Overactive BladderNCT00775281
Changes in Inflammatory and Contractile Protein Expression in Patients With Painful Bladder Syndrome/IC.
An observational study of Overactive Bladder and Painful Bladder Syndrome, run by Insel Gruppe AG, University Hospital Bern at 1 site in Switzerland.
Trial summary
Interstitial cystitis (IC)/chronic pelvic pain syndrome (CPPS) is a clinical syndrome of pelvic pain and/or urinary urgency/frequency in absence of a specific cause such as bacterial infection or damage to the bladder. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Overactive Bladder, Painful Bladder Syndrome, Chronic Pelvic Pain Syndrome
- How many people
- 45 participants
- Where
- 1 siteSwitzerland
- Study dates
- Oct 2006to Apr 2010
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Study population: university hospital clinic
Who may be able to join
- Clinical asymptomatic bladder function
- Clinical urgency frequency syndrome/ overactive bladder
- Clinical painful bladder syndrome/interstitial cystitis
Who cannot join
- Not able to understand patient information
- Other cause of symptoms
- Confusable diseases
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Mediators of Neurogenic Inflammation in the Urinary Tract as Key Factors in the Painful Bladder Syndrome / Interstitial Cystitis and Bladder Dysfunction
Interstitial cystitis (IC)/chronic pelvic pain syndrome (CPPS) is a clinical syndrome of pelvic pain and/or urinary urgency/frequency in absence of a specific cause such as bacterial infection or damage to the bladder. The pathogenetic mechanisms of IC/CPPS are as yet undefined and it is largely this lack of knowledge, which precludes a systematic therapeutic approach. Experimental evidence, including results from the animal models of cystitis and the knock-out mice, indicate a participation of tachykinin receptors, especially the NK1R, in neurogenic inflammation, which is considered an important element of the IC complex. However, there is very scant information about the molecular mechanisms of IC in humans, or of the types of receptors, which participate in neurogenic inflammation. Based on our molecular biological know-how and the clinical expertise, we propose to investigate the role of the tachykinin and bradykinin receptors and their signalling partners in CPPS and bladder dysfunction in humans.
Read the detailed description
Although IC has been recognised for more than a century, its pathophysiology remains a mystery, and as a consequence the treatment of IC is largely empirical. A multitude of mechanisms of the disease have been postulated ranging from neuroinflammatory to autoimmune or possibly infectious or toxic agents. Newer studies have hinted towards a genetic basis of the disease, but in most hypotheses an inflammatory component of some kind is involved and many findings support this theory. An often-cited hypothesis is the leaky epithelium. The healthy bladder is coated with a thin mucinous substance bladder surface mucin, which is composed of numerous sulfonated glycosaminoglycans and glycoproteins. In IC patients, in contrast to controls, as well as in some animal models of IC, qualitative changes to this surface layer have been observed (Lilly et al, 1990., Moskowitz et al, 1994). An initiating event (toxin) may lead to functional changes and increased permeability. This in turn leads to nerve sensitisation and possibly up-regulation. There is increasing evidence that the progression of IC is accompanied by a significant up-regulation of sensory nerves in the bladder (Letourneau, 1996). Nerve growth factor (NGF), a neurotropin that sensitises nociceptor fibres, was reported to be increased in bladders of IC patients (Lowe, 1997), and application of NGF in Wistar rats acutely induced bladder hyperactivity (Chuang, 2001). Sensory nerves in neurogenic inflammation secrete inflammatory mediators such as Substance P (SP), a nociceptive neurotransmitter in the central and peripheral nervous system. Increased amounts of the released Substance P have been found in the urine of IC patients (Hohenfellner, et al,1992, Pang et al., 1995, Pang et al., 1996), the concentration of Substance P reflecting the patients' degree of pain (Chen et al., 1999). Substance P and related tachykinins (TKs) mediate a variety of physiological processes in the genitourinary, pulmonary and gastrointestinal tract through stimulation of NK1 and NK2 receptors. Pre-clinical evidence obtained through use of selective tachykinin receptor antagonists indicates that endogenous tachykinins are involved in regulation of smooth muscle contraction, vasodilation, water metabolism and inflammation. Recently it was shown that mRNA encoding for SP receptor NK1 is in-creased in the bladder biopsies from patients with interstitial cystitis (Marchand et al., 1998). NK1R mRNA was found in detrusor muscle, urothelium and vascular structures, and the endothelial NK1R were markedly increased. SP binding to NK1R on endothelial cells results in vasodilation, plasma extravasation, cytokine release and activation and infiltration of immune cells, all characteristic of IC. Experiments with the NK1R knockout mice allowed for the first time to demonstrate the obligatory requirement of NK1R in cystitis and participation of these receptors in the chain of events linking mast cell degranulation and inflammation (Saban et al., 2000).
