lysis syndrome
E.1.2	System Organ Class	10027433 - Metabolism and nutrition disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To compare the efficacy of febuxostat with allopurinol, in terms of serum uric acid (sUA) level control and preservation of renal function after seven days of treatment (Day 8) starting from 2 days prior chemotherapy (Day 1).

Confrontare l’efficacia di febuxostat con allopurinolo, in termini di controllo del livello di acido urico nel siero (sUA) e conservazione della funzione renale dopo sette giorni di trattamento (Giorno 8) a partire da 2 giorni prima della chemioterapia (Giorno 1).

E.2.2

Secondary objectives of the trial

- To compare the efficacy of Febuxostat with Allopurinol, in terms of: • maintenance of sUA levels ≤ 7.5 mg/dL, • occurrence of laboratory TLS (LTLS) according to Cairo-Bishop criteria (see Appendix I, section 13.1). • occurrence of clinical TLS (CTLS) according to Cairo-Bishop criteria (see Appendix I, section 13.1). - To compare the safety of Febuxostat with Allopurinol during the entire treatment period.

Confrontare l’efficacia di febuxostat con allopurinolo, in termini di: - Mantenimento dei livelli sUA ≤ 7,5 mg/dl. - Incidenza di TLS in laboratorio (LTLS) e clinica (CTLS) in base ai criteri Cairo-Bishop (vedere Appendice I del protocollo, sezione 13.1) Confrontare la sicurezza di febuxostat con allopurinolo.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Male or female patients a. aged ≥ 18 years b. scheduled for first cytotoxic chemotherapy cycle, regardless of the line of tratment, because of hematologic malignancies, and c. at intermediate or high risk of TLS (see Appendix II, section 13.2 for risk stratification), and d. with baseline sUA levels < 10 mg/dL at randomization (Visit 1), and e. candidate to allopurinol tratment or have no access to rasburicase. 2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3 3. Female of childbearing potential may be enrolled providing a negative pregnancy test at baseline and using a highly effective method of birth control resulting in a low failure rate (i.e. less than 1% per year); 4. Able to give written informed consent before any study related procedure; 5. Able to attend all the visits scheduled in the study; 6. Life expectancy > 1 months.

1. Pazienti di sesso maschile e femminile di età ≥ 18 anni e, in lista per il primo ciclo di chemioterapia citotossica, indipendentemente dalla linea di trattamento, a causa di tumori ematologici, con un rischio intermedio o elevato di TLS (vedere Appendice II sezione 13.2 del protocollo, per stratificazione del rischio), con livelli sUA < 10 mg/dl alla randomizzazione (Visita 1) e candidati per il trattamento con allopurinolo o privi di accesso al Rasburicase. 2. Stato di performance ECOG (Eastern Cooperative Oncology Group) da 0 a 3. 3. Le pazienti femmine potenzialmente fertili possono essere arruolate a condizione che presentino un test di gravidanza negativo allo screening e utilizzino un metodo contraccettivo altamente efficace con basso tasso di insuccesso (cioè inferiore a 1% all’anno). 4. Soggetti in grado di fornire un consenso informato scritto prima di qualsiasi procedura correlata allo studio. 5. Soggetti in grado di presentarsi a tutte le visite previste dallo studio. 6. Aspettativa di vita > 1 mese.

E.4

Principal exclusion criteria

1. Patients known to be hypersensitive to Febuxostat or Allopurinol or to any of the components of the formulations; 2. Patients with hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose-galactase malabsoption; 3. Patients with ischemic heart disease or congestive heart failure (CHF); 4. Pregnant or breast feeding women; 5. Patients with sUA levels ≥ 10 mg/dL at baseline (Vist 1); 6. Patients receiving Febuxostat, Allopurinol or any other urate lowering therapy within 30 days prior to randomisation; 7. Patient receiving mercaptopurine and azathioprine within 14 days prior to randomization; 8. High risk patients NOT candidate to allopurinol treatment; 9. Patients with severe renal insuffuciency 10. Patients with severe hepatic insufficiency; 11. Patients with a diagnosis of LTLS or CTLS at randomization (Visit 1) 12. Patients with any serious concomitant illness which, in the opinion of the Investigator, is incompatible with the protocol; 13. Patients receiving any other investigational agent within 30 days prior to randomization.

1. Pazienti con ipersensibilità nota a febuxostat o allopurinolo o a qualsiasi altro componente delle formulazioni. 2. Pazienti con problemi ereditari di intolleranza al galattosio, deficit di lattasi di Lapp o malassorbimento di glucosio-galattosio. 3. Pazienti con patologia cardiaca ischemica o insufficienza cardiaca congestizia (CHF). 4. Donne in stato di gravidanza o allattamento. 5. Pazienti con livelli sUA ≥ 10 mg/dl alla randomizzazione (Visita 1). 6. Pazienti che ricevono febuxostat, allopurinolo o qualsiasi altra terapia per l’abbassamento dell’urato (ad es. rasburicase, probenecid) nei 30 giorni precedenti la randomizzazione. 7. Pazienti che ricevono mercaptopurina e azatioprina nei 14 giorni precedenti la randomizzazione. 8. Pazienti a elevato rischio, NON candidati per il trattamento con allopurinolo. 9. Pazienti con grave insufficienza renale. 10. Pazienti con insufficienza epatica grave. 11. Pazienti con diagnosi di LTLS o CTLS alla randomizzazione (Visita 1). 12. Pazienti con qualsiasi altra patologia concomitante grave che, a parere dello sperimentatore, sia incompatibile con il protocollo. 13. Pazienti che ricevono un qualsiasi altro farmaco sperimentale nei 30 giorni precedenti la randomizzazione (Visita 1).

E.5 End points

E.5.1

Primary end point(s)

Co-Primary Efficacy Endpoints: - Area under the curve of sUA from baseline (Day 1) to the evaluation visit (Day 8) (AUC sUA 1-8). - Change in serum creatinine level from baseline (Day 1) to the evaluation visit (Day 8).

Endpoint di efficacia co-primari: - Area sotto la curva di sUA dal basale (Giorno 1) alla visita di valutazione (Giorno 8) (AUC sUA 1-8). - Variazione nel livello di creatinina nel siero dal basale (Giorno 1) alla visita di valutazione (Giorno 8).

E.5.1.1

Timepoint(s) of evaluation of this end point

From baseline (Day 1) to the evaluation visit (Day 8).

Dal basale (Giorno 1) alla visita di valutazione (Giorno 8).

E.5.2

Secondary end point(s)

- Assessment of treatment responder rate, where treatment response is defined as maintenance of sUA ≤ 7.5 mg/dL for all measurements from start of chemotherapy (Day 3) to the evaluation visit (Day 8; treatment failure is defined as the presence of two or more consecutive values of sUA missing or >7.5 mg/dL. The assesment will be based on the central laboratory sUA result. - Assessment of LTLS, from start of chemotherapy (Day 3) to the evaluation visit (Day 8) based on local laboratory results. According to Cairo-Bishop definition LTLS is defined by the presence of 2 or more laboratory abnormalities including: a 25% increase or levels above normal for uric acid, potassium, and phosphate or a 25% decrease or levels below normal for calcium. For details, please refer to appendinx 13.1 of the study protocol. - Assessment of CTLS, from start of chemotherapy (Day 3) to the evaluation visit (Day 8). According to Cairo-Bishop definition, CTLS is defined by the presence of LTLS in addition to 1 or more of the following significant clinical complications: renal insufficiency, cardiac arrhythmias, sudden death and seizures. The grade of CTLS is defined by the maximal grade of the clinical manifestation. For details, please refer to appendinx 13.1 of the study protocol.

- Valutazione del tasso di risposta al trattamento, cioè il mantenimento di sUA ≤ 7,5 mg/dl dall’inizio della chemioterapia (Giorno 3) alla visita di valutazione (Giorno 8); l’insuccesso del trattamento viene definito come la presenza di due o più valori consecutivi di sUA mancanti o 7,5 mg/dl. La valutazione sarà basata sul risultato sUA ottenuto dal laboratorio centrale. - Valutazione di LTLS e CTLS, dall’inizio della chemioterapia (Giorno 3) alla visita di valutazione (Giorno 8) sulla base dei risultati del laboratorio locale.

E.5.2.1

Timepoint(s) of evaluation of this end point

from start of chemotherapy (Day 3) to the evaluation visit (Day 8)

dall’inizio della chemioterapia (Giorno 3) alla visita di valutazione (Giorno 8)

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

Yes

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)

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

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

Croatia

Russian Federation

Ukraine

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

last follow up visit of the last patient

ultima visita di follow up per l'ultimo paziente

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

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:

240

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

100

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

200

F.4.2.2

In the whole clinical trial

340

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 the completion of the trial participation, a standard TLS prevention treatment could be applied during the following chemotherapy cycles, as per local standard clinical practice.

Dopo il completamento di questo studio, durante i successivi cicli di chemioterapia, potrà essere istituito un trattamento preventivo standard per la sindrome da lisi tumorale, secondo la pratica clinica locale.

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

2012-07-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-06-27

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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