| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Lower Urinary Tract Symptoms (LUTS) |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10024981 |
| E.1.2 | Term | Lower urinary tract infection |
|
| 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 |
• A pilot study to assess the urodynamic changes induced by 100mg MR formulation
of UK-369,003 vs. placebo in men with LUTS.
• Assess the safety and tolerability of UK-369,003 in men with LUTS |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
*Male subjects, aged 40 years and above, with documented LUTS with an International Prostate Symptom Score ≥13 at both screening and baseline visit.
*Clinical diagnosis of BPH
*Qmax 5 to 15 ml/sec with a voided volume of >150 ml at screening visit.
*Urodynamically defined bladder outlet obstruction based on bladder outlet obstruction index >40; calculated as PdetQmax –2Qmax and measured at visit 2 (baseline).
*A minimum of 50% of the patient population will also have urodynamically confirmed DO (an involuntary detrusor contraction of ≥ 10cm H2O during baseline filling cystometry and volume to first contraction ≤ 350ml)
*Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the trial.
*Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests and other trial procedures. |
|
| E.4 | Principal exclusion criteria |
*History, evidence or suspicion of prostate cancer (includes total PSA value > 10 ng/ml unless prostate cancer previously excluded by biopsy)
*Post-void residual urine volume >200 ml based on bladder ultrasound at screening
*Documented UTI; subjects with a positive (1+ or greater) leukocyte or nitrite result in urine dipstick test will be excluded unless UTI can be ruled out via urine culture.
*Greater than 1+ of hematuria on dipstick test, unless fully investigated prior to randomization to rule out significant urological disease.
*History of relevant urological surgery or procedures that may contribute to LUTS (e.g. prostatectomy, bladder neck surgery, minimally invasive procedures of the prostate, prostatic stent insertion, pelvic irradiation, cystoscopy < 30 days prior to randomization)
*Chronic persistent local lower urinary tract pathology (e.g. bladder neck contracture, prostatitis, bladder stone, cystitis, urethral stricture, carcinoma, large bladder diverticulum, recurrent gross hematuria).
*Known primary neurological condition such as multiple sclerosis, Parkinson’s disease, or other neurological diseases known to affect bladder function.
*History of catheterization for outflow obstruction in the previous 12 month (includes intermittent self-catheterization).
*Subjects with history of difficult catheterization.
*Subjects receiving or who are likely to receive during the study any of the medications:
• α-blockers, muscarinic receptor antagonists, PDE5 inhibitors, and agents known to affect vesico-urethral function.
• 5-α-RIs
• Diuretics, beta-blockers or other anti-hypertensive agents
• Nitrates or nitric oxide donors in any form on either regular or intermittent basis (oral, sublingual, buccal, transdermal, inhalation or aerosols).
• Potent CYP3A4 inhibitors
• Topical agents are permitted.
• Warfarin.
*Significant allergy to or known hypersensitivity or intolerance to PDE5 inhibitors.
*Increased susceptibility to vasodilators including those with left ventricular outflow obstruction (e.g., hypertrophic obstructive cardiomyopathy)
*Poorly controlled type I or type II diabetes mellitus as defined by Hemoglobin A1C >7%.
*Loss of vision in one eye due to non-arteritic ischemic optic neuropathy (NAION) regardless of whether or not this event was temporarily associated with the use of a PDE5 inhibitor.
*Hereditary degenerative retinal disorders (e.g. retinitis pigmentosa).
*History of recurrent syncope or evidence of low blood pressure (BP) (<90mmHg systolic or <40mmHg diastolic) or evidence of symptomatic postural hypotension. This includes relevant postural symptoms associated with fall in systolic BP of > 20 mmHg or diastolic BP > 10 mmHg on standing.
*Any relevant clinically significant abnormalities on the screening physical exam or laboratory tests including patients with moderate liver function tests abnormalities (>1.5 x upper limit of normal) and renal function abnormalities (serum creatinine ≥2.5 mg/dl or ≥220 µmol/l).
*Family history of prolonged QT syndrome or who themselves have a QTc of >450msec at the screening visit as measured by a 12-lead supine ECG.
*Risk of priapism e.g. sickle cell disease, multiple myeloma and myeloproliferative disorders (e.g. myeloid leukemia, polycythemia, thrombocythemia).
*Subjects currently experiencing any clinically significant or unstable medical condition that might limit their ability to complete the study, or to comply with the requirements of the protocol, including: dermatologic disease, hematological disease, pulmonary disease, renal disease, hepatic disease, gastrointestinal disease, genitourinary disease, endocrine disease, neurological disease and psychiatric disease. Significant cardiovascular disease, including congestive heart failure, myocardial infarction, unstable angina, stroke, symptomatic or clinically significant cardiac arrhythmia in the last 6 months is also an exclusion criterion
*Any malignancy not considered cured (except basal cell carcinoma of the skin). A subject is considered cured if there has been no evidence of cancer recurrence
for the 5 years prior to screening. History of bladder or prostate cancer is an exclusion criterion regardless of status.
*Blood donation 4 weeks prior to screening, or stated intention to donate blood or blood products during the period of the study or within one month following completion of the study.
*Subjects who, in the opinion of the investigator, abuse alcohol or drugs, are not likely to complete the study for whatever reason, or who are unable or unwilling to consistently and accurately complete the diary and answer the required questionnaires.
*Subjects who have received any investigational drug during the preceding 30 days or five times the plasma half life (if known), whichever is longer. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The following urodynamic parameters/assessments will be used to assess the treatment efficacy:
• Change from baseline in Pdet, Qmax (detrusor pressure at maximum flow rate)
• Change from baseline in Qmax
• Change from baseline in Cystometric capacity
• Change from baseline in post-void residual urine volume (PVR)
• Change from baseline in Qave (average flow rate = volume voided/flow time)
• Change from baseline in volume at first unstable contraction
• Change from baseline in average detrusor pressure during micturition
Subjects will be asked to complete the “one week” version of the IPSS at Screening,
prior to each treatment period and end of each treatment period.
From the IPSS, the following endpoints will be derived and analyzed:
• the change in the IPSS total score: sum of the IPSS questions 1-7;
• the change in the IPSS storage subscore: sum of the IPSS questions 2, 4 and 7;
• the change in the IPSS voiding subscore: sum of the IPSS questions 1, 3, 5 and 6.
Where the change will be calculated as the difference in the specified score between thebaseline and end of treatment for each period.
• Change from baseline in BOOI (bladder outlet obstruction index= Pdet,Qmax –2Qmax; formerly the AG number)
• Change from baseline in BCI (bladder contractility index= Pdet,Qmax +5Qmax)
• Change from baseline in BE (Bladder voiding efficiency= (Voided volume/total
bladder capacity) X 100)
The change from baseline for each endpoint during each period will be calculated by
using the baseline value for that endpoint that was measured prior to period. |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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 | Information not present in EudraCT |
| 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
|
End of Trial in a Member State of the European Union is defined as the time at which it is deemed that sufficient subjects have been recruited and completed the trial as stated in the regulatory application and ethics application in the Member State.
End of Trial in all participating countries is defined as Last Subject Last Visit. |
|
| 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 |
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