Changes in the sarcolemma, and altered expression of the tachykinin and bradykinin receptors might significantly influence the downstream signalling events leading to propagation of the symptoms of chronic pelvic pain/IC. By uncovering the link between clinical symptoms and the molecular regulation of the atypical inflammatory response, we may be able to offer novel and specific options for treatment. In the current proposal, we would like to further our studies of urinary bladder pathology, in particular the symptomatic complex of PBS/interstitial cystitis, and investigate the effect of changes in human urothelium and detrusor muscle cells on the NK1R-mediated signalling.
Biopsies from controls and PBS patients will be obtained in either general or spinal anesthesia transurethrally from the bladder dome and trigone with a biopsy tong. RNA will be extracted, and the expression levels of selected genes analyzed using Taqman real-time PCR and gene expression arrays (Applied Biosystems). Calcium imaging will be used to monitor the receptor activation and protein levels analysed by SDS-PAGE and Western Blotting. Receptor tissue distribution will be analysed by immuno-cytochemistry.
- Conditions
- Overactive Bladder, Painful Bladder Syndrome, Chronic Pelvic Pain Syndrome, Cystitis, Interstitial
- Keywords
- Tachykinin receptors, Protein expression, Contractile proteins, Inflammatory proteins
- Medical subject headings
- Urinary Bladder, Overactive, Cystitis, Interstitial
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| 1 | Not described | |
| 2 | Not described | |
| 3 | Not described |
What is being measured
The primary outcome is the main question the study is designed to answer.
Receptor expression in disease states versus control
Measured: at time of biospy
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Oct 2008 (estimated)
- Study startOct 2006
- Primary completionApr 2010
- Study completionApr 2010
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (10)Papers the sponsor has linked to this study.
- Other trials for Overactive BladderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Enrolment
- 45 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Insel Gruppe AG, University Hospital Bern
- Sponsor type
- University, hospital or other
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00775281
- Sponsor's protocol ID
- KEK_146_05
- Status last verified
- Apr 2010
- First submitted
- 17 Oct 2008
- Last updated
- 27 Apr 2010
- Results posted
- No
- Data monitoring committee
- No
Publications
Lilly JD, Parsons CL. Bladder surface glycosaminoglycans is a human epithelial permeability barrier. Surg Gynecol Obstet. 1990 Dec;171(6):493-6.
PubMed 2244283Letourneau R, Pang X, Sant GR, Theoharides TC. Intragranular activation of bladder mast cells and their association with nerve processes in interstitial cystitis. Br J Urol. 1996 Jan;77(1):41-54. doi: 10.1046/j.1464-410x.1996.08178.x.
PubMed 8653316Lowe EM, Anand P, Terenghi G, Williams-Chestnut RE, Sinicropi DV, Osborne JL. Increased nerve growth factor levels in the urinary bladder of women with idiopathic sensory urgency and interstitial cystitis. Br J Urol. 1997 Apr;79(4):572-7. doi: 10.1046/j.1464-410x.1997.00097.x.
