Ignite Creation Date:
2024-05-06 @ 1:18 PM
Last Modification Date:
2024-10-26 @ 1:11 PM
Study NCT ID:
NCT03981458
Status:
UNKNOWN
Last Update Posted:
2019-07-08
First Post:
2019-01-29
Brief Title:
Hyaluronate for the Treatment and Prevention of Recurrent Urinary Tract Infection in Women Suffering Atrophic Vaginitis
Sponsor:
Newcastle-upon-Tyne Hospitals NHS Trust
Organization:
Newcastle-upon-Tyne Hospitals NHS Trust
Study Overview
Official Title:
Hyaluronate for the Treatment and Prevention of Recurrent Urinary Tract Infection in Women Suffering Atrophic Vaginitis
Status:
UNKNOWN
Status Verified Date:
2019-07
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
HATPIN
Brief Summary:
In post-menopausal women the condition atrophic vaginitis results from the loss of oestrogen and is characterised by dyspareunia pain during intercourse vaginal dryness and vaginal irritation It is often diagnosed alongside recurrent urinary tract infections rUTIs and may increase susceptibility to rUTI Topical vaginal oestrogen can be used to re-condition the vaginal epithelium and also reduces the incidence of rUTIs However patients often express concerns about using oestrogen a hormonal treatment Studies also report side-effects including vaginal bleeding discharge burning and itching that underpin significant 28 drop-out rates Hence alternative non-hormonal non-antibiotic based therapies that treat the vaginal atrophy but also reduce the incidence of rUTI are needed
Recurrent UTI in adult women is common Bacteria from the gut can colonise the vulvar epithelia and then the bladder causing uncomfortable urinary symptoms cystitis The lifetime risk of a UTI is around 40 in adult women which increases in post-menopausal women Annually UTI incidence is 3 Of those affected 5 will suffer rUTI rising to 13 in the over 60 population This equates to over 300000 of the adult female UK population annually affected by rUTI The most frequent treatment for rUTIs is low dose antibiotics but this treatment causes the bacteria carried by such women to become antibiotic resistant which exacerbates the clinical problem The prevalence of antimicrobial multi-resistance within post-menopausal women suffering from rUTI is around 25 and was shown to rise to more than 80 following prolonged antibiotics These data support the use of non-antibiotic treatment strategies that prevent rUTI and the emergence of drug resistant micro-organisms
This study will compare two groups with differing treatment strategies One group will be primarily treated for atrophic vaginitis with topical vaginal hyaluronate and the other will be primarily treated for their recurrent UTI with intravesical hyaluronate
Recurrent UTI in adult women is common Bacteria from the gut can colonise the vulvar epithelia and then the bladder causing uncomfortable urinary symptoms cystitis The lifetime risk of a UTI is around 40 in adult women which increases in post-menopausal women Annually UTI incidence is 3 Of those affected 5 will suffer rUTI rising to 13 in the over 60 population This equates to over 300000 of the adult female UK population annually affected by rUTI The most frequent treatment for rUTIs is low dose antibiotics but this treatment causes the bacteria carried by such women to become antibiotic resistant which exacerbates the clinical problem The prevalence of antimicrobial multi-resistance within post-menopausal women suffering from rUTI is around 25 and was shown to rise to more than 80 following prolonged antibiotics These data support the use of non-antibiotic treatment strategies that prevent rUTI and the emergence of drug resistant micro-organisms
This study will compare two groups with differing treatment strategies One group will be primarily treated for atrophic vaginitis with topical vaginal hyaluronate and the other will be primarily treated for their recurrent UTI with intravesical hyaluronate
Detailed Description:
Study purpose A potential alternative to prophylactic antibiotic treatment and topical vaginal estrogen treatments is the compound hyaluronate HA HA is already utilised in the UK to treat rUTIs but is delivered as a bladder instillation Ialuril A small meta-analysis of intravesical hyaluronate therapy incorporating four studies two randomised two non-randomised 143 patients investigating the use of this treatment in recurrent UTI reported a statistically significant improvement in the rates of recurrent UTI mean difference -34 episodes per patient year 95 confidence interval -43 to -25 HA is also available as a vaginal cream Hyalofemme which is used clinically to treat atrophic vaginitis The evidence suggests that many women suffering vaginal atrophy also experience recurrent UTIs However the effect of HA treatment in reducing concomitant rUTIs in such patients has not been reported
The need for this study is also supported by current guidance documents The 2012 Scottish Intercollegiate Guideline Network SIGN guideline emphasises the need to avoid unnecessary antibiotic prescribing specifically highlighting the issue of antibiotic-resistant E coli UTI Additionally the UK antimicrobial resistance strategy documents antibiotic resistance as a key concern and as such lends support to the investigation and use of alternative antimicrobial therapies The use of non-antibiotic preventative treatments for rUTI has also been accentuated by current UK European and USA guidelines to minimise antibiotic resistance Therefore this pilot study investigating the efficacy of a treatment already prescribed for vaginal atrophy in reducing concomitant rUTI is not only addressing current directives but will help inform whether topical HA therapy can be extended to all rUTI sufferers thus helping to reduce global antibiotic use
