Clinical Trials Register

Summary
EudraCT Number:	2015-002277-38
Sponsor's Protocol Code Number:	KMD3213ITCL0477
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:	2017-12-15
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

2015-002277-38

A.3

Full title of the trial

Urodynamic evaluation by pressure flow urodynamic study of the new α1A-adrenoceptor antagonist silodosin 8 mg qd in patients with benign prostatic obstruction. Explorative, single-arm, phase IV clinical study.

A.3.1

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

Urodynamic study to verify the effects of silodosin on benign outlet obstruction in patient with benign prostatic hyperplasia

Studio urodinamico per verificare l'efficacia di silodosina sull'ostruzione del collo vescicale in pazienti con iperplasia prostatica benigna

A.3.2

Name or abbreviated title of the trial where available

Urodynamic effects of silodosin

Effetti urodinamici di silodosina

A.4.1

Sponsor's protocol code number

KMD3213ITCL0477

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	RECORDATI 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	Recordati 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	Recordati S.p.A.
B.5.2	Functional name of contact point	Direzione Medica
B.5.3	Address:
B.5.3.1	Street Address	V. Civitali 1
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20148
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390248787456
B.5.5	Fax number	+390248787668
B.5.6	E-mail	casi.m@recordati.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	UROREC - 8 MG - CAPSULA RIGIDA - USO ORALE - BLISTER(PVC/PVDC/ALU) 10 CAPSULE
D.2.1.1.2	Name of the Marketing Authorisation holder	RECORDATI IRELAND LTD
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	UROREC
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
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	Yes
D.3.11.13.1	Other medicinal product type	alfa-bloccante, agente uroseletiivo

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

Benign prostatic hyperplasia

Iperplasia prostatica benigna

E.1.1.1

Medical condition in easily understood language

Benign prostatic hyperplasia

Iperplasia prostatica benigna

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10004446
E.1.2	Term	Benign prostatic hyperplasia
E.1.2	System Organ Class	10038604 - Reproductive system and breast 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

The primary objective of the study is to evaluate the effects of silodosin on the change from baseline in Bladder Outlet Obstruction Index (BOOI).

L’obiettivo primario dello studio è la valutazione degli effetti di silodosina sulla variazione rispetto al basale dell’indice di ostruzione del collo della vescica (Bladder Outlet Obstruction Index – BOOI)

E.2.2

Secondary objectives of the trial

Secondary objectives are to evaluate:
the effects on LUTS and QoL due to urinary symptoms, as assessed by the International Prostate Symptoms Score (IPSS);
the percentage of subjects considering their condition improved enough to spare or delay the surgical intervention for BPH;
the effects on other urodynamic parameters;
the categorical improvement from baseline in obstruction class (obstructed, equivocal, unobstructed) on the ICS BOOI nomogram;
the effects on post-void residual volume, as assessed by ultrasound;
the safety profile of the drug.

Obiettivi secondari sono: valutare gli effetti sui LUTS e la qualità della vita dovuta ai sintomi urinari, mediante questionario International Prostate Symptoms Score (IPSS); valutare la percentuale di soggetti che considerano la loro condizione sufficientemente migliorata da evitare o posticipare l’intervento chirurgico per BPH; valutare
gli effetti su altri parametri urodinamici; valutare il
miglioramento nella categoria della classe di ostruzione rispetto al basale (ostruito, equivoco, non ostruito) sul nomogramma ICS BOOI;valutare gli effetti sul volume residuo post-minzionale, valutato mediante ecografia; valutare il profilo di sicurezza del farmaco.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Male subjects aged 50 years or older;
Patients waiting to undergo surgical intervention for LUTS/BPH;
No pharmacological treatment for LUTS/BPH in the last 4 weeks;
Presence of moderate-severe LUTS, as assessed by an IPSS total score  13 at Visit 1 (Screening);
Quality of life affected by LUTS, as assessed by a IPSS-QoL score ≥ 3 at Visit 1 (Screening);
Prostate volume of  30 ml, assessed by suprapubic ultrasound;
Maximum urine flow rate (Qmax) ≤ 15 mL/sec., with a minimum voided volume of  125 mL;
Presence of obstruction in urodynamic study performed at Visit 2 (Baseline), according to Inetrnational Continence Society (ICS) nomogram, based on the Bladder Outlet Obstruction Index (BOOI) > 40;
Agree not to use any other approved or experimental BPH or overactive bladder medication anytime during the study;
Able to comply with protocol procedures;
Written informed consent obtained before beginning any investigational procedures.

