E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) |
SINTOMATOLOGIA DELLE BASSE VIE URINARIE (LUTS) ASSOCIATA AD IPERPLASIA PROSTATICA BENIGNA (BPH) |
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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 | 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 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the efficacy of fixed dose combinations of tamsulosin OCAS 0.4 mg and solifenacin (6 mg and 9 mg) in comparison with tamsulosin OCAS 0.4 mg monotherapy in male subjects with LUTS associated with BPH with a substantial storage component |
Valutare l'efficacia delle combinazioni a dose fissa di tamsulina OCAS (Sistema Orale di Assorbimento Controllato) 0.4 mg e solifenacina (6 mg e 9 mg) in confronto a tamsulosina OCAS 0.4 mg in monoterapia in soggetti di sesso maschile affetti da sintomatologia delle basse vie urinarie (LUTS) associata ad iperplasia prostatica benigna (BPH) con prevalente sintomatologia da accumulo |
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E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of fixed dose combinations of tamsulosin OCAS 0.4 mg and solifenacin (6 mg and 9 mg) in male subjects with LUTS associated with BPH with a substantial storage component; To assess the efficacy of fixed dose combinations of tamsulosin OCAS 0.4 mg and solifenacin (6 mg and 9 mg) in comparison with placebo in male subjects with LUTS associated with BPH with a substantial storage component. |
Valutare sicurezza e tollerabilita' delle combinazioni a dose fissa di tamsulosina OCAS 0.4 mg e solifenacina (6 mg e 9 mg) in soggetti di sesso maschile con LUTS associata a BPH con prevalente sintomatologia da accumulo Valutare l'efficacia delle combinazioni a dose fissa di tamsulosina OCAS 0.4 mg e solifenacina (6 mg e 9 mg) rispetto a placebo in soggetti di sesso maschile con LUTS associato a BPH con prevalente sintomatologia da accumulo |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
At study entry (Visit 1): 1. Male subjects aged ≥45 years. 2. Written informed consent has been obtained. 3.Subject is willing and able to complete the micturition diary and questionnaires correctly. 4. Voiding symptoms (including incomplete emptying of the bladder, intermittency, weak stream or hesitancy) and storage symptoms (including frequency and urgency), diagnosed as LUTS associated with BPH for ≥3 months. 5. Total I-PSS of ≥13. 6. Substantial amount of storage symptoms for ≥3 months (at the discretion of the investigator, expected to have a micturition frequency of ≥8 and at least 2 episodes of urgency with PPIUS grade 3 or 4 per day). 7. A maximum urinary flow rate of ≥4.0 mL/s and ≤12.0 mL/s, with a voided volume of ≥120 mL during free flow. At randomization (Visit 2): 8. Total I-PSS of ≥13. 9. Maximum urinary flow rate of ≥4.0 mL/s and ≤12.0 mL/s, with a voided volume of ≥120 mL during free flow. 10. A micturition frequency of ≥8 and at least 2 episodes of urgency (PPIUS grade 3 or 4) per day on average during the 3 day micturition diary. 11. Subject continues to meet all inclusion criteria of Visit 1. |
Al momento dell'inclusione nello studio (Visita 1): 1. Soggetto di sesso maschile di eta' >45 anni. 2. Ottenimento del consenso informato scritto. 3. Soggetto disponibile ed in grado di compilare in maniera corretta il diario relativo alla minzione ed i questionari. 4. Sintomi di svuotamento (inclusi lo svuotamento incompleto della vescica, intermittenza, flusso debole oppure esitazione) e sintomi di accumulo (fra cui frequenza ed impellenza), diagnosticati quale LUTS associata a BPH da ≥ 3 mesi. 5. Punteggio totale I-PSS ≥13. 6. Prevalente sintomatologia da accumulo da ≥3 mesi (a giudizio dello sperimentatore, ma sono comunque previsti frequenza urinaria ≥8 ed almeno 2 episodi di impellenza al giorno con punteggio alla Scala della Percezione dell'intensita' dell'impellenza da parte del Paziente (PPIUS) di grado 3 o 4). 7. Velocita' massima del flusso urinario ≥ 4.0 mL/s e ≤ 12.0 mL/s, con un volume di svuotamento ≥ 120 mL durante il flusso libero. Alla randomizzazione (Visita 2): 8. Punteggio totale I-PSS ≥13. 9. Velocita' massima del flusso urinario ≥ 4.0 mL/s e ≤ 12.0 mL/s, con un volume di svuotamento ≥ 120 mL durante il flusso libero. 10. Frequenza urinaria ≥8 ed almeno 2 episodi in media al giorno di impellenza con PPIUS di grado 3 o 4 nel corso dei 3 giorni di registrazione del diario relativo alla minzione. 11. Il soggetto continua a soddisfare tutti i criteri di inclusione della Visita 1. |