Evidence supporting the effectiveness of hyaluronate HA in treating rUTI is available but at present the therapy is administered directly to the bladder which involves catheterisation managed through hospital visits In contrast a HA topical treatment can be patient managed at home If from the data collated the topical HA therapy shows a comparable efficacy in reducing rUTI then these data will underpin a large-scale clinical trial examining the use of this non-hormonal non-antibiotic based agent for the treatment and prevention of rUTI in patients
While the focus of this initial study is on post-menopausal women suffering vaginal atrophy and rUTI it is also anticipated that this treatment could be broadened to all women suffering rUTIs One particular target group are females carrying the TLR5392Stop polymorphism who are at increased risk of rUTI thus signalling an era of personalised medicine for an infection related disease It is also envisaged that topical HA therapy could be prescribed as a urethral barrier cream for men suffering uncomplicated rUTI
Study design This study was designed through a collaboration of clinical urologists and basic scientists with an interest in the concomitance of atrophic vaginitis and recurrent UTI The proposal was peer-reviewed before funding was granted by The Urology Foundation This single-centre study is located at the Urology Department Freeman Hospital Newcastle upon Tyne Hospitals NHS Foundation Trust NE7 7DN Participants recruited will be post-menopausal women identified as either having gone through the menopause naturally or having had an oophorectomy and not on hormone replacement therapy HRT in the last two years and who suffer from vaginal atrophy and rUTI Patients will have either 3 confirmed episodes of UTI in the preceding year or 2 episodes in the last 6 months Patients will exhibit the symptoms and signs of atrophic vaginitis which will be diagnosed by their responsible clinician The study duration is 24 months with a patient recruitment period of 12 months Patient follow up and laboratory work will proceed until the end of month 23 with data analyses and final report preparation in the final month
The design incorporates a patient-randomised study that directly compares two treatments for women with atrophic vaginitis and rUTI during a 9-month period One treatment is an intravesical instillation of hyaluronate into the bladder Ialuril delivered via catheter focussed primarily on treating rUTI This is once weekly for 6 weeks followed by once every two weeks for 6 weeks then once per month maintenance for the remaining study period The alternative treatment is focussed on primarily treating atrophic vaginitis using a licensed vaginal hyaluronate product Hyalofemme used topically once every 3 days continually for the 9 month study period
Participants in both study arms would continue to receive antibiotic treatment for breakthrough UTI as needed Recruitment is planned at 3-4 patients per month allowing us to meet a target of 40 participants over the recruitment period which allows for a 25 attrition rate Using data from Damiano et al two groups of 16 patients are required to achieve 80 power at the 5 significance level for detecting a clinically significant reduction of one less UTI during the 9-month treatment and monitoring period
Recruitment
1 Patient Identification All adult women with atrophic vaginitis and rUTI will be made aware of the study during their clinic appointment and those eligible can consider whether they wish to participate prior to assessment The study will also be publicised so that colleagues in allied specialities such as urogynaecology and nephrology who may receive referrals of women with atrophic vaginitis and rUTI are aware of the study and can identify potential participants
For the study post-menopausal women with symptoms or signs of atrophic vaginitis referred to a hospital urology clinic with associated rUTI will be asked if they would like to participate In the study atrophic vaginitis will be diagnosed on clinical grounds and rUTI will be defined as at least 3 episodes in the past year or 2 episodes in the last 6 months Patients will undergo routine tests to rule out any structural or functional abnormality of their urinary system The treatment given to each participant will be decided randomly
Patients with underlying structural or functional abnormalities of the urinary tract following diagnosis by renal tract ultrasound scan USS and an endoscopic examination of the bladder under local anaesthesia flexible cystoscopy will be excluded from the study A recent local audit in Newcastle unpublished data n200 has revealed that contributory structural or functional abnormalities are detected in less than 10 of patients Therefore it is estimated that approximately 90 of patients matching our criteria and referred with atrophic vaginitis and rUTI will be eligible to be approached for inclusion to the study
Recruitment will involve a clear explanation of the trial including the background study protocol and aims
2 Screening Clinical staff at each site will identify eligible participants through direct contact or by searches of electronic records held in each Trust They will then give or send potentially eligible patients brief study information If interested potential participants can then agree to be approached by research staff and be provided with further study information Invitation material will include brief details of the need and purpose of the study and eligibility criteria It will emphasise the pragmatic nature of the study and give a realistic indication of the burden to participants All patients given study information will be recorded in the screening log All subjects who agree to consider participation will be seen by local research staff or the study coordinator to go through the consent and randomisation procedure A case report form will be initiated and baseline data collected
A screening log will be kept by local site research staff to document details of subjects invited to participate in the study and reasons for non-participation The log will also ensure potential participants who are ineligible or decline participation are approached only once
3 Consent All participants will undergo a process of informed consent Participants will be free to withdraw their consent at any time
The informed consent discussion will be undertaken by appropriately trained staff This will include medical staff and research nursesstudy coordinators involved in the study who will give time for participants to ask any questions they may have following review of the study information pack The consent process will include written information concerning the need and overall benefit of the study as well as verbal discussions The latter will include a check of understanding concerning benefits and risks and ensuring that participants accept that the treatment will be allocated at random regardless of any personal preference they may have
Following delivery of the study information participants will be given at least 24 hours and as much time as they need to decide whether they would like to participate Those wishing to take part will provide written informed consent by signing and dating the study consent form which will be witnessed and dated by a member of the research team with documented delegated responsibility to do so Written informed consent will always be obtained prior to randomisation The original signed consent form will be retained in the Investigator Site File with a copy filed in the clinical notes a copy given to the participant The participant will specifically consent to their General Practitioner GP being informed of their participation in the study The right to refuse to participate without giving reasons will be respected
Participants will be given the option of consenting to storage of blood urine and vaginal douche samples for future research They will also be asked if they would be willing for the inclusion of data collected for this study in future research Any further research would be subject to separate review by an ethics committee
Inclusionexclusion and risk Selection bias will be minimised by including all post-menopausal female patients with atrophic vaginitis and recurrent uncomplicated UTI and not receiving hormonal supplements or hyaluronate as eligible participants There are deliberately few exclusion criteria set to enable the findings of this study to be generalised Both treatments are licensed exhibit a low side-effect profile and have little interaction with other common medications which limits absolute contra-indications to either therapy Eligible patients and their responsible clinician will need to be sufficiently uncertain of the optimum treatment for vaginal atrophy and rUTI to allow randomisation and prevent selection bias
Confidentiality Initial screening of patients will be carried out by trained clinical staff associated with either the urology clinic at Freeman Hospital or the network of Research Nurses Following this informed consent will be taken by appropriately trained staff and the patients randomised into the trial Case Report Forms to collect the information required by researchers will contain the minimum required patient-identifiers All staff have completed GDPR training
Conflict of interest This study is pragmatic in design and apart from random allocation of treatment option and participant completion of diaries and questionnaires participant care will follow standard pathways in participating secondary care NHS sites Both Ialuril and Hyalofemme are licensed and approved for routine NHS use It will be ensured that all participants have access as desired to the use of other measures to reduce the risk of UTI such as adequate fluid intake avoidance of constipation and cranberry extract However patients receiving hormonal supplementation are not appropriate for this study Participants in both study groups will receive on demand discrete courses of antibiotics as decided by the responsible clinician for symptomatic UTI Use of all these adjunctive treatments will be recorded on case report forms
Participants will be given the option of consenting to storage of blood urine and vaginal douche samples for future research Participants will also be asked if they would be willing for the inclusion of data collected for this study in future research Any further research would be subject to separate review by an ethics committee Upon completion a short clearly written summary of the research findings will be supplied to all participants Any findings resulting from the research will be published in scientific or medical journals
