E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of Lower Urinary Tract Symptoms (LUTS) due to Benign Prostatic Hyperplasia (BPH). |
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E.1.1.1 | Medical condition in easily understood language |
Lower urinary tract symptoms associated with an enlarged prostate such as a slow or weak urinary stream or frequent urination during the night. |
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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 | 14.0 |
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 |
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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 intraprostatic administration of BOTOX 200 U compared with placebo to treat LUTS due to BPH |
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E.2.2 | Secondary objectives of the trial |
To assess the safety of BOTOX from intraprostatic injections |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Male, aged 45 years and older
• Weight ≥ 50 kilograms or 110 pounds
• LUTS due to BPH for at least 6 months prior to screening
• Previous (during the last 36 months) or current usage of a licensed oral treatment for BPH at an approved dose, for at least a 4 week duration for alpha-adrenergic antagonists and for at least a 24 weeks (6 months) duration for 5ARIs
- Patients who will continue on adjuvant alpha antagonist therapy during the trial must have been on a stable dose for at least 3 months prior to screening and agree to remain on the same alpha antagonist and dose for the entire duration of the study.
- Patients who will continue on adjuvant 5ARI therapy during the trial
must have been on a stable dose for at least 18 months prior to
screening and agree to remain on the same 5ARI and dose for the entire duration of the study
• If engaging in sexual activities, all patients must be willing to use a male condom for 48 hours following each treatment
• Ability to follow study instructions and likely to complete all required visits
• Written informed consent and data protection consent has been obtained
• IPSS ≥ 14 at any time prior to Treatment B
• Peak urinary flow rate of ≥ 4 mL/sec, but ≤ 15 mL/sec (with a voided urine volume ≥125 mL, but ≤ 600 mL)
• Post void residual (PVR) urine volume ≤ 200 mL
• Total prostate volume of ≥ 30 mL, but ≤ 80 mL (assessed by transrectal ultrasound, immediately prior to performing the sham procedure).
• Less than or equal to a 4 point decrease in IPSS from treatment visit A (prior to run in period) to the qualification for treatment B visit (following run-in period) |
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E.4 | Principal exclusion criteria |
•Acute prostatitis within 12 months of screening
•History or evidence of chronic prostatitis
•History of two or more UTIs in the 12 months prior to screening or a single UTI in the 6 months prior to screening
•History or evidence of bladder stones
•Symptomatic kidney stones or planned active intervention for symptomatic/asymptomatic kidney stones
•Patient has current or previous uninvestigated hematuria
•Previous or current diagnosis of bladder cancer, prostate cancer or any other chronic prostate disease other than BPH
•Prostate biopsy within 24 weeks of screening visit
•History of previous prostate surgery, including minimally invasive procedures
•History or evidence of any urological abnormalities, bladder surgery or disease (other than BPH) that may affect lower urinary tract function
•History of symptoms suggestive of overactive bladder (OAB) in the investigator’s opinion or previous use of an anticholinergic to treat OAB
•History of any urinary incontinence within 52 weeks of screening visit
•History or evidence of interstitial cystitis based on investigator’s opinion
•History or evidence of anal stenosis, stricture, fissure, or any other condition that, in the investigator’s opinion, may preclude the patient from receiving transrectal administration of study treatment
•Acute urinary retention or previous use of an indwelling catheter for urinary retention within 12 weeks of screening (except if urinary retention was associated with non-urinary tract surgery and/or general/regional anesthesia and has resolved without further intervention)
•Urethral instrumentation within 2 weeks of screening
•Any previous or current usage of botulinum toxin therapy of any serotype for any urological condition
•Botulinum toxin therapy of any serotype for any non-urological usage during the 12 weeks prior to treatment A
•Patient has been immunized for any botulinum toxin serotype
•Known allergy or sensitivity to any botulinum toxins or the components of the study medication, anesthetics, sedatives or prophylactic antibiotics to be used during the study
•Patient who is immunocompromised or has any systemic or local condition which may increase the risk of developing an infection following treatment
•Any medical condition that may put the patient at increased risk with exposure to BOTOX, including diagnosed myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, or any other condition that might interfere with neuromuscular function
•Current or history of a neurologic condition known to affect lower urinary tract function or findings at study entry which may be consistent with a neurological condition known to affect lower urinary tract function
•Current or history of clotting factor deficiencies, platelet disorders or disorders that cause bleeding diathesis
•Unable to discontinue medications with anti-platelet or anti-coagulant effects including aspirin (acetylsalicylic acid) for a minimum of 3 days prior to any study treatment until the day following study treatment
•Patient is unable or unwilling to discontinue the following classes of medication for the required washout period and throughout the duration of the study
oAlpha-adrenergic antagonists (alpha blockers) or 5ARIs (eg, finasteride, dutasteride), unless continuing as adjuvant therapy
oCombination therapy with alpha antagonists and 5ARIs
oPhytotherapy (ie, herbal or plant extracts) for BPH
oAlpha-adrenergic agonists
oAnticholinergics/antimuscarinics for any bowel or LUTS, or any other medications indicated for the treatment of OAB
oAntispasmodics, including those indicated for gastrointestinal discomfort
oAndrogens (eg testosterone) and drugs with androgenic activity
oDrugs with anti-androgenic activity (eg spironolactone)
oAny other medication which in the investigator’s opinion may affect lower urinary tract function
•Current or previous participation in another therapeutic or device study within 30 days of screening
•Patient has a condition or is in a situation which in the investigator's opinion may put the patient at significant risk, may confound the study results, or may interfere significantly with the patient's participation in the study
•Prominent median lobe of the prostate, in the investigator’s opinion (eg, prominent median lobe noticed during the TRUS at the start of sham procedure, or prominent median lobe previously detected during cystoscopy)
•UTI, defined as a bacteriuria count of >105 colony forming units/mL conjoint with leukocyturia >5/high power field (hpf). Patients with a lower bacteriuria count who, in the opinion of the investigator, have a UTI should also be excluded
•Prostate specific antigen (PSA) level of ≥10 μg/L. (Patients with a total PSA level of ≥4.0 μg/L and <10 µg/L must have prostate cancer ruled out to the satisfaction of the investigator according to local site practice, prior to randomization)
•Creatinine level ≥1.5 times the upper limit of the normal range
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E.5 End points |
E.5.1 | Primary end point(s) |
Intraprostatic BOTOX 200 U is more effective than placebo in improving symptoms due to BPH, as measured by a difference between BOTOX and placebo in mean International Prostate Symptom Score (IPSS). BOTOX 200 U has an acceptable safety profile when administered via the transrectal route into the prostate. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Week 12 post treatment visit B |
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E.5.2 | Secondary end point(s) |
• Change from baseline in the total IPSS score at other visits
• Change from baseline for Qmax |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
All visits post treatment B |
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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 | 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 | 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) | 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 | 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) | 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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 | No |
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 |
Canada |
Korea, Republic of |
Philippines |
United States |
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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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The end of the trial is the last visit of the last patient |
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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 | 3 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |