Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT05955001 |
| Other study ID # |
MS.22.11.2208 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
Phase 2/Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
April 1, 2023 |
| Est. completion date |
May 1, 2025 |
Study information
| Verified date |
July 2023 |
| Source |
Mansoura University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
From previous studies, the investigators found that sexual outcomes after prostate surgery
may show insignificant improvement, remain unchanged or deteriorate in non-negligible number
of patients especially those with high preoperative IIEF scores. Deterioration of erectile
function could be attributed to persistence of storage symptoms specially nocturia. Several
pathophysiologic mechanisms, described before, are involved in pathogenesis of LUTS and ED
and one can imagine that after relief of obstruction, the erectile function should improve,
however lack of improvement or even deterioration suggests that damage associated with these
mechanisms is irreversible and patients may require some sort of penile rehabilitation after
surgery.
The investigators hypothesized that Tadalafil may enhance relief of storage symptoms and
enhance recovery of erectile function after surgery for BPH. With this assumption, a RCT was
designed to examine the utility and efficacy of Tadalafil, once daily dose, to relieve
persistent/ de novo storage symptoms and early erectile function deterioration after
endoscopic prostate surgery.
Description:
I. Introduction
Benign prostatic hyperplasia (BPH) accompanied by bothersome lower urinary tract symptoms
(LUTS) is a common and progressive condition that significantly affects quality of life (QOL)
in men. LUTS include storage, voiding, and post-micturition symptoms. Storage symptoms are
referred as particularly bothersome and cause significant morbidity . Several population
based studies demonstrated a strong association between LUTS and erectile dysfunction (ED)
among BPH patients. This is believed to be independent of age and associated comorbidities
like cardiovascular disease and diabetes mellitus.
Several mechanisms have been postulated to explain the relationship between LUTS and ED.
First, impairment of nitric oxide (NO) production specially with conditions like hypertension
and metabolic syndrome . Second, enhanced Rho/ROCK pathway that leads to impaired smooth
muscle relaxation resulting in ED and LUTS. Overexpression of Rho/ROCK pathway has been found
in hypertensive rats . Third, sympathetic over- activity, in particular, overexpression of
α1A and α1D adrenergic receptors that are present mainly in prostate and hypertrophied
detrusor muscle, respectively. Experimental studies demonstrated that hypertensive rats had
increased sympathetic innervation to bladder and prostate, LUTS and ED. Furthermore,
improvement of ED occurred after control of hypertension. Lastly, pelvic ischemia that
results from atherosclerosis plays an important role in development of LUTS and ED via
induction of fibrosis and decreased NO levels. In a cross sectional study by Berger et al ,
the authors found that patients with BPH and ED had lower perfusion and higher resistive
index of the transition zone of prostate compared to young adults.
The main objective for treatment of BPH is to relieve LUTS and consequently improving quality
of life. Anatomical endoscopic enucleation of prostate (AEEP) including, HoLEP and ThuLEP is
recommended by the European Urological Association guideline as an efficient and advanced
minimally invasive, size-independent surgical therapy of BPO. Their long-term efficacy,
durability and safety have been proven in several prospective and randomized controlled
studies .
I.1 Problems frequently encountered after AEEP that affect quality of life.
I.1.1 Persistent or De novo Storage Symptoms
Following HoLEP, a significant proportion of patients complain of persistent or even de novo
storage symptoms. In a randomized trial comparing between HoLEP and TURP, Montorsi et al
found that 44% of HoLEP patients experienced urgency, dysuria and urgency incontinence. Ahyai
and colleagues prospectively analysed the incidence of storage symptoms after HoLEP among 144
patients. They found a significant (rebound) increase in storage symptoms at 6th and 8th week
postoperatively that was attributed to the wound healing process and tissue edema. Moreover,
persistence of storage symptoms led to delayed improvement in QoL that didn't significantly
improved till 12 weeks after surgery when storage symptoms subsided.
Elkoushy et al compared the incidence of postoperative storage symptoms between HoLEP and PVP
and found a significantly lower incidence in HoLEP group . The authors identified, baseline
IPSS-storage subscore≥9, prolonged operative time>100 minutes and lower percentage of
postoperative PSA reduction as independent predictors of less improvement of postoperative
storage symptoms.