The need for this study is also supported by current guidance documents The 2012 Scottish Intercollegiate Guideline Network SIGN guideline emphasises the need to avoid unnecessary antibiotic prescribing specifically highlighting the issue of antibiotic-resistant E coli UTI Additionally the UK antimicrobial resistance strategy documents antibiotic resistance as a key concern and as such lends support to the investigation and use of alternative antimicrobial therapies The use of non-antibiotic preventative treatments for rUTI has also been accentuated by current UK European and USA guidelines to minimise antibiotic resistance Therefore this pilot study investigating the efficacy of a treatment already prescribed for vaginal atrophy in reducing concomitant rUTI is not only addressing current directives but will help inform whether topical HA therapy can be extended to all rUTI sufferers thus helping to reduce global antibiotic use
Evidence supporting the effectiveness of hyaluronate HA in treating rUTI is available but at present the therapy is administered directly to the bladder which involves catheterisation managed through hospital visits In contrast a HA topical treatment can be patient managed at home If from the data collated the topical HA therapy shows a comparable efficacy in reducing rUTI then these data will underpin a large-scale clinical trial examining the use of this non-hormonal non-antibiotic based agent for the treatment and prevention of rUTI in patients
While the focus of this initial study is on post-menopausal women suffering vaginal atrophy and rUTI it is also anticipated that this treatment could be broadened to all women suffering rUTIs One particular target group are females carrying the TLR5392Stop polymorphism who are at increased risk of rUTI thus signalling an era of personalised medicine for an infection related disease It is also envisaged that topical HA therapy could be prescribed as a urethral barrier cream for men suffering uncomplicated rUTI
Study design This study was designed through a collaboration of clinical urologists and basic scientists with an interest in the concomitance of atrophic vaginitis and recurrent UTI The proposal was peer-reviewed before funding was granted by The Urology Foundation This single-centre study is located at the Urology Department Freeman Hospital Newcastle upon Tyne Hospitals NHS Foundation Trust NE7 7DN Participants recruited will be post-menopausal women identified as either having gone through the menopause naturally or having had an oophorectomy and not on hormone replacement therapy HRT in the last two years and who suffer from vaginal atrophy and rUTI Patients will have either 3 confirmed episodes of UTI in the preceding year or 2 episodes in the last 6 months Patients will exhibit the symptoms and signs of atrophic vaginitis which will be diagnosed by their responsible clinician The study duration is 24 months with a patient recruitment period of 12 months Patient follow up and laboratory work will proceed until the end of month 23 with data analyses and final report preparation in the final month
The design incorporates a patient-randomised study that directly compares two treatments for women with atrophic vaginitis and rUTI during a 9-month period One treatment is an intravesical instillation of hyaluronate into the bladder Ialuril delivered via catheter focussed primarily on treating rUTI This is once weekly for 6 weeks followed by once every two weeks for 6 weeks then once per month maintenance for the remaining study period The alternative treatment is focussed on primarily treating atrophic vaginitis using a licensed vaginal hyaluronate product Hyalofemme used topically once every 3 days continually for the 9 month study period
Participants in both study arms would continue to receive antibiotic treatment for breakthrough UTI as needed Recruitment is planned at 3-4 patients per month allowing us to meet a target of 40 participants over the recruitment period which allows for a 25 attrition rate Using data from Damiano et al two groups of 16 patients are required to achieve 80 power at the 5 significance level for detecting a clinically significant reduction of one less UTI during the 9-month treatment and monitoring period
Recruitment
1 Patient Identification All adult women with atrophic vaginitis and rUTI will be made aware of the study during their clinic appointment and those eligible can consider whether they wish to participate prior to assessment The study will also be publicised so that colleagues in allied specialities such as urogynaecology and nephrology who may receive referrals of women with atrophic vaginitis and rUTI are aware of the study and can identify potential participants
For the study post-menopausal women with symptoms or signs of atrophic vaginitis referred to a hospital urology clinic with associated rUTI will be asked if they would like to participate In the study atrophic vaginitis will be diagnosed on clinical grounds and rUTI will be defined as at least 3 episodes in the past year or 2 episodes in the last 6 months Patients will undergo routine tests to rule out any structural or functional abnormality of their urinary system The treatment given to each participant will be decided randomly
Patients with underlying structural or functional abnormalities of the urinary tract following diagnosis by renal tract ultrasound scan USS and an endoscopic examination of the bladder under local anaesthesia flexible cystoscopy will be excluded from the study A recent local audit in Newcastle unpublished data n200 has revealed that contributory structural or functional abnormalities are detected in less than 10 of patients Therefore it is estimated that approximately 90 of patients matching our criteria and referred with atrophic vaginitis and rUTI will be eligible to be approached for inclusion to the study
Recruitment will involve a clear explanation of the trial including the background study protocol and aims