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E.4 | Principal exclusion criteria |
At study entry(V1):1.Any significant PVR >150mL 2.Prostate with estimated weight ≥75g as assessed by transvesical or transrectal ultrasound.3.Evidence of symptomatic urinary tract infection or known history or diagnosis of any of the following urinary conditions:- Recurrent symptomatic urinary tract infection -Urological Pain Syndromes as classified by the EAU Guideline on Chronic Pelvic Pain,update 2008 -Chronic prostatitis comprising type A (inflammatory) and type B (noninflammatory) -Evidence of current symptomatic or asymptomatic urolithiasis -Previous or current malignant disease of pelvic and urogenital organs with exception of carcinoma of bladder if longer than 5 years recurrence-free -Previous pelvic radiation therapy -Previous surgery to bladder neck or prostate -Bladder neck stenosis -Urethral stricture.4.Narrow angle glaucoma, myasthenia gravis, severe gastrointestinal condition (incl.toxic megacolon),hiatal hernia,gastroesophageal reflux or subject is at risk for these conditions;urinary or gastric retention or any other medical condition,which in the opinion of the investigator presents a contraindication for the use of anticholinergics.5.Clinically significant significant cardiovascular or cerebrovascular diseases within 6 months prior to V1.6.Any other cardiovascular or cerebrovascular disease which in the opinion of the investigator makes the subject unsuitable for participation in study.7.Non-drug treatment for LUTS associated with BPH or OAB,including electrostimulation therapy at start of the study or start of a bladder training program during the 2weeks prior to or during the study.8.Use of prohibited concomitant medication -Other pharmacological treatment used for LUTS/BPH, such as alpha-adrenoceptor (α-AR)-antagonists and plant extracts.-5α-reductase inhibitors (within 3 months prior to V1) -Other drugs which may influence the pharmacodynamic effects of solifenacin or tamsulosin,phosphodiesterase type 5 (PDE5) inhibitors,anticholinergics,or CYP 3A4 inhibitors or inducers that may influence the PK of solifenacin or tamsulosin.9.Use of combined α/ß-AR-antagonists,α2-agonists,oral and systemic β-agonists,cholinergics and any drugs with cholinergic or anticholinergic side effects,or diuretics However,long term dosage stable therapy (>1month prior to randomization) is permitted.10.Diabetic neuropathy.11.Planned cataract surgery during Study 905-CL-055 or Study 905-CL-057 or within 30 days after completion of any of the studies.12.Severe renal impairment (including hemodialysis) or moderate or severe hepatic impairment.13.Known polyuria.14.Known or suspected hypersensitivity to solifenacin,other anticholinergics,tamsulosina,other α-AR-antagonists,lactose or any of the other excipients of study medication.15.Any clinically significant condition,which in the opinion of the investigator makes the subject unsuitable for the trial.16.Participation in any clinical trial within 30 days (or limit set by national law,whichever is longer) prior to randomization.17.Employee of Astellas, of CROs involved or of investigator site executing study.At randomization (V2):18.Subject did not complete micturition diary or I-PSS questionnaire according to instructions.19.Significant PVR>150 mL.20.Total daily urine volume >3L/day on any day during the 3days of micturition diary.21.Any clinically significant abnormal ECG,which in the opinion of the investigator makes the subject unsuitable for the trial.22.Severe renal impairment,including hemodialysis (creatinine clearance <30mL/min using the tools indicated in the protocol) or moderate or severe hepatic impairment ALAT,ASAT outside 2 times the normal range,gamma GT outside 3 times the normal range) 23.Any other clinically significant out of normal range result of urinalysis,biochemistry (including PSA) or hematology.24.Subject fulfills any exclusion criteria of V1 |