I.1.2. Sexual function deterioration
The impact of HoLEP on sexual function has been extensively addressed in literature with
conflicting results. Some studies showed that HoLEP resulted in reduction of International
Index of Erectile Function (IIEF) questionnaires postoperatively because of retrograde
ejaculation that lowered IIEF orgasmic function domain . In a prospective controlled study,
Elshal et al demonstrated a decline in erectile function (EF) domain after HoLEP in patients
with normal preoperative EF (score >25). The authors also noted higher utilization of PDE5I
from 27% to 30% at last follow up . In a retrospective study comparing effects of HoLEP,
HoLAP and PVP on sexual function, the authors reported a decline in IIEF in 17% of patients
after HoLEP . Higher baseline IIEF and high Energy/Prostate ratio were independent predictors
of sexual function deterioration. In a recent prospective study including 144 patients
treated with HoLEP, significant deterioration of IIEF for 24 weeks follow up after surgery.
Jeong et al analysed serial changes in sexual function at 1,3,6 and 12 months after HoLEP and
found early deterioration and return to baseline at 12 months follow up.
Theoretically, HoLEP has minimal effects on erection because of its pulsed nature, shallow
depth of penetration (0.4mm) and majority of the procedure is performed with bunt dissection
and laser energy is used mainly for control of blood vessels. Thus, the potential thermal
effect on cavernous tissue or neurovascular bundles is minimal. Other factors could be
attributed to early decline in erectile function including: anxiety after surgery, pain,
postoperative complications, lack of ejaculation and bothering LUTS. Kim et al evaluated
sexual outcomes after HoLEP using MSHQ and found a strong correlation between postoperative
erectile function and nocturia. The authors explained their finding as decrease in nocturia
led to better sleep quality and decreased overall physical fatigue thus increasing penile
tumescence and erections.
I.2. Can penile rehabilitation enhance recovery of erectile function??? The concepts of
penile rehabilitation has been studied after radical prostatectomy (RP) and can be defined as
the use of any drug or device at or after RP to maximize erectile function recovery. Although
there are different treatment methods used in penile rehabilitation, the most common approach
of penile rehabilitation after RP are oral phosphodiesterase type 5 inhibitors (PDE5-I).
Tadalafil is a long-acting PDE5 inhibitor (PDE5-I) that has been approved by US Food and Drug
Administration (FDA) and by the European Medical Agency (EMA) for men with BPH-LUTS and for
those with coexisting erectile dysfunction (ED) and BPH-LUTS. Clinical studies showed that
Tadalafil improved symptoms of BPH, including both storage and voiding symptoms, in men with
or without erectile dysfunction (ED).
I.3. Role of Phosphodiesterase 5 inhibitors (PDE5Is) in treatment of LUTS/ED
Mechanism of action:
PDE5 isoenzymes are highly expressed in human lower urinary tract (LUT) tissues. PDE5Is
increase intracellular cyclic guanosine monophosphate (cGMP), leading to smooth muscle
relaxation. The effect of PDE5 inhibition leading to elevated NO/cGMP concentration in the
corpus cavernosum and pulmonary arteries has been observed, as well, in the smooth muscle of
the prostate and bladder and their vascular supply. Moreover, chronic treatment with PDE5Is
seems to increase blood perfusion and oxygenation in the LUT reducing chronic pelvic ischemia
with its related functional and morphologic changes on bladder and prostate. PDE5I could also
reduce chronic inflammation in the prostate and bladder. Nitric oxide and PDE5Is might also
alter reflex pathways in the spinal cord and neurotransmission in the urethra, prostate, or
bladder decreasing perception of bladder fullness and feeling of urgency.
II. Aim of the work From previous studies, we can conclude that sexual outcomes after
prostate surgery may show insignificant improvement, remain unchanged or deteriorate in
non-negligible number of patients especially those with high preoperative IIEF scores.
Deterioration of erectile function could be attributed to persistence of storage symptoms
specially nocturia. Several pathophysiologic mechanisms, described before, are involved in
pathogenesis of LUTS and ED and one can imagine that after relief of obstruction, the
erectile function should improve, however lack of improvement or even deterioration suggests
that damage associated with these mechanisms is irreversible and patients may require some
sort of penile rehabilitation after surgery.
The investigators hypothesized that Tadalafil may enhance relief of storage symptoms and
enhance recovery of erectile function after surgery for BPH. With this assumption, a RCT was
designed to examine the utility and efficacy of Tadalafil, once daily dose, to relieve
persistent/ de novo storage symptoms and early erectile function deterioration after
endoscopic prostate surgery.