Soggetti maschi di età uguale o superiore a 50 anni;
Pazienti in attesa di essere sottoposti ad intervento chirurgico per LUTS/BPH;
Nessun trattamento farmacologico per LUTS/BPH nelle precedenti 4 settimane;
Presenza di LUTS di grado moderato/severo, con un punteggio totale del questionario IPSS > 13 alla Visita 1 (Screening);
Qualità della vita influenzata dai LUTS con un punteggio IPSS/QoL > 3 alla Visita 1 (Screening);
Volume prostatico > 30 ml, valutato mediante ecografia sovrapubica;
Flusso urinario massimo (Qmax) < 15 mL/sec., con un volume di svuotamento minimo > 125 mL;
Presenza di ostruzione allo studio urodinamico effettuato a Visita 2 (Basale), con un indice di ostruzione del collo della vescica (Bladder Outlet Obstruction Index – BOOI) > 40, secondo il nomogramma ICS;
D’accordo a non utilizzare nessun altro farmaco approvato o sperimentale per BPH o iperattività della vescica durante il corso dello studio;
In grado di rispettare le procedure del protocollo;
Consenso informato scritto ottenuto prima dell’avvio di qualsiasi procedura sperimentale.

E.4

Principal exclusion criteria

Hypersensitivity to the active substance or to any of the excipients;
Absolute indication for surgery therapy (such as recurrent or refractory urinary retention, overflow incontinence, recurrent UTIs, bladder stones or diverticula, treatment resistant macroscopic haematuria due to BPH/BPE, or dilatation of the upper urinary tract due to BPO, with or without renal insufficiency) for which any delay in the intervention is not recommended;
Neurological causes of detrusor overactivity (e.g. multiple sclerosis, Parkinson’s disease, diabetic neurophathy);
Presence of active urinary tract infections;
Presence or history of bladder calculi;
Presence of prostate cancer. Subjects with a PSA > 10.0 ng/mL will be excluded. Subjects with a PSA between 4.0 and 10.0 should have prostate cancer ruled out to the satisfaction of the clinical Investigator with appropriate documentation of the physician’s assessment;
Post-void residual urine volume > 300 mL, assessed by suprapubic ultrasound;
Clinically significant cardiovascular and cerebrovascular disease within 6 months prior to screening, including myocardial infarction, unstable angina, significant ventricular arrhythmias, heart failure (NYHA classes III-IV), stroke, transient ischemic attack;
Renal impairment (serum creatinine > 2.0 mg/dL);
Hepatic impairment (GGT, AST or ALT > 3xULN);
Patients for whom cataract surgery is scheduled;
History of orthostatic hypotension or syncope;
Participation in an investigational drug study within 30 days prior to the start of the study;
Any other condition which, in the investigator's judgement, renders the subject unable to complete the study or which prevents optimal participation in achieving the objectives of the study;
Prohibited concomitant medications:
• α-adrenoceptor antagonists, 5--reductase inhibitors such as dutasteride and finasteride, natural/herbal products known to have an effect on LUTS (e.g. saw palmetto - serenoa serulata/repens), tadalafil 5 mg daily, anticholinergic agents, antidepressants, anti-anxiety agents during study participation. Note: occasional use of PDE-5 inhibitors for erectile dysfunction is allowed but not within 48 hours of any study visit.
• Concomitant use with potent CYP3A4 inhibitors, such as ketoconazole, itraconazole or ritonavir (possible PK interaction).

Ipersensibilità al principio attivo o ad uno qualsiasi degli eccipienti;
Indicazione assoluta all’intervento chirurgico (quale ritenzione urinaria ricorrente o refrattaria, incontinenza da rigurgito, infezioni ricorrenti del tratto urinario, calcoli o diverticoli della vescica, ematuria macroscopica dovuta a BPH/BPE resistente al trattamento, o dilatazione del tratto urinario superiore causata da BPO, con o senza insufficienza renale) per cui non sia raccomandabile alcun ritardo nell’intervento ;
Cause neurologiche di iperattività detrusoriale (es. sclerosi multipla, malattia di Parkinson, neuropatia diabetica);
Presenza di infezioni attive del tratto urinario;
Presenza o anamnesi di calcolosi della vescica;
Presenza di carcinoma prostatico. I soggetti con un PSA > 10.0 ng/ml saranno esclusi dalla sperimentazione. I soggetti con un PSA compreso tra 4.0 e 10.0, l’Investigatore deve escludere la possibilità della presenza di un carcinoma della prostata, con adeguata documentazione di valutazione da parte del medico;
Residuo post-minzionale > 300 mL, valutato mediante ecografia sovrapubica;
Malattie cardiovascolari e cerebrovascolari clinicamente significative entro i 6 mesi precedenti lo screening, tra cui infarto miocardico, angina instabile, aritmie ventricolari significative, insufficienza cardiaca (classi NYHA III-IV), ictus, accidente ischemico transitorio;
Insufficienza renale (creatinina serica > 2.0 mg/dL);
Insufficienza epatica; GGT, AST o ALT > 3 volte i valori limite della norma;
Pazienti per i quali è programmato un intervento chirurgico di cataratta;
Anamnesi di ipotensione ortostatica o sincope;
Partecipazione ad uno studio con la somministrazione di un farmaco sperimentale nei 30 giorni prima dell’inizio dello studio;
Qualsiasi altra condizione che, a giudizio dello sperimentatore, renda il soggetto non in grado di portare a termine lo studio, o che impedisca la partecipazione ottimale per il raggiungimento degli obiettivi dello studio;
Farmaci concomitanti proibiti:
• Antagonisti degli adrenorecettori α, inibitori della 5--reduttasi, quali dutasteride e finasteride, prodotti naturali/derivati da piante noti per avere effetti sui LUTS (es. saw palmetto – serenoa serulata/repens), tadalafil 5 mg al giorno, farmaci anticolinergici, antidepressivi, ansiolitici, durante la partecipazione allo studio; Nota: è permesso l’uso occasionale di inibitori della PDE-5 per la disfunzione erettile purché non entro le 48 ore da qualsiasi visita dello studio.
• Uso concomitante di potenti inibitori del citocromo CYP3A4, quali ketoconazolo, itraconazolo, ritonavir (possibile interazione farmacocinetica).