PubMed 9126085Chuang YC, Fraser MO, Yu Y, Chancellor MB, de Groat WC, Yoshimura N. The role of bladder afferent pathways in bladder hyperactivity induced by the intravesical administration of nerve growth factor. J Urol. 2001 Mar;165(3):975-9.
PubMed 11176525Hohenfellner M, Nunes L, Schmidt RA, Lampel A, Thuroff JW, Tanagho EA. Interstitial cystitis: increased sympathetic innervation and related neuropeptide synthesis. J Urol. 1992 Mar;147(3):587-91. doi: 10.1016/s0022-5347(17)37314-7.
PubMed 1538434Pang X, Marchand J, Sant GR, Kream RM, Theoharides TC. Increased number of substance P positive nerve fibres in interstitial cystitis. Br J Urol. 1995 Jun;75(6):744-50. doi: 10.1111/j.1464-410x.1995.tb07384.x.
PubMed 7542136Pang X, Boucher W, Triadafilopoulos G, Sant GR, Theoharides TC. Mast cell and substance P-positive nerve involvement in a patient with both irritable bowel syndrome and interstitial cystitis. Urology. 1996 Mar;47(3):436-8. doi: 10.1016/S0090-4295(99)80469-5.
PubMed 8633418Marchand JE, Sant GR, Kream RM. Increased expression of substance P receptor-encoding mRNA in bladder biopsies from patients with interstitial cystitis. Br J Urol. 1998 Feb;81(2):224-8. doi: 10.1046/j.1464-410x.1998.00507.x.
PubMed 9488063Moskowitz MO, Byrne DS, Callahan HJ, Parsons CL, Valderrama E, Moldwin RM. Decreased expression of a glycoprotein component of bladder surface mucin (GP1) in interstitial cystitis. J Urol. 1994 Feb;151(2):343-5. doi: 10.1016/s0022-5347(17)34944-3.
PubMed 8283520Saban R, Saban MR, Nguyen NB, Lu B, Gerard C, Gerard NP, Hammond TG. Neurokinin-1 (NK-1) receptor is required in antigen-induced cystitis. Am J Pathol. 2000 Mar;156(3):775-80. doi: 10.1016/S0002-9440(10)64944-9.
PubMed 10702392
Study at a glance
From the registry record, last updated by the sponsor on 27 Apr 2010. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Mediators of Neurogenic Inflammation in the Urinary Tract as Key Factors in the Painful Bladder Syndrome / Interstitial Cystitis and Bladder Dysfunction
- ClinicalTrials.gov ID
- NCT00775281
- Acronym / sponsor ID
- KEK_146_05
- Conditions
- Overactive Bladder, Painful Bladder Syndrome, Chronic Pelvic Pain Syndrome, Cystitis, Interstitial
- Keywords
- Tachykinin receptors, Protein expression, Contractile proteins, Inflammatory proteins
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 45 participants (estimated)
- Lead sponsor
- Insel Gruppe AG, University Hospital BernUniversity, hospital or other
- Study start
- Oct 2006
- Primary completion
- Apr 2010 (actual)
- Study completion
- Apr 2010 (actual)
- First posted
- 20 Oct 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Interstitial cystitis (IC)/chronic pelvic pain syndrome (CPPS) is a clinical syndrome of pelvic pain and/or urinary urgency/frequency in absence of a specific cause such as bacterial infection or damage to the bladder. The pathogenetic mechanisms of IC/CPPS are as yet undefined and it is largely this lack of knowledge, which precludes a systematic therapeutic approach. Experimental evidence, including results from the animal models of cystitis and the knock-out mice, indicate a participation of tachykinin receptors, especially the NK1R, in neurogenic inflammation, which is considered an important element of the IC complex. However, there is very scant information about the molecular mechanisms of IC in humans, or of the types of receptors, which participate in neurogenic inflammation. Based on our molecular biological know-how and the clinical expertise, we propose to investigate the role of the tachykinin and bradykinin receptors and their signalling partners in CPPS and bladder dysfunction in humans.
Detailed description
Although IC has been recognised for more than a century, its pathophysiology remains a mystery, and as a consequence the treatment of IC is largely empirical. A multitude of mechanisms of the disease have been postulated ranging from neuroinflammatory to autoimmune or possibly infectious or toxic agents. Newer studies have hinted towards a genetic basis of the disease, but in most hypotheses an inflammatory component of some kind is involved and many findings support this theory. An often-cited hypothesis is the leaky epithelium. The healthy bladder is coated with a thin mucinous substance bladder surface mucin, which is composed of numerous sulfonated glycosaminoglycans and glycoproteins. In IC patients, in contrast to controls, as well as in some animal models of IC, qualitative changes to this surface layer have been observed (Lilly et al, 1990., Moskowitz et al, 1994). An initiating event (toxin) may lead to functional changes and increased permeability. This in turn leads to nerve sensitisation and possibly up-regulation. There is increasing evidence that the progression of IC is accompanied by a significant up-regulation of sensory nerves in the bladder (Letourneau, 1996). Nerve growth factor (NGF), a neurotropin that sensitises nociceptor fibres, was reported to be increased in bladders of IC patients (Lowe, 1997), and application of NGF in Wistar rats acutely induced bladder hyperactivity (Chuang, 2001). Sensory nerves in neurogenic inflammation secrete inflammatory mediators such as Substance P (SP), a nociceptive neurotransmitter in the central and peripheral nervous system. Increased amounts of the released Substance P have been found in the urine of IC patients (Hohenfellner, et al,1992, Pang et al., 1995, Pang et al., 1996), the concentration of Substance P reflecting the patients' degree of pain (Chen et al., 1999). Substance P and related tachykinins (TKs) mediate a variety of physiological processes in the genitourinary, pulmonary and gastrointestinal tract through stimulation of NK1 and NK2 receptors. Pre-clinical evidence obtained through use of selective tachykinin receptor antagonists indicates that endogenous tachykinins are involved in regulation of smooth muscle contraction, vasodilation, water metabolism and inflammation. Recently it was shown that mRNA encoding for SP receptor NK1 is in-creased in the bladder biopsies from patients with interstitial cystitis (Marchand et al., 1998). NK1R mRNA was found in detrusor muscle, urothelium and vascular structures, and the endothelial NK1R were markedly increased. SP binding to NK1R on endothelial cells results in vasodilation, plasma extravasation, cytokine release and activation and infiltration of immune cells, all characteristic of IC. Experiments with the NK1R knockout mice allowed for the first time to demonstrate the obligatory requirement of NK1R in cystitis and participation of these receptors in the chain of events linking mast cell degranulation and inflammation (Saban et al., 2000).
Changes in the sarcolemma, and altered expression of the tachykinin and bradykinin receptors might significantly influence the downstream signalling events leading to propagation of the symptoms of chronic pelvic pain/IC. By uncovering the link between clinical symptoms and the molecular regulation of the atypical inflammatory response, we may be able to offer novel and specific options for treatment. In the current proposal, we would like to further our studies of urinary bladder pathology, in particular the symptomatic complex of PBS/interstitial cystitis, and investigate the effect of changes in human urothelium and detrusor muscle cells on the NK1R-mediated signalling.
Biopsies from controls and PBS patients will be obtained in either general or spinal anesthesia transurethrally from the bladder dome and trigone with a biopsy tong. RNA will be extracted, and the expression levels of selected genes analyzed using Taqman real-time PCR and gene expression arrays (Applied Biosystems). Calcium imaging will be used to monitor the receptor activation and protein levels analysed by SDS-PAGE and Western Blotting. Receptor tissue distribution will be analysed by immuno-cytochemistry.