All'inclusione nello studio (V1): 1.Significativo PVR>150 mL 2.Prostata di peso stimato ≥75g 3.Infezione sintomatica delle vie urinarie,storia nota/diagnosi di una fra le seguenti patologie: Infezione sintomatica ricorrente delle vie urinarie Sindromi Urologiche Dolorose classificate in base alle Linee Guida sul Dolore Pelvico Cronico della EAU (2008) Prostatite cronica infiammatoria e non Urolitiasi in atto Malattia neoplastica pregressa o in atto a carico degli organi pelvici ed urogenitali tranne il carcinoma vescicale se non in recidiva da piu' di 5anni Pregressa radioterapia pelvica Pregressa chirurgia a carico del collo vescicale o della prostata Stenosi del collo vescicale Stenosi uretrale 4.Glaucoma ad angolo stretto,miastenia grave,gravi patologie a livello gastrointestinale,ritenzione urinaria o gastrica o altra controindicazione all'uso di anticolinergici 5.Malattie cardiovascolari o cerebrovascolari clinicamente significative nei 6 mesi precedenti la V1 6.Qualsiasi altra patologia cardiovascolare o cerebrovascolare,che a giudizio dello sperimentatore rendano il paziente inadatto allo studio.7.Trattamento non-farmacologico per LUTS associata a BPH o per iperattivita' vescicale (OAB),fra cui elettrostimolazione ad inizio studio o inizio di un training vescicale nel corso delle 2settimane precedenti o nel corso dello studio 8.Uso di farmaci concomitanti proibiti: Altro trattamento farmacologico per LUTS/BPH e gli estratti vegetali.Inibitori della 5α- reduttasi (nei 3 mesi precedenti la V1) Altri farmaci che possono influenzare gli effetti farmacodinamici della solifenacina o della tamsulosina: inibitori della fosfodiesterasi di tipo5 (PDE5),anticolinergici,inibitori o induttori del CYP 3A4 che possono influenzare la PK della solifenacina o tamsulosina 9.Uso di antagonisti combinati degli α/ β-AR, α2-agonisti, β-agonisti orali e sistemici,agenti colinergici e di qualsiasi farmaco con effetti collaterali di tipo colinergico o anticolinergico,o diuretici.Terapia a lungo termine con un dosaggio stabile di tali farmaci e' permessa.10.Neuropatia diabetica.11.Intervento chirurgico programmato per cataratta nel corso degli Studii 905-CL-055 o 905-CL-057 o entro 30 giorni dalla conclusione di uno dei due.12.Grave insufficienza renale (inclusa emodialisi) o insufficienza epatica da moderata a grave.13.Nota poliuria.14.Ipersensibilita' nota o sospetta alla solifenacina,ad altri anticolinergici,alla tamsulosina, ad altri antagonisti degli α-AR,al lattosio o ad uno qualsiasi degli altri eccipienti del farmaco in studio 15.Qualsiasi patologia clinicamente significativa,che a giudizio dello sperimentatore renda il paziente inadatto allo studio.16.Partecipazione a qualsiasi studio clinico entro 30 giorni (o il limite stabilito dalla normativa nazionale qualora il periodo previsto dalla stessa sia piu' lungo) prima della randomizzazione 17.Personale Astellas,CRO coinvolte,o del centro che conduce lo studio. Alla randomizzazione (V2):18.Il soggetto non ha compilato il diario relativo alla minzione o il questionario I-PSS secondo istruzioni.19.Significativo PVR (>150 mL).20.Volume totale giornaliero urine >3L in uno qualsiasi dei 3 giorni di registrazione del diario relativo alla minzione.21.Qualsiasi alterazione ECG clinicamente significativa,che a giudizio dello sperimentatore renda il soggetto inadatto allo studio.22.Insufficienza renale grave,inclusa emodialisi (clearance della creatinina <30 mL/min mediante strumenti descritti in protocollo) o insufficienza epatica da moderata a grave (ALAT, ASAT oltre 2volte il limite,gamma GT oltre 3volte il limite).23.Altro valore alterato in maniera clinicamente significativa delle urine,del profilo biochimico (incluso il PSA) o dei paramentri ematologici,che a giudizio dello sperimentatore rendano il paziente inadatto allo studio.24.Il soggetto presenta un criterio esclusione di V1 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint 1: change from baseline to endpoint in total I-PSS. Primary endpoint 2: change from baseline to endpoint in Total Urgency Score (TUS, from micturition diary) |
End-point Primario N° 1: modifica del Punteggio totale I-PSS all'endpoint rispetto al basale. End-point Primario N° 2: modifica del Punteggio Totale relativo all'impellenza (Total urgency score - TUS, derivante dal diario relativo alla minzione) all'endpoint rispetto al basale |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
- Stesso farmaco ad altro dosaggio |
- same IMP used at different dosage |
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E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
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 | 14 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 115 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |