Clinical Trials Register

Summary
EudraCT Number:	2012-003494-26
Sponsor's Protocol Code Number:	Florence-PROTEST
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:	2012-07-26
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

2012-003494-26

A.3

Full title of the trial

EVALUATION OF THE EFFECT OF TESTOSTERONE REPLACEMENT THERAPY ON PROSTATIC INFLAMMATION AND LOWER URINARY TRACT SYMPTOMS IN HYPOGONADAL SUBJECTS

Valutazione della efficacia della terapia sostitutiva con testosterone sul miglioramento dei sintomi dell' infiammazione prostatica e del basso tratta urinario in soggetti ipogonadici affetti da ipertrofia prostatica benigna e sindrome metabolica

A.3.1

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

EFFECT OF TESTOSTERON THERAPY ON LOW URINARY TRACT

EFFETTO DELLA TERAPIA CON TESTOSTERONE SUL BASSO TRATTO URINARIO

A.3.2

Name or abbreviated title of the trial where available

Florence-PROTEST

A.4.1

Sponsor's protocol code number

Florence-PROTEST

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 OSPEDALIERA UNIVERSITARIA CAREGGI
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	Strakan Pharmaceuticals Ltd
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Azienda Ospedaliero-Universitaria Careggi
B.5.2	Functional name of contact point	Med. della Sessualitࠥ Andrologia
B.5.3	Address:
B.5.3.1	Street Address	Viale Pieraccini 6
B.5.3.2	Town/ city	Firenze
B.5.3.3	Post code	50139
B.5.3.4	Country	Italy
B.5.4	Telephone number	0554271403/415
B.5.5	Fax number	0554271371
B.5.6	E-mail	l.vignozzi@dfc.unifi.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	TOSTREX*GEL MULTID 60G 2%+DOSA
D.2.1.1.2	Name of the Marketing Authorisation holder	PROSTRAKAN Srl
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.3.4	Pharmaceutical form	Gel
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Cutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TESTOSTERONE
D.3.9.1	CAS number	58-22-0
D.3.9.4	EV Substance Code	SUB10937MIG
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	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

metabolic syndrome and BPH patients who will undergo simple prostatectomy

pazienti affetti da BPH in lista di attesa per intervento di prostatectomia e affetti da sindrome metabolica

E.1.1.1

Medical condition in easily understood language

patients who will undergo simple prostatectomy

pazienti candidati ad intervento di prostatectomia

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10004447
E.1.2	Term	Benign prostatic hypertrophy
E.1.2	System Organ Class	100000004872

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluation of the effect of testosterone replacement tharapy on improving lower urinary tract symptoms in hypogonadal patients affected by BPH and metabolic syndrome

Valutazione nei pazienti ipogonadici affetti sia da BPH che sindrome metabolica (MetS) dell’efficacia di 6 mesi di trattamento con testosterone comparato con placebo nel migliorare i sintomi di LUTS (valutati utilizzando il questionario IPSS, International Prostate Symptom Score) ed i sintomi di prostatite (valutati utilizzando il questionario NIH-CPSI, National Institute of Health Chronic Prostatitis Symptom Index) associati a BPH

E.2.2

Secondary objectives of the trial

Evaluation of the effect of testosterone replacement tharapy in hypogonadal patients affected by BPH and metabolic syndrome on improving : 1- ultrasonographic features of prostate 2- prostatic inflammation 3- metabolic parameters 4- semen IL-8 level 5-sexual function 6- hypogonadism-related symptoms 7- urodynamic parametrs

Valutazione nei pazienti ipogonadici affetti sia da BPH che sindrome metabolica (MetS) dell’efficacia di 6 mesi di trattamento con testosterone comparato con placebo nel migliorare: 1- le caratteristiche ultrasonografiche 2- l’infiammazione prostatica 3- i parametri metabolici 4- i livelli seminali di IL-8 5-la funzione sessuale 6- La sintomatologia dell’ipogonadismo 7- I parametri urodinamici

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Adult male subjects (≥18 years old) who are planned fror simple prostatectomy for BPH 2. Diagnosis of Metabolic syndrome(according to AHA/NHLBI) 3. ddiagnosis of prostatic inflammation (NIH-CPSI score >15) 4. Able to understand the study procedures and to sign informed written consent

1. Soggetti maschi di età ≥18 anni in lista di attesa per intervento di prostatectomia semplice per BPH 2. Diagnosi di sindrome metabolica (AHA/NHLBI) definita per la presenza di tre o più dei seguenti parametri: obesità viscerale (circonferenza vita > o =102 cm), glicemia a digiuno (> o =100 mg/dL) o anamnesi positiva per diabete mellito o trattamento con farmaci ipoglicemizzanti; elevati trigliceridi (> o =150 mg/dL) o trattamento, elevati livelli di pressione arteriosa (BP > or = 130/85 mm Hg) o trattamento farmacologico e ridotti livelli di HDL colesterolo (< or =40 mg/dL) o trattamento. 3. Diagnosi di infiammazione prostatica definita per uno punteggio superiore a 15 al questionario NIH-CPSI 4. Capacità ad esprimere il proprio consenso per la partecipazione allo studio, dopo essere stato debitamente informato su scopi, benefici, rischi, tempi e metodi dello studio

E.4

Principal exclusion criteria

1. Partecipation to another clinical study 2. Previous diagnosis of breast or prostatic cancer 3. PSA >4ng/mL 4. Hematocrit ≥52% 5. Use of 5alpha-reductase inhibitors in the previous 3 months ; 6. Psychiatruic disorders 7. Severe disease that unable the patient to partecipate to the study 8. Severe hypersensitivity to the drug

1. Partecipazione ad altra sperimentazione clinica; 2. Diagnosi pregressa, presenza o sospetto di neoplasia maligna della prostata o della mammella; 3. Valori di PSA >4ng/mL 4. Valori di ematocrito≥52% 5. Utilizzo di farmaci inibitori della 5alpha-reduttasi nei tre mesi precedenti; 6. Presenza di una seria patologia organica o mentale diagnosticata da uno specialista psichiatra (per esempio: depressione maggiore in trattamento farmacologico) sospettata sulla base della storia medica e/o sull’esame fisico del paziente 7. Presenza di condizioni che possano condizionare la compliance allo studio; 8. Presenza di severa allergia o ipersensibilità al farmaco in studio (sostanza attiva o eccipienti della formulazione);

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint: to visit 4 each patient will be classified as success / failure based on the following criteria: successful improvement of the score in at least two of the three questionnaires (''NIH-CPSI,'' ''total IPSS'' and ''IPSS bother'') for the evaluation of symptoms related to inflammation protstatica, compared to the values observed at visit 1. For each questionnaire will be considered improved their score based on the following table: NIH-CPSI reduction of at least 2 points of the score to visit 4 compared to visit 1 Reduction of total IPSS score of at least 3 points to visit 4 compared to visit 1 Reduction in IPSS bother score of at least 1 point to visit 4 compared to visit 1 failure: failure to improve the score in at least two of the three questionnaires.

Endpoint primario: alla visita 4 ciascun paziente verrà classificato come successo/insuccesso in base ai seguenti criteri: successo: miglioramento dello score in almeno due di tre questionari (“NHI-CPSI”, “total IPSS” e “bother IPSS”) per la valutazione dei sintomi legati alla flogosi protstatica, rispetto ai valori osservati a visita 1. Per ciascun questionario si considererà migliorato lo score sulla base della seguente tabella: NIH-CPSI Riduzione di almeno 2 punti del punteggio a visita 4 rispetto a visita 1 total IPSS Riduzione di almeno 3 punti del punteggio a visita 4 rispetto a visita 1 bother IPSS Riduzione di almeno 1 punti del punteggio a visita 4 rispetto a visita 1 insuccesso: mancato miglioramento dello score in almeno due dei tre questionari.

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months

6 mesi

E.5.2

Secondary end point(s)

Volumetric change of the prostate: is calculated as the difference between the prostate volume measured at visit 4 and that measured at visit 1. The value of prostate volume is obtained by transrectal ultrasonography and measured using the planimetric method as described by Behre et al., 1995 and Vicari, 1999. Change in the number of macrocalcifications intraprostatiche: will be calculated as the difference between the number of macrocalcifications observed at visit 4 and those observed at visit 1. For macrocalcificazione means the presence of calcification of a diameter> 3 mm, as already reported by Dahnert et al., 1986, Dagash & Mackinnon, 2007, Isidori & Lenzi, 2008 and Lotti et al., 2011. Histological score of inflammation: will be given after surgery to prostatectomy, using immunohistochemical analysis. The degree of inflammation of the prostate will be measured through the use of a score based on the score of 'NHI (Nickel et al., 2001). The parameters of the score will be evaluated by optical microscopy of tissue obtained from the piece at the Institute of Surgical Pathology dell'AOU Careggi. Presence of MetS: In each patient, the diagnosis of MetS parameters will be reevaluated at visit 4, to confirm the presence or absence at the end of treatment. Variation of the concentration of IL-8 in the seminal liquid: it will be calculated as the difference between the value of the concentration of IL-8 in the seminal fluid measured at visit 4 and that measured at visit 1. The dose of IL-8 will be performed by Immuno-absorbent Assay for Enzyme linked (Enzyme-linked immunosorbent assay, ELISA) of fresh semen, collected at visit 1 and visit 4. Improvement of sexual function: for each patient is evaluated the presence of an improvement of sexual function to visit 4, defined as the increase of at least 3 points to the questionnaire IIEF-5, compared to the value observed at visit 1. The IIEF-5 assesses erectile function by 5 questions with a score from 0 to 5, by giving 5 to the best erectile function. Scores range from 1 to 25, and a cut-off of 21 defines erectile dysfunction (score <21). This evaluation will be performed only in the subgroup of patients with score > 22 at visit 1. Improvement of symptoms of hypogonadism: for each patient is evaluated the presence of an improvement in symptoms of hypogonadism at visit 4, defined as a reduction of the score such as to enable to classify the subject in a class of seriousness of symptoms less than that present at the Visit 1 (eg. severe to moderate, moderate to mild, mild to absent). AMS consists of 17 questions (Table 1). The questions investigate the disturbances of the psychological, somatic and sexual, for each question the patient gives a numerical answer ranging from 1 (no symptom) to 5 (very severe symptoms). The assessment of symptoms is obtained from the numerical sum of 17 responses. The symptoms are classified as: • absent: score 17 to 26; • mild: score 27 to 36; • moderate: score 37 to 49; • severe: score ≥ 50. Changes in urodynamic parameters: it will be calculated as the difference between the values of maximum flow rate (Qmax), average flow rate (Qave), void volume (VCOMP) and residual volume post-discharge (PVR) measured at visit 1 and visit 4. The occurrence of adverse events and no serial number and will be recorded for each patient's entire course of treatment.

Variazione volumetrica della prostata: sarà calcolata come differenza fra il volume prostatico misurato a visita 4 e quello misurato a visita 1. Il valore del volume prostatico verrà ricavato mediante esame ecografico transrettale e misurato usando il metodo planimetrico come descritto da Behre et al., 1995 e Vicari, 1999. Variazione del numero delle macrocalcificazioni intraprostatiche: sarà calcolata come differenza fra il numero di macrocalcificazioni osservate a visita 4 e quelle osservate a visita 1. Per macrocalcificazione si intende la presenza di una calcificazione di diametro >3 mm, secondo quanto già riportato da Dahnert et al., 1986, Dagash & Mackinnon, 2007, Isidori & Lenzi, 2008 e Lotti et al., 2011. Score istologico di infiammazione: verrà attribuito, dopo l’intervento chirurgico di prostatectomia, mediante analisi immunoistologica. Il grado di infiammazione prostatica verrà misurato tramite l’uso di un punteggio basato sullo score dell’ NHI (Nickel et al., 2001). I parametri dello score saranno valutati tramite microscopia ottica su tessuto ottenuto dal pezzo chirurgico presso l’Istituto di Anatomia Patologica dell’AOU Careggi. Presenza di MetS: in ciascun paziente, i parametri diagnostici di MetS verranno rivalutati a visita 4, per confermarne o meno la presenza al termine del trattamento. Variazione della concentrazione di IL-8 nel liquido seminale: sarà calcolata come differenza fra il valore della concentrazione di IL-8 nel liquido seminale misurato a visita 4 e quello misurato a visita 1. Il dosaggio di IL-8 sarà eseguito tramite Saggio Immuno-Assorbente legato ad Enzima (Enzyme-Linked ImmunoSorbent Assay; ELISA) su liquido seminale fresco, raccolto alla visita 1 e alla visita 4. Miglioramento della funzione sessuale: per ciascun paziente verrà valutata la presenza di un miglioramento della funzione sessuale a visita 4, definito come l’incremento di almeno 3 punti al questionario IIEF-5, rispetto al valore osservato a visita 1. L’IIEF-5 valuta la funzione erettile tramite 5 domande con punteggio da 0 a 5, attribuendo 5 alla funzione erettile migliore. I punteggi possibili vanno da 1 a 25, ed un cut-off di 21 definisce la disfunzione erettile (punteggio <21). Tale valutazione verrà eseguita solo nel sottogruppo di pazienti con punteggio 22 alla visita 1. Miglioramento della sintomatologia dell’ipogonadismo: per ciascun paziente verrà valutata la presenza di un miglioramento della sintomatologia dell’ipogonadismo a visita 4, definito come riduzione del punteggio tale da permettere di classificare il soggetto in una classe di gravità di sintomatologia inferiore a quella presente alla visita 1 (per es. da severa a moderata; da moderata a lieve; da lieve ad assente). AMS comprende 17 domande (Tabella 1). Le domande indagano i disturbi della sfera psicologica, somatica e sessuale; per ogni domanda il paziente fornisce una risposta numerica variabile da 1 (sintomo assente) a 5 (sintomo molto grave). La valutazione dei sintomi si ottiene dalla somma numerica delle 17 risposte. I sintomi sono classificati come: • assenti: punteggio da 17 a 26; • lievi: punteggio da 27 a 36; • moderati: punteggio da 37 a 49; • severi: punteggio ≥ di 50. Variazione dei parametri urodinamici: sarà calcolata come differenza fra i valori di portata massima (Qmax), portata media (Qave), volume di svuotamento (VCOMP) e volume del residuo post-svuotamento (PVR) misurati a visita 4 e visita 1. La comparsa di eventi e reazioni avverse non serie e serie verrà registrata per ciascun paziente sull’intero corso del trattamento.

E.5.2.1

Timepoint(s) of evaluation of this end point

6 months

6 mesi

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

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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)

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

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

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:

100

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

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

120

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)

STANDARD FOLLOW-UP IN OUTPATIENT CLINIC

NORMALE FOLLOW-UP 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

2012-10-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-07-16

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

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