2 Screening Clinical staff at each site will identify eligible participants through direct contact or by searches of electronic records held in each Trust They will then give or send potentially eligible patients brief study information If interested potential participants can then agree to be approached by research staff and be provided with further study information Invitation material will include brief details of the need and purpose of the study and eligibility criteria It will emphasise the pragmatic nature of the study and give a realistic indication of the burden to participants All patients given study information will be recorded in the screening log All subjects who agree to consider participation will be seen by local research staff or the study coordinator to go through the consent and randomisation procedure A case report form will be initiated and baseline data collected
A screening log will be kept by local site research staff to document details of subjects invited to participate in the study and reasons for non-participation The log will also ensure potential participants who are ineligible or decline participation are approached only once
3 Consent All participants will undergo a process of informed consent Participants will be free to withdraw their consent at any time
The informed consent discussion will be undertaken by appropriately trained staff This will include medical staff and research nursesstudy coordinators involved in the study who will give time for participants to ask any questions they may have following review of the study information pack The consent process will include written information concerning the need and overall benefit of the study as well as verbal discussions The latter will include a check of understanding concerning benefits and risks and ensuring that participants accept that the treatment will be allocated at random regardless of any personal preference they may have
Following delivery of the study information participants will be given at least 24 hours and as much time as they need to decide whether they would like to participate Those wishing to take part will provide written informed consent by signing and dating the study consent form which will be witnessed and dated by a member of the research team with documented delegated responsibility to do so Written informed consent will always be obtained prior to randomisation The original signed consent form will be retained in the Investigator Site File with a copy filed in the clinical notes a copy given to the participant The participant will specifically consent to their General Practitioner GP being informed of their participation in the study The right to refuse to participate without giving reasons will be respected
Participants will be given the option of consenting to storage of blood urine and vaginal douche samples for future research They will also be asked if they would be willing for the inclusion of data collected for this study in future research Any further research would be subject to separate review by an ethics committee
Inclusionexclusion and risk Selection bias will be minimised by including all post-menopausal female patients with atrophic vaginitis and recurrent uncomplicated UTI and not receiving hormonal supplements or hyaluronate as eligible participants There are deliberately few exclusion criteria set to enable the findings of this study to be generalised Both treatments are licensed exhibit a low side-effect profile and have little interaction with other common medications which limits absolute contra-indications to either therapy Eligible patients and their responsible clinician will need to be sufficiently uncertain of the optimum treatment for vaginal atrophy and rUTI to allow randomisation and prevent selection bias
Confidentiality Initial screening of patients will be carried out by trained clinical staff associated with either the urology clinic at Freeman Hospital or the network of Research Nurses Following this informed consent will be taken by appropriately trained staff and the patients randomised into the trial Case Report Forms to collect the information required by researchers will contain the minimum required patient-identifiers All staff have completed GDPR training
Conflict of interest This study is pragmatic in design and apart from random allocation of treatment option and participant completion of diaries and questionnaires participant care will follow standard pathways in participating secondary care NHS sites Both Ialuril and Hyalofemme are licensed and approved for routine NHS use It will be ensured that all participants have access as desired to the use of other measures to reduce the risk of UTI such as adequate fluid intake avoidance of constipation and cranberry extract However patients receiving hormonal supplementation are not appropriate for this study Participants in both study groups will receive on demand discrete courses of antibiotics as decided by the responsible clinician for symptomatic UTI Use of all these adjunctive treatments will be recorded on case report forms
Participants will be given the option of consenting to storage of blood urine and vaginal douche samples for future research Participants will also be asked if they would be willing for the inclusion of data collected for this study in future research Any further research would be subject to separate review by an ethics committee Upon completion a short clearly written summary of the research findings will be supplied to all participants Any findings resulting from the research will be published in scientific or medical journals
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 8904 | OTHER | RD Number Newcastle Hospitals | None |