Study design
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| 1 | – | – |
| 2 | – | – |
| 3 | – | – |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- university hospital clinic
Key inclusion criteria (3 listed)
- Clinical asymptomatic bladder function
- Clinical urgency frequency syndrome/ overactive bladder
- Clinical painful bladder syndrome/interstitial cystitis
Key exclusion criteria (3 listed)
- Not able to understand patient information
- Other cause of symptoms
- Confusable diseases
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Receptor expression in disease states versus control
Time frame: at time of biospy
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Apr 2010.
- Background: PubMed 2244283Lilly JD, Parsons CL. Bladder surface glycosaminoglycans is a human epithelial permeability barrier. Surg Gynecol Obstet. 1990 Dec;171(6):493-6.
- Background: PubMed 8653316Letourneau R, Pang X, Sant GR, Theoharides TC. Intragranular activation of bladder mast cells and their association with nerve processes in interstitial cystitis. Br J Urol. 1996 Jan;77(1):41-54. doi: 10.1046/j.1464-410x.1996.08178.x.
- Background: PubMed 9126085Lowe EM, Anand P, Terenghi G, Williams-Chestnut RE, Sinicropi DV, Osborne JL. Increased nerve growth factor levels in the urinary bladder of women with idiopathic sensory urgency and interstitial cystitis. Br J Urol. 1997 Apr;79(4):572-7. doi: 10.1046/j.1464-410x.1997.00097.x.
- Background: PubMed 11176525Chuang YC, Fraser MO, Yu Y, Chancellor MB, de Groat WC, Yoshimura N. The role of bladder afferent pathways in bladder hyperactivity induced by the intravesical administration of nerve growth factor. J Urol. 2001 Mar;165(3):975-9.
- Background: PubMed 1538434Hohenfellner M, Nunes L, Schmidt RA, Lampel A, Thuroff JW, Tanagho EA. Interstitial cystitis: increased sympathetic innervation and related neuropeptide synthesis. J Urol. 1992 Mar;147(3):587-91. doi: 10.1016/s0022-5347(17)37314-7.
- Background: PubMed 7542136Pang X, Marchand J, Sant GR, Kream RM, Theoharides TC. Increased number of substance P positive nerve fibres in interstitial cystitis. Br J Urol. 1995 Jun;75(6):744-50. doi: 10.1111/j.1464-410x.1995.tb07384.x.
- Background: PubMed 8633418Pang X, Boucher W, Triadafilopoulos G, Sant GR, Theoharides TC. Mast cell and substance P-positive nerve involvement in a patient with both irritable bowel syndrome and interstitial cystitis. Urology. 1996 Mar;47(3):436-8. doi: 10.1016/S0090-4295(99)80469-5.
- Background: PubMed 9488063Marchand JE, Sant GR, Kream RM. Increased expression of substance P receptor-encoding mRNA in bladder biopsies from patients with interstitial cystitis. Br J Urol. 1998 Feb;81(2):224-8. doi: 10.1046/j.1464-410x.1998.00507.x.
- Background: PubMed 8283520Moskowitz MO, Byrne DS, Callahan HJ, Parsons CL, Valderrama E, Moldwin RM. Decreased expression of a glycoprotein component of bladder surface mucin (GP1) in interstitial cystitis. J Urol. 1994 Feb;151(2):343-5. doi: 10.1016/s0022-5347(17)34944-3.
- Background: PubMed 10702392Saban R, Saban MR, Nguyen NB, Lu B, Gerard C, Gerard NP, Hammond TG. Neurokinin-1 (NK-1) receptor is required in antigen-induced cystitis. Am J Pathol. 2000 Mar;156(3):775-80. doi: 10.1016/S0002-9440(10)64944-9.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Overactive Bladder and Painful Bladder Syndrome, run by Insel Gruppe AG, University Hospital Bern at 1 site in Switzerland.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Apr 2010. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Receptor expression in disease states versus control (time frame: at time of biospy). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00775281, which also lists 10 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Apr 2010.