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in Bladder Outlet Obstruction Index (BOOI), calculated from the pressure-flow parameters detrusor pressure at maximum flow (pdetQmax) and maximum flow rate (Qmax), according to the following equation: BOOI= pdetQmax – (2x Qmax).

Variazione rispetto al basale dell’indice di ostruzione del collo della vescica (Bladder Outlet Obstruction Index – BOOI), calcolato sulla base dei parametri pressione/flusso di pressione detrusoriale al flusso massimo (pdetQmax) e flusso urinario massimo (Qmax), in accordo con la seguente equazione:
BOOI = pdetQmax – (2xQmax).

E.5.1.1

Timepoint(s) of evaluation of this end point

after 8 weeks of treatment with the study drug

dopo 8 settimane di trattamento con il farmaco in studio

E.5.2

Secondary end point(s)

Change from baseline in the total International Prostate Symptoms Score (IPSS).
Percentage of subjects completing the treatment period who answer “yes” to the question: “After the treatment with silosodin, is your condition improved enough to spare or delay the surgical intervention for BPH?”;

Change from baseline in other urodynamic parameters:
- Maximum flow rate (Qmax)
- Max detrusor pressure (pdet.max),
- Detrusor pressure at maximum flow (pdetQmax)
- Volume at first desire to void (FD)
- Maximum cystometric capacity (MCC)
- Bladder compliance (MCC/Pves at MCC – Pves at baseline)
- Percentage of patients showing detrusor overactivity (DO)
- Amplitude of largest involuntary contraction
- Volume at first involuntary contraction
- Bladder Contraction Index (BCI).

Categorical improvement from baseline in obstruction class (obstructed, equivocal, unobstructed) on the ICS BOOI nomogram.
Post-void residual volume (PVR), by ultrasound.
Change from baseline in IPSS storage and voiding subscores.
Change from baseline in IPSS Q8 (QoL).

Variazione rispetto al basale del valore totale dell’International Prostate Symptoms Score (IPSS).
Percentuale di soggetti arruolati che rispondono “SI” alla domanda: “Dopo il trattamento con silodosin, la sua situazione è migliorata abbastanza da rinunciare o ritardare l’intervento chirurgico per la BPH?

Variazione rispetto al basale in altri parametri urodinamici:
- Flusso urinario massimo (Qmax)
- Pressione detrusoriale massima (pdet.max)
- Pressione detrusoriale al flusso massimo (pdetQmax)
- Volume al primo desiderio di svuotamento (FD)
- Massima capacità cistometrica (MCC)
- Compliance della vescica (MCC/Pves at MCC - Pves at baseline)
- Percentuale di pazienti con iperattività detrusorale (DO)
- Ampiezza della più larga contrazione involontaria
- Volume alla prima contrazione involontaria
- Indice di contrazione della vescica (BCI);

Miglioramento nella categoria della classe di ostruzione rispetto al basale (ostruito, equivoco, non ostruito) sul nomogramma ICS BOOI.
Volume residuo post-minzionale (PVR), mediante ecografia.
Variazione rispetto al basale nel punteggio relativo ai sintomi irritativi ed ostruttivi del questionario IPSS.
Variazione rispetto al basale nella domanda 8 (Q8-QoL- qualità della vita) dell’IPSS.

E.5.2.1

Timepoint(s) of evaluation of this end point

after 8 weeks of treatment with the study drug

dopo 8 settimane di trattamento con il farmaco in 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

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)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Information not present in EudraCT

E.8.1.6

Cross over

Information not present in EudraCT

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

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.8.5.1

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

Number of subjects for this age range:

F.1.1.1

In Utero

Information not present in EudraCT

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

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

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

Information not present in EudraCT

F.3.3.2

Women of child-bearing potential using contraception

Information not present in EudraCT

F.3.3.3

Pregnant women

Information not present in EudraCT

F.3.3.4

Nursing women

Information not present in EudraCT

F.3.3.5

Emergency situation

Information not present in EudraCT

F.3.3.6

Subjects incapable of giving consent personally

Information not present in EudraCT

F.3.3.7

Others

Information not present in EudraCT

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)

At the study end, the study physician will evaluate the patient condition and his response to the treatment with the drug and will prescribe the best therapy to be followed.

Al termine di questo studio, il medico dello studio valuterà le condizioni del paziente e la sua risposta al trattamento con farmaco e gli indicherà la miglior linea terapeutica da seguire per il suo caso.

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

2015-07-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-07-29

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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