| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent urinary tract infection in women |
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| E.1.1.1 | Medical condition in easily understood language |
| Repeated episodes of Cystitis in women |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064736 |
| E.1.2 | Term | Antibiotic prophylaxis |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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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 |
| Our principal research questions are: Is a twice daily dose of Methenamine Hippurate at least as effective as low dose prophylactic antibiotics in offering symptomatic relief to women with recurrent Urinary Tract Infection (rUTI)? This is reported by comparing the number of symptomatic episodes of rUTI by women in each trial group over a 12 month treatment period. We are also trying to determine whether the use of Methanamine Hippurate is no worse in terms of value for money to the NHS than the use of prophylactic antibiotics over the 12 months. |
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| E.2.2 | Secondary objectives of the trial |
To determine the number of symptomatic antibiotic-treated UTI self-reported by patients during the 6 month period after completion of allocated treatment.
To determine the total number of days spent on urinary specific antibiotics (prophylactic or treatment) during 12 month active study period and six month follow up.
To determine if there is any ecological change in bacteria and their resistance patterns in samples taken from participant’s i) urine and ii) faecal reservoir during the 12 month treatment period and in the 6 months following completion of treatment.
To determine the number of microbiologically proven urinary tract infections during the 12 month treatment and 6 month follow-up periods.
To determine the incidence of asymptomatic bacteriuria (ABU) during the study period.
To determine the rate of hospitalization due to urinary tract infections during the study period.
To determine overall patients satisfaction with antibiotic versus antiseptic treatment.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Women aged 18 years and over.
• Women with rUTI who, in consultation with a clinician, have decided that prophylaxis is an appropriate option (to include women who have suffered at least three episodes of symptomatic UTI within the preceding 12 months or two episodes in the last 6 months or a single severe infection requiring hospitalisation).
• Able to take a once daily oral dose of at least one of nitrofurantoin, or trimethoprim, or cephalexin.
• Able to take Methenamine hippurate.
• Women who agree to take part in the trial but who are already taking Methenamine or antibiotic prophylaxis will be consented for participation and will stop their preventative therapy for a 3-month washout period. They will then be reassessed and if still eligible undergo baseline assessment and randomisation.
• Able to give informed consent for participation in trial.
• Able and willing to adhere to an 18-month study period.
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| E.4 | Principal exclusion criteria |
• Women unable to take Methenamine hippurate e.g. known allergy to Methenamine hippurate, severe hepatic impairment (Childs –Pugh class C, score of 10 or more, see appendix 4), gout, eGFR < 10 ml/min, Proteus sp. as consistent proven causative organism for rUTIs.
• Women who are unable to take nitrofurantoin and trimethoprim and cephalexin.
• Women with correctable urinary tract abnormalities that are considered to be contributory to the occurrence of rUTI.
• Presence of symptomatic UTI – this will be treated and symptoms resolved prior to randomisation.
• Pregnancy or intended pregnancy in next 12 months.
• Women who are breast feeding.
• Women already taking methenamine or antibiotic prophylaxis and declining a 3-month washout period.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The Primary clinical outcome is the incidence of symptomatic antibiotic-treated UTI self-reported by participants over the 12-month treatment period. This will be defined as the presence of at least one patient-reported or clinician-recorded symptom from a predefined list encompassing the recommendations of the British Infection Association (BIA) together with taking a discrete treatment course of antibiotic for UTI prescribed by a clinician or as part of patient-initiated self-start treatment. The rate of UTI will be defined as the incident density rate; the number of UTI suffered during the 12 months of therapy minus days spent taking treatment courses of antibiotics active against urinary tract organisms.
The primary economic outcome will measure the cost effectiveness of the two treatments (antiseptic and antibiotic) by incremental cost per quality-adjusted life year (QALY) gained during the 12 month treatment period. Incremental costs to the NHS, personal social services, and the patient at 12 months.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
The number of symptomatic antibiotic-treated UTI self-reported by participants in the 6 months follow up period after completing the allocated preventative therapy.
Total antibiotic use during the study period, reported by patients and verified where necessary from medical records.
Phenotype and genotype of Escherichia coli (E. coli) isolated from urine and perineal swabs sent by participants directly to the central reference laboratory.
The number of microbiologically confirmed urinary tract infections occurring during both the 12 months of treatment and the subsequent 6 months of follow-up . A positive culture will be classified according to standard Public Health England (PHE) definitions; the laboratory report of two isolates at ≥ 105 cfu/mL or a single isolate at ≥ 104 cfu/mL.
Presence of asymptomatic bacteriuria (ABU) identified by urine culture performed at patient visits for study follow-up. ABU is defined as the presence of bacteria in the urine in the absence of symptoms suggestive of urinary tract infection. For the purposes of this study, a positive culture was defined in line with the routine PHE definitions above.
The rate of hospitalisation due to urinary tract infections during the treatment and follow-up phases of the study.
Overall satisfaction with treatment measured by Treatment Questionnaire on Satisfaction with Medication (TQSM) administered at both the end of treatment (12 months) and then again at the end of follow-up (18 months).
Qualitative analysis of patients and clinicians views regarding trial processes and participation.
QALYs based on responses to the EQ-5D -5L at 3, 6, 9, 12, 15 and 18 months and after a UTI episode.
Treatment costs for drug and healthcare services from a standard NHS source such as British Formulary (BNF) and published tariffs from NHS reference costs.
Health resource utilisation questionnaire at 3,6, 9, 12,15 and 18 months.
Incremental cost per quality-adjusted life year (QALY) gained during the total 18 month trial period. Incremental costs to the NHS, personal social services, and the patient at 18 months.
Costs and QALYs will be combined in a cost-utility analysis for both a “within” trial analysis and modelled over the patient’s lifetime using previously developed methods and data from other relevant RCTs that collected patient costs.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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